HLA-B27、PDCD-1、IL-23R基因多态性与强直性脊柱炎的相关性研究
|
摘要
强直性脊柱炎(Ankylosing Spondylitis, AS)是一种与免疫相关的复杂疾病,受遗传和环境等多种因素的共同影响。多个研究显示遗传因素在AS发病中起着十分重要的作用。
位于6号染色体短臂上的人类主要组织相容性符合体(major histocompatibility complex, MHC)是与AS相关的主要遗传位点。MHCⅠ编码的人类白细胞抗原B27(human leukocyte antigen-B27, HLA-B27)是迄今所知的、与疾病相关中最强的HLA抗原。全基因组扫描发现除HLA-B27基因外,还有其他的非MHC基因参与AS的发病机制,由于AS属于自身免疫性疾病范畴,一些和免疫相关基因与疾病的关联性研究,已成为研究AS遗传背景的一大亮点,例如白介素(interleukin, IL)基因、程序性凋亡(programmed cell death, PDCD)基因等。然而受多种因素影响,造成这些研究结果并不完全一致,尤其是各种基因单核苷酸多态性(single nucleotide polymorphisms, SNP)与AS的关系尚未完全澄清,有待进一步研究。
本课题首先采用聚合酶链反应-序列特异性引物(polymerase chain reaction-sequence-specific primer, PCR-SSP)法研究了中国湖北地区HLA-B27基因亚型与AS的相关性,然后再应用聚合酶链反应-限制性内切酶片段长度多态性(polymerase chain reaction-restriction fragment length polymorphisms, PCR-RFLP)技术对PDCD-1基因的3个SNP进行了AS疾病的关联研究,最后,应用meta分析探讨了白介素-23受体(interleukin-23 receptor, IL-23R)基因中10个SNP与AS的相关性。本研究共分以下三部分：
目的：分析在中国湖北地区HLA-B27基因亚型与AS的相关性,探讨HLA-B27基因亚型在AS发病中的作用,同时评价HLA-B27基因亚型检测的临床意义。
方法：收集HLA-B27阳性的研究对象共346例。其中AS患者190例,男129名,女61名,平均年龄(39±9)岁,健康对照者156名,来男81名,女75名,平均年龄(30±11)岁。采用病例对照研究方案,通过PCR-SSP进行HLA-B27基因亚型检测。
结果：共检出6种亚型,分别是B*2702、B*2703、B*2704、B*2705、B*2706及B*2713。在AS患者与健康对照组中,都以B*2704亚型(72.1%和56.4%)为主,其次为B*2705亚型(21.6%和31.4%),两组中均检测到频率较低的B*2702亚型(0.5%和1.3%)及B*2703亚型(5.3%和8.3%),而B*2713亚型只在AS组测到1例(0.5%),B*2706亚型只在健康对照组测到4例(2.6%)。AS患者组与健康对照组相比,尽管B*2703及B*2705亚型在对照组频率较高,但两组间的差异均无统计学意义(χ2=1.301,P>0.05；χ2=4.032,P>0.05),OR值和95%可信区分别为为0.611和0.601,0.262-0.701和0.371-0.937。B*2704亚型在两组中所占比例均为最高且组间存在显著性差异(χ2=9.279,P<0.01),OR值为1.997,95%可信区为1.279-3.119,显示B*2704亚型与AS发病危险度相关。
结论：中国湖北地区人群中B*2704和B*2705为主要亚型,其中B*2704与AS呈强相关,B*2706可能与AS呈负相关,其他低频率基因亚型与AS的相关性有待进一步探讨,HLA-B27基因亚型可作为AS早期诊断的重要参考指标。另外本研究所使用的PCR-SSP法能检测出29个HLA-B27亚型(B*2701-B*2730,B*2722除外),能满足当前对HLA-B27基因亚型检测的需要。
目的：分析PDCD-1基因SNP在AS患者与健康对照人群中的分布,比较两组人群分布差异,探讨PDCD-1基因多态性与AS易感性的关联,以期对深入研究AS的病因、发病机制提供一些理论依据。
方法：采用病例对照研究方案,收集408名研究对象的血标本,其中包含216名AS患者标本。通过PCR-RFLP技术对PDCD-1基因的3个SNP位点(rs11568821,rs2227981，rs2227982)进行分型,χ2检验比较患者组及对照组基因型和等位基因频率的分布差异,运用SHESIS在线软件进行LD和基因相关性分析。
结果：位点一(rs11568821)在所有AS患者和健康对照组中仅发现GG纯合子基因型,呈非多态性；位点二(rs2227981)在AS患者和健康对照组中均检出CC纯合子、CT杂合子和TT纯合子三种基因型,但在两组中该位点基因型和等位基因分布频率相近,χ2检验差异无显著性(P=0.145)；位点三(rs2227982)在AS患者和健康对照组中均检出TT纯合子、CT杂合子和CC纯合子三种基因型,且基因型和等位基因分布频率在两组中具有显著性差异(P=0.025),AS患者组具有更高的CT杂合子基因型(P=0.026,OR=1.542,95%CI=1.051-2.261)和T等位基因的频率(P=0.004,OR=1.553,95%CI=1.144-2.109)。运用SHESIS在线软件分析rs2227981和rs2227982,发现两者存在较强程度连锁(D＇=0.729)；在该两个位点构建了4种单体型,CT单体型的频率在AS患者组(21.6%)高于健康对照组(13.9%)(P=0.002,OR=1.712,95%CI=1.222-2.397),CC单体型在健康对照组(57.1%)比AS患者组(44.6%)更普遍(P=0.000,OR=0.603,95%CI=0.467-0.780)。
结论：在中国汉族人群中, rs2227982中CT杂合子和T等位基因、特定单体型CT (PDCD-1.5/1.9)与AS发病呈正相关,CC单体型与AS发病呈负相关,PDCD-1基因多态性与AS之间存在遗传相关性。PDCD-1基因多态性与AS的相关性还需在更大规模不同人群中研究,以便得到更多证据
目的：对国内外有关IL-23R基因多态性与AS的研究结果作meta分析,综合评价IL-23R基因SNP与AS的关系,为人群AS易感基因的评估提供依据。
方法：电子检索Medline数据库和中国期刊全文数据库,根据一定纳入标准进行质量评价以及数据提取,卡方检验各个研究之间的异质性,采用Review Manager 4.2软件进行统计分析。
结果：共有6篇文献符合纳入标准,被研究的人群涉及9类,基因型频率分布全部符合Hardy-Weinberg遗传平衡,Egger检验均未发现发表偏倚。共对10个IL-23R SNP位点(rsll209026,rsl004819,rsl0489629,rsll465804,rsl34315,rsl0889677,rsl 1209032,rsl495965,rs7517847,rs2201841)等位基因的各项研究进行meta分析,齐性检验中除rs10889677外,均未发现异质性(P>0.05),因此rs10889677采用随机效应模型,其它位点采用固定效应模型对等位基因频率进行分析,综合结果表明所有位点等位基因在两组之间分布均存在差异(P<0.05),5个位点(rsll209026、rsl0489629、rsll465804、rsl343151、rs7517847)等位基因在对照组分布频率高于AS组,另5个位点反之。
结论：IL-23R SNP与AS呈正相关或负相关,被研究的10个等位基因中,与AS呈负相关性(对患者起保护作用)的位点有：rs11209026(G>A)、rsl0489629(G>A)、rs11465804(T>G)、rsl343151(C>T)、rs7517847(T>G)。其余位点与AS均呈正相关。meta分析可获得更高的统计学效能,为进一步的研究提供方向和思路。
Ankylosing Spondylitis (AS) is an immune-related complex disease caused by a combination of genetic and environmental factors. A lot of studies show that genetic factors play an important role in the development of AS.
The MHC (major histocompatibility complex) on chromosome 6p is strongly linked and associated with AS. The association of HLA-B27 (human leukocyte antigen-B27) coded by MHCⅠwith AS is the strongest among genetic association with other disease. Genome-wide screening studies have led to the identification of several non-MHC genes possibly linked to AS. Due to autoimmune mechanisms participating in the pathogeneisis of AS, studies on the disease association with certain genes involved in the autoimmune response may highlight the genetic background of AS, such as the genes IL (interleukin), PDCD (programmed cell death) and et al. However, the results are not unified and repeated because of many reasons, especially relation between SNPs (single nucleotide polymorphisms) and AS. Therefore, a more thorough search for polymorphisms in the locus will be needed.
In this study, we firstly investigated the the association of the B27 subtypes with AS in the HuBei population of China by PCR-SSP (polymerase chain reaction-sequence-specific primer). Then, by employing PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphisms), we analyzed the association of PDCD-1 (programmed cell death) SNP and haplotypes with AS. At last, a meta-analysis was conducted to determine the contribution of IL-23R (interleukin-23 receptor) gene SNP previously implicated in AS susceptibility. The present study can be divided into the following three parts.
OBJECTIVE To analyze the association of the B27 subtypes with AS in the HuBei population of China, investigate the role of B27 subtypes in the etiology of AS, and evaluate the usefulness of HLA-B27 subtype in clinical diagnosis of AS.
METHODS A total of 190 patients with AS and a control group of 156 subjects were recruited for the study. Of 190 AS patients,129 were men and 61 women, with a mean age of 39±9. HLA-B27 subtypes were confirmed by PCR-SSP.
RESULTS Six B27 subtypes were determined:B*2702,03,04,05,06 and B*13. HLA-B*2704 (patients 72.1% vs. controls 56.4%) and HLA-B*2705 (patients 21.6% vs. controls 31.4%) were the two high frequency genotypes in controls and patients. There were significant differences in the distribution of B*2704 subtypes between patients with AS and controls (χ2=9.279, P<0.01, OR=1.997,95% CI=1.279-3.119). Compared with the controls, the AS patients had high frequency of B*2704 and low frequency of B*2705. B*2703 was detected in 10 (5.3%) patients and in 13 (8.3%) controls. B*2702, B*2706 and B*2713 were relatively rare. Other HLA-B27 subtypes were relatively rare. One B*2713 was solely detected in AS group but not in controls, four B*2706 were found only in controls.
CONCLUSION B*2704 was the dominant subtypes followed by B*2705. B*2704 is strongly associatied with AS. B*2706 may have a negative association with AS. Subtyping for HLA-B27 by PCR-SSP has been proved to be suitable for clinical application. It is useful to diagnose AS in clinic.
OBJECTIVE To investigate the association of PDCD-1 polymorphisms and haplotypes with AS in Chinese Han population.
METHODS In a case-control association study, three SNP, PDCD-1.3 G/A, PDCD-1.5 C/T and PDCD-1.9 T/C, were genotyped in 216 AS patients and 264 healthy controls using PCR-RFLP assay.
RESULTS All genotype distributions in the patients and in the controls were in Hardy-Weinberg equilibrium. The associations of genotypes and alleles with AS were analyzed. The genotype distributions of PDCD-1.9 were significantly different between the patients with AS and the controls (P=0.025). The frequencies of TC genotype and T allele of PDCD-1.9 were higher in the patients than those in the controls (P=0.026 and 0.004). No association for PDCD-1.5 in AS was found, and PDCD-1.3 was nonpolymorphic in Chinese Han population. Moreover, significant LD was found between PDCD-1.5 and PDCD-1.9 (D'=0.729). Four haplotypes between SNPs PDCD-1.5 and PDCD-1.9 were constructed. The frequency of the CT haplotype was higher in the AS patients (21.6%) than the controls (13.9%) (P=0.002, OR=1.712,95%CI=1.222-2.397). The CC haplotype was more common in controls (57.1%) than in patients (44.6%) (P=0.000, OR=0.603,95% CI=0.467-0.780).
CONCLUSION The results support a genetic association between the PDCD-1 polymorphism and susceptibility to AS in Chinese Han population. A more thorough search in other populations will be needed.
OBJECTIVE To determine the contribution of IL-23R gene SNP previously implicated in AS susceptibility in different populations worldwide.
METHODS An electric search was performed in PubMed and Chinese periodical full-text database. Association between IL-R23 SNP and AS was examined. Data on allele frequency was extracted. Heterogeneity, power and publication bias were explored. Odds ratio Was summarized. All were perfermed by Review Manager 4.2 software.
RESULTS Six studies of IL-R23 SNP were enrolled. The alleles frequency of 10 SNP (rs11209026, rs1004819, rs10489629, rs11465804, rs134315,rs10889677, rs11209032,rs1495965, rs7517847, rs2201841) were analyzed in AS cases and controls recruited in 9 different centres. No heterogeneity and publication bias were observed (P>0.05) except rs10889677. Thus, random effect mode (DerSimonian-Laird test) was used to calculate OR of rs10889677, fixed effect mode (Peto test) was used in others SNPs. All allele distributions were significantly different between the patients with AS and the controls (P<0.05). The alleles frequency of 5 SNP (rs11209026, rs10489629, rs11465804, rs1343151, rs7517847) was higher in the controls than in AS patients.
CONCLUSION This study confirms that IL-23R SNP is associated with susceptibility to AS. Meta-analysis is a useful tool by providing sufficiently large sample sizes to produce robust findings.
位于6号染色体短臂上的人类主要组织相容性符合体(major histocompatibility complex, MHC)是与AS相关的主要遗传位点。MHCⅠ编码的人类白细胞抗原B27(human leukocyte antigen-B27, HLA-B27)是迄今所知的、与疾病相关中最强的HLA抗原。全基因组扫描发现除HLA-B27基因外,还有其他的非MHC基因参与AS的发病机制,由于AS属于自身免疫性疾病范畴,一些和免疫相关基因与疾病的关联性研究,已成为研究AS遗传背景的一大亮点,例如白介素(interleukin, IL)基因、程序性凋亡(programmed cell death, PDCD)基因等。然而受多种因素影响,造成这些研究结果并不完全一致,尤其是各种基因单核苷酸多态性(single nucleotide polymorphisms, SNP)与AS的关系尚未完全澄清,有待进一步研究。
本课题首先采用聚合酶链反应-序列特异性引物(polymerase chain reaction-sequence-specific primer, PCR-SSP)法研究了中国湖北地区HLA-B27基因亚型与AS的相关性,然后再应用聚合酶链反应-限制性内切酶片段长度多态性(polymerase chain reaction-restriction fragment length polymorphisms, PCR-RFLP)技术对PDCD-1基因的3个SNP进行了AS疾病的关联研究,最后,应用meta分析探讨了白介素-23受体(interleukin-23 receptor, IL-23R)基因中10个SNP与AS的相关性。本研究共分以下三部分：
目的：分析在中国湖北地区HLA-B27基因亚型与AS的相关性,探讨HLA-B27基因亚型在AS发病中的作用,同时评价HLA-B27基因亚型检测的临床意义。
方法：收集HLA-B27阳性的研究对象共346例。其中AS患者190例,男129名,女61名,平均年龄(39±9)岁,健康对照者156名,来男81名,女75名,平均年龄(30±11)岁。采用病例对照研究方案,通过PCR-SSP进行HLA-B27基因亚型检测。
结果：共检出6种亚型,分别是B*2702、B*2703、B*2704、B*2705、B*2706及B*2713。在AS患者与健康对照组中,都以B*2704亚型(72.1%和56.4%)为主,其次为B*2705亚型(21.6%和31.4%),两组中均检测到频率较低的B*2702亚型(0.5%和1.3%)及B*2703亚型(5.3%和8.3%),而B*2713亚型只在AS组测到1例(0.5%),B*2706亚型只在健康对照组测到4例(2.6%)。AS患者组与健康对照组相比,尽管B*2703及B*2705亚型在对照组频率较高,但两组间的差异均无统计学意义(χ2=1.301,P>0.05；χ2=4.032,P>0.05),OR值和95%可信区分别为为0.611和0.601,0.262-0.701和0.371-0.937。B*2704亚型在两组中所占比例均为最高且组间存在显著性差异(χ2=9.279,P<0.01),OR值为1.997,95%可信区为1.279-3.119,显示B*2704亚型与AS发病危险度相关。
结论：中国湖北地区人群中B*2704和B*2705为主要亚型,其中B*2704与AS呈强相关,B*2706可能与AS呈负相关,其他低频率基因亚型与AS的相关性有待进一步探讨,HLA-B27基因亚型可作为AS早期诊断的重要参考指标。另外本研究所使用的PCR-SSP法能检测出29个HLA-B27亚型(B*2701-B*2730,B*2722除外),能满足当前对HLA-B27基因亚型检测的需要。
目的：分析PDCD-1基因SNP在AS患者与健康对照人群中的分布,比较两组人群分布差异,探讨PDCD-1基因多态性与AS易感性的关联,以期对深入研究AS的病因、发病机制提供一些理论依据。
方法：采用病例对照研究方案,收集408名研究对象的血标本,其中包含216名AS患者标本。通过PCR-RFLP技术对PDCD-1基因的3个SNP位点(rs11568821,rs2227981，rs2227982)进行分型,χ2检验比较患者组及对照组基因型和等位基因频率的分布差异,运用SHESIS在线软件进行LD和基因相关性分析。
结果：位点一(rs11568821)在所有AS患者和健康对照组中仅发现GG纯合子基因型,呈非多态性；位点二(rs2227981)在AS患者和健康对照组中均检出CC纯合子、CT杂合子和TT纯合子三种基因型,但在两组中该位点基因型和等位基因分布频率相近,χ2检验差异无显著性(P=0.145)；位点三(rs2227982)在AS患者和健康对照组中均检出TT纯合子、CT杂合子和CC纯合子三种基因型,且基因型和等位基因分布频率在两组中具有显著性差异(P=0.025),AS患者组具有更高的CT杂合子基因型(P=0.026,OR=1.542,95%CI=1.051-2.261)和T等位基因的频率(P=0.004,OR=1.553,95%CI=1.144-2.109)。运用SHESIS在线软件分析rs2227981和rs2227982,发现两者存在较强程度连锁(D＇=0.729)；在该两个位点构建了4种单体型,CT单体型的频率在AS患者组(21.6%)高于健康对照组(13.9%)(P=0.002,OR=1.712,95%CI=1.222-2.397),CC单体型在健康对照组(57.1%)比AS患者组(44.6%)更普遍(P=0.000,OR=0.603,95%CI=0.467-0.780)。
结论：在中国汉族人群中, rs2227982中CT杂合子和T等位基因、特定单体型CT (PDCD-1.5/1.9)与AS发病呈正相关,CC单体型与AS发病呈负相关,PDCD-1基因多态性与AS之间存在遗传相关性。PDCD-1基因多态性与AS的相关性还需在更大规模不同人群中研究,以便得到更多证据
目的：对国内外有关IL-23R基因多态性与AS的研究结果作meta分析,综合评价IL-23R基因SNP与AS的关系,为人群AS易感基因的评估提供依据。
方法：电子检索Medline数据库和中国期刊全文数据库,根据一定纳入标准进行质量评价以及数据提取,卡方检验各个研究之间的异质性,采用Review Manager 4.2软件进行统计分析。
结果：共有6篇文献符合纳入标准,被研究的人群涉及9类,基因型频率分布全部符合Hardy-Weinberg遗传平衡,Egger检验均未发现发表偏倚。共对10个IL-23R SNP位点(rsll209026,rsl004819,rsl0489629,rsll465804,rsl34315,rsl0889677,rsl 1209032,rsl495965,rs7517847,rs2201841)等位基因的各项研究进行meta分析,齐性检验中除rs10889677外,均未发现异质性(P>0.05),因此rs10889677采用随机效应模型,其它位点采用固定效应模型对等位基因频率进行分析,综合结果表明所有位点等位基因在两组之间分布均存在差异(P<0.05),5个位点(rsll209026、rsl0489629、rsll465804、rsl343151、rs7517847)等位基因在对照组分布频率高于AS组,另5个位点反之。
结论：IL-23R SNP与AS呈正相关或负相关,被研究的10个等位基因中,与AS呈负相关性(对患者起保护作用)的位点有：rs11209026(G>A)、rsl0489629(G>A)、rs11465804(T>G)、rsl343151(C>T)、rs7517847(T>G)。其余位点与AS均呈正相关。meta分析可获得更高的统计学效能,为进一步的研究提供方向和思路。
Ankylosing Spondylitis (AS) is an immune-related complex disease caused by a combination of genetic and environmental factors. A lot of studies show that genetic factors play an important role in the development of AS.
The MHC (major histocompatibility complex) on chromosome 6p is strongly linked and associated with AS. The association of HLA-B27 (human leukocyte antigen-B27) coded by MHCⅠwith AS is the strongest among genetic association with other disease. Genome-wide screening studies have led to the identification of several non-MHC genes possibly linked to AS. Due to autoimmune mechanisms participating in the pathogeneisis of AS, studies on the disease association with certain genes involved in the autoimmune response may highlight the genetic background of AS, such as the genes IL (interleukin), PDCD (programmed cell death) and et al. However, the results are not unified and repeated because of many reasons, especially relation between SNPs (single nucleotide polymorphisms) and AS. Therefore, a more thorough search for polymorphisms in the locus will be needed.
In this study, we firstly investigated the the association of the B27 subtypes with AS in the HuBei population of China by PCR-SSP (polymerase chain reaction-sequence-specific primer). Then, by employing PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphisms), we analyzed the association of PDCD-1 (programmed cell death) SNP and haplotypes with AS. At last, a meta-analysis was conducted to determine the contribution of IL-23R (interleukin-23 receptor) gene SNP previously implicated in AS susceptibility. The present study can be divided into the following three parts.
OBJECTIVE To analyze the association of the B27 subtypes with AS in the HuBei population of China, investigate the role of B27 subtypes in the etiology of AS, and evaluate the usefulness of HLA-B27 subtype in clinical diagnosis of AS.
METHODS A total of 190 patients with AS and a control group of 156 subjects were recruited for the study. Of 190 AS patients,129 were men and 61 women, with a mean age of 39±9. HLA-B27 subtypes were confirmed by PCR-SSP.
RESULTS Six B27 subtypes were determined:B*2702,03,04,05,06 and B*13. HLA-B*2704 (patients 72.1% vs. controls 56.4%) and HLA-B*2705 (patients 21.6% vs. controls 31.4%) were the two high frequency genotypes in controls and patients. There were significant differences in the distribution of B*2704 subtypes between patients with AS and controls (χ2=9.279, P<0.01, OR=1.997,95% CI=1.279-3.119). Compared with the controls, the AS patients had high frequency of B*2704 and low frequency of B*2705. B*2703 was detected in 10 (5.3%) patients and in 13 (8.3%) controls. B*2702, B*2706 and B*2713 were relatively rare. Other HLA-B27 subtypes were relatively rare. One B*2713 was solely detected in AS group but not in controls, four B*2706 were found only in controls.
CONCLUSION B*2704 was the dominant subtypes followed by B*2705. B*2704 is strongly associatied with AS. B*2706 may have a negative association with AS. Subtyping for HLA-B27 by PCR-SSP has been proved to be suitable for clinical application. It is useful to diagnose AS in clinic.
OBJECTIVE To investigate the association of PDCD-1 polymorphisms and haplotypes with AS in Chinese Han population.
METHODS In a case-control association study, three SNP, PDCD-1.3 G/A, PDCD-1.5 C/T and PDCD-1.9 T/C, were genotyped in 216 AS patients and 264 healthy controls using PCR-RFLP assay.
RESULTS All genotype distributions in the patients and in the controls were in Hardy-Weinberg equilibrium. The associations of genotypes and alleles with AS were analyzed. The genotype distributions of PDCD-1.9 were significantly different between the patients with AS and the controls (P=0.025). The frequencies of TC genotype and T allele of PDCD-1.9 were higher in the patients than those in the controls (P=0.026 and 0.004). No association for PDCD-1.5 in AS was found, and PDCD-1.3 was nonpolymorphic in Chinese Han population. Moreover, significant LD was found between PDCD-1.5 and PDCD-1.9 (D'=0.729). Four haplotypes between SNPs PDCD-1.5 and PDCD-1.9 were constructed. The frequency of the CT haplotype was higher in the AS patients (21.6%) than the controls (13.9%) (P=0.002, OR=1.712,95%CI=1.222-2.397). The CC haplotype was more common in controls (57.1%) than in patients (44.6%) (P=0.000, OR=0.603,95% CI=0.467-0.780).
CONCLUSION The results support a genetic association between the PDCD-1 polymorphism and susceptibility to AS in Chinese Han population. A more thorough search in other populations will be needed.
OBJECTIVE To determine the contribution of IL-23R gene SNP previously implicated in AS susceptibility in different populations worldwide.
METHODS An electric search was performed in PubMed and Chinese periodical full-text database. Association between IL-R23 SNP and AS was examined. Data on allele frequency was extracted. Heterogeneity, power and publication bias were explored. Odds ratio Was summarized. All were perfermed by Review Manager 4.2 software.
RESULTS Six studies of IL-R23 SNP were enrolled. The alleles frequency of 10 SNP (rs11209026, rs1004819, rs10489629, rs11465804, rs134315,rs10889677, rs11209032,rs1495965, rs7517847, rs2201841) were analyzed in AS cases and controls recruited in 9 different centres. No heterogeneity and publication bias were observed (P>0.05) except rs10889677. Thus, random effect mode (DerSimonian-Laird test) was used to calculate OR of rs10889677, fixed effect mode (Peto test) was used in others SNPs. All allele distributions were significantly different between the patients with AS and the controls (P<0.05). The alleles frequency of 5 SNP (rs11209026, rs10489629, rs11465804, rs1343151, rs7517847) was higher in the controls than in AS patients.
CONCLUSION This study confirms that IL-23R SNP is associated with susceptibility to AS. Meta-analysis is a useful tool by providing sufficiently large sample sizes to produce robust findings.
引文
[1]Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome [J]. Science,2001,291(5507):1304-1351.
[2]Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome [J]. Nature,2001,409(6822):860-921.
[3]Sieper J, Braun J, Rudwaleit M, et al. Ankylosing spondylitis:an overview [J]. Ann Rheum Dis,2002,61(Suppl 3):ⅲ8-ⅲ18.
[4]Brown J, B ollow M, Remlinger G, et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors [J]. Arthritis Rheum,1998,41:58-67.
[5]Gu MM, Yuan WT, Yang JQ, et al. A genomewide scan for the susceptibility gene loci to ankylosing spondylitis in Chinese populatin [J]. Acta Genetica Sinica,2004,3: 217-220.
[6]Brown MA. Breakthroughs in genetic studies of ankylosing spondylitis [J]. Rheumatology,2008,47:132-137.
[7]Said-Nahal R, Miceli-Richard C, Berthelot JM, et al. The familial form of spondylarthropathy:a clinical study of 115 multiplex families [J]. Arthritis Rheum, 2000,43:1356-1365.
[8]van der Linden SM, Valkenburg HA, de Jongh BM, et al. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals [J]. Arthritis Rheum,1984,27: 361-368.
[9]Braun J, BollowM, Remlinger G, et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors [J]. Arthritis Rheum,1998,41:58-67.
[10]Khan MA. Update on spondyloarthropathies [J]. Ann Intern Med,2002,136: 896-907.
[11]Amor B, Feldmann JL, Delbarre F, et al. HLA antigen W27-a genetic link between ankylosing spondylitis and Reiter's syndrome [J]? N Engl J Med,1974,290:572-576.
[12]Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HLA-B27 [J]. Lancet,1973,1:904-907.
[13]Brionez TF, Reveille JD. The contribution of genes outside the major histocompatibility complex to susceptibility to ankylosing spondylitis [J]. Curr Opin Rheumatol,2008,20:384-391.
[14]Breban M, Miceli-Richard C, Zinovieva E, et al. The genetics of spondyloarthropathies [J]. Joint Bone Spine,2006,73:355-362.
[15]Brown MA, Kennedy LG, Mac Gregor AJ, et al. Susceptibility to ankylosing spondylitis in twins:the role of genes, HLA, and the environment [J]. Arthritis Rheum, 1997,40:1823-1828.
[16]Muhammad AK, Alessandro M, Rosa S, et al. The pathogenetic role of HLA-B27 and its subtypes [J]. Autoimmunity Reviews,2007,6:183-189.
[17]Carter KW, Pluzhnikov A, Timms AE, et al. Combined analysis of three whole genome linkage scans for ankylosing spondylitis [J]. Rheumatology,2007,48: 763-771.
[18]The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J]. Nature,2007, 447:661-683.
[19]Wellcome Trust Case Control Consortium, The Australo-Anglo-American Spondylitis Consortium. A genome-wide scan of 14,000 non-synonymous coding SNP in 5,500 individuals [J]. Nat Genet,2007,39:1329-1336.
[1]Brown MA, Laval SH, Brophy S, et al. Recurrence risk modeling of the genetic susceptibility to ankylosing spondylitis [J]. Ann Rheum Dis,2000,59:883-886.
[2]Brewerton DA, Hart FD, NichollsA, et al. Ankylosing spondylitis and HLA-27 [J]. Lancet,1973,1:904-907.
[3]SchlossteinL, Terasaki PI, BluestoneR, et al. High Association of an HLA antigen, w27, with Ankylosing spondylitis [J]. New Ensl J Med,1973,288(14):704-706.
[4]Hammer RE, Maika SD, Richardson JA, et al. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m:an animal model of HLA-B27-associated human disorders [J]. Cell,1990,63:1099-1112.
[5]Tran TM, Dorris ML, Satumtira N, et al. Additional human beta2m curbs HLA-B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA-B27 transgenic rats [J]. Arthritis Rheum,2006,54:1317-1327.
[6]Madden DR, Gorga JC, Strominger JL, et al. The three dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC [J]. Cell,1992,70:1035-1048.
[7]Muhammad AK, Alessandro M, Rosa S, et al. The pathogenetic role of HLA-B27 and its subtypes [J]. Autoimmunity Reviews,2007,6:183-189.
[8]Sims AM, Wordsworth BP, Brown MA. Genetic susceptibility to ankylosing spondylitis [J]. Curr Mol Med,2004,4:13-20.
[9]Khan MA. Update on spondyloarthropathies [J]. Ann Intern Med,2002,136:896-907.
[10]Paladini F, Taccari E, Fiorillo MT,, et al. Distribution of HLA-B27 subtypes in Sardinia and continental Italy and their association with spondylarthropathies [J]. Arthritis Rheum,2005,52:3319-3321.
[11]Ma HJ, Hu FP. Diversity of human leukocyte antigen-B27 alleles in Han population of Hunan province, southern China [J]. Tissue Antigens,2006,68:163-166.
[12]Chou CT, Chen JM, Chang MH, et al. HLA-B27 and its subtypes in 4 Taiwanese aborigine tribes:a comparison to Han Chinese patients with ankylosing spondylitis [J]. J Rheumatol,2003,30:321-325.
[13]Yang KL, Chen IH, Hsiao CK, et al. Polymorphism of HLA-B27 in Taiwanese Chinese. Tissue Antigens,2004,63:476-479.
[14]Dowing J, Coates E, Street J, et al. A High-Resolution Polymerase Chain Reaction-Sequence-Specific Primer HLA-B*27 Typing Set and Its Application in Routine HLA-B27 Testing [J]. Genet Test,2006,10:98-103.
[15]Downing J, Guttridge MG, Thompson J, et al. Five-locus HLA typing of haematopoietic stem cell donor volunteers by PCR using sequence specific primers [J]. Genet Test,2004,8:301-312.
[16]Van der Linden S, Valkenberg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis:a proposal for modification of the New York criteria [J]. Arthritis Rheum,1984,27:361-368.
[17]李一荣,胡丽华,陈凤花等.应用SYBR Green I实时荧光PCR法对中国汉族人群HLA-B27进行快速基因分型[J].临床血液学杂志,2008,21(5)：526-529.
[18]Sieper J, Braun J, Rudwaleit M, et al. Ankylosing spondylitis:an overview [J]. Ann Rheum Dis,2002,61(Suppl 3):ⅲ8-ⅲ18.
[19]Conde RA. Fxequeucy of the HLA-B27 alleles in Brazilieus patients with AS [J]. J Rhenmatol,2003,30(11):2512.
[20]Khan MA, Akkoc N. Etiopathogenic role of HLA-B27 alleles in ankylosing spondylitis [J]. APPLAR J Rheumatol,2005,8:146-153.
[21]Archer J, Keat A. Ankylosing spondylitis:time to focus on ankylosis [J]. J Rheumatol, 1999,26(4):761-764.
[22]Mclean L, Hammer R, Taurog J, et al. Immunosusceptibility genes in rheumatoid arthritis [J]. Hum Immunol,1996,51 (1):32-40.
[23]Allen RL, Callaghan CA, Mcmichael AJ, et al. Cutting edge:HLA-B27 can form a novel beta 22microglobulin2free heavy chain homodimer structure [J]. J Immunol, 1999,162(9):5045-5048.
[24]Reineli S, Dedier S, Asuni G, et al. Mutation of Cys-67 alters the thermodynamic stability of the human leukocyte antigen HLA-B2705 [J]. J Biol Chem,2001,276(21): 18472-18477.
[25]Khan MA. Update:the twenty subtypes of HLA-B27 [J]. Curr Opin Rheumatol,2000, 12:235-238.
[26]Blanco-Gelaz MA, Lopez-Vazquez A, Garcia-Fernandez Sl. Genetic variability, molecular evolution, and geographic diversity of HLA B27 [J]. Hum Immunol,2001, 62:1042-1050.
[27]Hill AVS, Allsopp CEM, Kwiatkowski D. HLA class I typing by PCR:HLA B27 and an African subtype [J]. Lancet,2001,337:640-642.
[28]Lopez-Larrea C, Sujirachato K, Mehra. NKHLA B27 subtypes in Asian patients with ankylosing spondylitis [J]. Tissue Antigens,1995,45:169-176.
[29]Toubert A, Tieng V, Boisgerault F. Subtypes of the HLA B27 molecule and association with spondyloarthropathies [J]. Ann Med Interne,1998,149(3):145.
[30]Chou CT, Chen JM, Chang MH, et al. HLA-B27 and its subtypes in 4 Taiwanese aborigine tribes:a comparison to Han Chinese patients with ankylosing spondylitis [J]. J Rheumatol,2003,30:321-325.
[31]Lopez-Larrea C, Sujirachato K, Mehra NK. HLA B27 subtypes in Asian patients with ankylosing spondylitis [J]. Tissue Antigens,1995,45:169-176.
[32]Garcia-Fernandez S, Gonzalez S, Mina Blanco A. New insights regarding HLA-B27 diversity in the Asian population [J]. Tissue Antigens,2001,58:259-262.
[33]Chen IH, Yang KL, Lee A, et al. Low frequency of HLA-B*2706 in Taiwanese patients with ankylosing spondylitis [J]. Eur J Immunogenet,2002,29:435-438.
[34]Lee SH, Choi IA, Lee YA, et al. Human leukocyte antigen-B*2705 is the predominant subtype in the Korean population with ankylosing spondylitis, unlike in other Asians. Rheumatol Int,2008,29:43-46.
[35]Birinci A, Bilgici A, Kuru O, et al. HLA-B27 polymorphism in Turkish patients with ankylosing spondylitis [J]. Rheumatol Int,2006,26:285-287.
[36]Fiorillo MT, Maragno M, Butler R, et al. CD8(+) T-cell autoreactivity to an HLA-B27-restricted selfepitope correlates with ankylosing spondylitis [J]. Arthritis Rheum,2005,52:3319-3321.
[37]Sesma L, Montserrat V, Lamas JR, et al. The peptide repertoires of HLA-B27 subtypes differentially associated to spondyloarthropathy(B*2704 and B*2706) differ by specific changes at three anchor positions [J]. J Biol Chem,2002,277(19): 16744-16779.
[38]Ramos M, Paradela A, Vazquez M, et al. Differential association of HLA-B*2705 and B*2709 to ankylosing spondylitis correlates with limited peptide subsets but not with altered cell surface stability [J]. J Biol Chem,2002,277(32):28749-28756.
[39]Choo SY, St John T, Orr HT. Molecular analysis of the variant alloantigen HLA-B27d(HLA-B*2703) identifies a unique single amino acid substitution [J]. Hum Immunol,1988,21:209-219.
[40]Gul A, Uyar FA, Inanc M. A weak association of HLA-B*2702 with Behcet's disease [J]. Genes Immun,2002,3:368-372.
[41]崔刘福,宋海澄,李宏芬等.HLA-B27等位基因与强直性脊柱炎的相关性研究[J].中华风湿病学杂志,2003,7(1)：55-56.
[1]Brown MA, Laval SH, Brophy S, et al. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis [J]. Ann Rheum Dis,2000,59:883-886.
[2]Brown MA, Kennedy LG, MacGregor AJ, et al. Susceptibility to ankylosing spondylitis in twins:the role of genes, HLA, and the environment [J]. Arthritis Rheum, 1997,40:1823-1828.
[3]Sims AM, Wordsworth BP, Brown MA. Genetic susceptibility to ankylosing spondylitis [J]. Curr Mol Med,2004,4:13-20.
[4]Reveille JD, Ball EJ, Khan MA. HLA-B27 and genetic predisposing factors in spondyloarthropathies [J]. Curr Opin Rheumatol,2001,13:265-272.
[5]Khan MA, Mathieu A, Sorrentino R, et al. The pathogenetic role of HLA-B27 and its subtypes [J]. Autoimmun Rev,2007,6:183-189.
[6]Kuon W, Kuhne M, Busch DH, et al. Identification of novel human aggrecan T cell epitopes in HLA-B27 transgenic mice associated with spondyloarthropathy [J]. J Immunol,2004,173 (8):4859-4866.
[7]Atagunduz P, Appel H, Kuon W, et al. HLA-B27-restricted CD8+ T cell response to cartilagederived self peptides in ankylosing spondylitis [J]. Arthritis Rheum,2005,52: 892-901.
[8]Ishida Y, Agata Y, Ahibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death [J]. EMBOJ, 1992,11:3887-3895.
[9]Magnusson V, Lindqvist AK, Castillejo-Lopez C, et al. Fine mapping of the SLEB2 locus involved in susceptibility to systemic lupus erythematosus [J]. Genomics,2000, 70:307-314.
[10]Shinohara T, Taniwaki M, Ishida Y, et al. Structure and chromosomal localization of the human PD-1 gene (PDCD1) [J]. Genomics,1994,23:704-706.
[11]Okazaki T, Wang J. PD-1/PD-L pathways and autoimmunity [J]. Autoimmunity, 2005,38:353-357.
[12]Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity [J]. Annu Rev Immunol,2008,26:677-704.
[13]Gregersen PK, Behrens TW. Genetics of autoimmune diseases-disorders of immune homeostasis[J]. Nat Rev Genet,2006,7:917-928.
[14]Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection [J]. Nat Immunol,2007,8: 239-245.
[15]Keir ME, Francisco LM, Sharpe AH. PD-1 and its ligands in T-cell immunity [J]. Curr Opin Immunol,2007,19:309-314.
[16]Ferreiros-Vidal I, Gomez-Reino JJ, Barros F, et al. Association of PDCD1 with susceptibility to systemic lupus erythematosus:evidence of population-specific effects [J]. Arthritis Rheum,2004,50:2590-2597.
[17]Johansson M, Arlestig L, Moller B, rt al. Association of a PDCD1 polymorphism with renal manifestations in systemic lupus erythematosus [J]. Arthritis Rheum,2005,52: 1665-1669.
[18]Nielsen C, Laustrup H, Voss A, et al. A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients [J]. Lupus,2004,13:510-516.
[19]Wang Q, Ye D, Yin J, Li X, et al. Programmed cell death 1 genotypes are associated with susceptibility to systemic lupus erythematosus among Chinese [J]. Arch Dermatol Res,2008,300:91-93.
[20]Velazquez-Cruz R, Orozco L, Espinosa-Rosales F, et al. Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus [J]. Eur J Hum Genet,2007,15:336-341.
[21]Prokunina L, Castillejo-Lopez C, Oberg F, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans [J]. Nat Genet,2002,32:666-669.
[22]Thorburn CM, Prokunina-Olsson L, Sterba KA, et al. Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort [J]. Genes Immun,2007,8:279-287.
[23]Wang SC, Chen YJ, Ou TT, et al. Programmed Death-1 Gene Polymorphisms in Patients With Systemic Lupus Erythematosus in Taiwan [J]. J Clin Immunol,2006, 26(6):506-511.
[24]Kong EK, Prokunina-Olsson L, Wong WH, et al. A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese [J]. Arthritis Rheum,2005, 52:1058-1062.
[25]Lin SC, Yen JH, Tsai JJ, et al. Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus [J]. Arthritis Rheum,2004,50:770-775.
[26]Prokunina L, Padyukov L, Bennet A, et al. Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope [J]. Arthritis Rheum,2004,50:1770-1773.
[27]Nielsen C, Hansen D, Husby S, et al. Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes [J]. Tissue Antigens,2003,62:492-497.
[28]Ronghua Ni, Kenji I, Kenichi M, et al. PD-1 gene haplotype is associated with the development of type 1 diabetes mellitus in Japanese children [J]. Hum Genet,2007, 121:223-232.
[29]Kroner A, Mehling M, Hemmer B, et al. A PD-1 polymorphism is associated with disease progression in multiple sclerosis [J]. Ann Neurol,2005,58:50-57.
[30]Lee SH, Lee YA, Woo DH, et al. Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population [J]. Arthritis Res Ther,2006,8:R163.
[31]Van der Linden S, Valkenberg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis:a proposal for modification of the New York criteria [J]. Arthritis Rheum,1984,27:361-368.
[32]Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci [J]. Cell Res,2005,15:97-98.
[33]Li Z, Zhang Z, He Z, et al. A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers:update of the SHEsis (http://analysis.bio-x.cn) [J]. Cell Res,2009,19(4):519-523.
[34]Finger LR, Pu J, Wasserman R, et al. The human PD-1 gene:compplete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors [J]. Gene,1997,197:177-187.
[35]Saunders PA, Hendrycks VR, LidinskyWA, et al. PD-L2:PD-1 involvement in T cell proliferation, cytokine p roduction, and integrinmediated adhesion [J]. Eur J Immunol, 2005,35:3561-3569.
[36]Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation [J]. Nat Immunol,2001,2:261-268.
[37]Ravetch JV, Lanier LL. Immune inhibitory receptors [J]. Science,2000,290:84-89.
[38]Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation [J]. T Exp Med,2000,192:1027-1034.
[39]Dong H, Zhu G, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion [J]. Nat Med,1999,5: 1365-1369.
[40]Tseng SY, Otsuji M, Gorski K, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cell [J]. J Exp Med,2001,193:839-846.
[41]Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor [J]. Immunity,1999,11:141-151.
[42]Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice [J]. Science,2001,291:319-322.
[43]Ansari MJ, Salama AD, Chitnis T, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic(NOD) mice [J]. J Exp Med,2003, 198:63-69.
[44]Iwamoto T, Ikari K, Inoue E, et al. Failure to confirm association between PDCD1 polymorphisms and rheumatoid arthritis in a Japanese population [J]. J Hum Genet, 2007,52:557-560.
[45]Fawwaz S, Nikamo P, Torn C, et al. No evidence of association of the PDCD1 gene with Type 1 diabetes [J]. Diabet Med,2007,24:1473-1477.
[46]Meng Q, Liu X, Yang P, et al. PDCD1 genes may protect against extraocular manifestations in Chinese Han patients with Vogt-Koyanagi-Harada syndrome [J]. Mol Vis,2009,15:386-392.
[47]Akey J, Jin L, Xiong M. Haplotypes vs single marker linkage disequilibrium tests: what do we gain [J]? Eur J Hum Genet,2001,9(4):291-300.
[48]Zollner S, von Haeseler A. A coalescent approach to study linkage disequilibrium between single-nucleotide polymorphisms [J]. Am J Hum Genet,2000,66(2): 615-628.
[1]Braun J, Sieper J. Ankylosing spondylitis [J]. Lancet,2007,369:1379-1390.
[2]Brown MA. Breakthroughs in genetic studies of ankylosing spondylitis [J]. Rheumatology,2008,47:132-137.
[3]Trinchieri G, Pflanz S, Kastelein RA. The IL-12 family of heterodimeric cytokines:new players in the regulation of T cell responses [J]. Immunity,2003,19:641-644.
[4]Parham C, Chirica M, Timans J, et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbetal and a novel cytokine receptor subunit, IL-23R [J]. J Immunol,2002,168:5699-5708.
[5]Cua DJ, Sherlock J, Chen Y et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain [J]. Nature,2003,421:744-748.
[6]Murphy CA, Langrish CL, Chen Y et al. Divergent pro-and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation [J]. J Exp Med,2003,198: 1951-1957.
[7]Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage [J]. Nat Med,2007,13:139-145.
[8]Cargill M, Schrodi SJ, Chang M et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes [J]. Am J Hum Genet,2007,80:273-290.
[9]Duerr RH, Taylor KD, Brant SR et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene [J]. Science,2006,314:1461-1463.
[10]Nunez C, Dema B, Cenit MC et al. IL23R:a susceptibility locus for celiac disease and multiple sclerosis [J]? Genes Immun,2008,9:289-293.
[11]Burton PR, Calyton DG, Cardon LR, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants [J]. Nat Genet, 2007,39:1329-1337.
[12]Rahman P, Inman RD, Gladman DD, et al. Association of interleukin-23 receptor variants with ankylosing spondylitis [J]. Arthritis Rheum,2008,58:1020-1025.
[13]Rueda B, Orozco G, Raya E, et al. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis [J]. Ann Rheum Dis, 2008,67:1451-1454.
[14]杨清锐,张源潮,孙红胜等.强直性脊柱炎与肿瘤坏死因子α基因启动子一308位点多态性关联研究的Meta分析[J].中华风湿病学杂志,2007,6(11)：365-369.
[15]Salanti G, Sanderson S, Higgins JP. Obstacles and opportunities in meta-analysis of genetic association studies [J]. Genet Med,2005,7:13-20.
[16]Karaderi T, Harvey D, Farrar C, et al. Association between the interleukin 23 receptor and ankylosing spondylitis is confirmed by a new UK case-control study and meta-analysis of published series [J]. Rheumatology,2009,48:386-389.
[17]Safrany E, Pazar. B, Csongei V, et al. Variants of the IL23R Gene are Associated with Ankylosing Spondylitis but not with Sjogren Syndrome in Hungarian Population Samples [J]. Scandinavian Journal of Immunology,2009,70:68-74.
[18]王新卫,黄进贤,林智明等.白细胞介素-23R单核苷酸多态性与中国汉族人群强直性脊柱炎的关联分析[J].中华风湿病学杂志,2008,10(12)：670-672.
[19]Brown MA. Non-major-histocompatibility-complex genetics of ankylosing spondylitis [J]. Best Pract Res Clin Rheumatol,2006,20:611-621.
[20]Glass GV. Primary, secondary, and meta analysis of research [J]. Education Research, 1976,6(5):3.
[21]方积乾,陆盈.Meta分析.现代医学统计学[M].北京：人民卫生出版社,2002,150-209.
[22]钟文昭,吴一龙,谷力加.Review Manager-临床医生通向meta分析的桥梁[J].循证医学,2003,3(4)：234-246.
[1]van der Linden SM, van der Heijde D, Maksymowych WP. Ankylosing spondylitis [J]. 8th edition. Philadelphia:Saunders-Elsevier,2008.1169-1190.
[2]曾宪国.强直性脊柱炎死亡原因分析[J].海南医学,2006,17(2)：57-58.
[3]Brionez TF, Reveille JD. The contribution of genes outside the major histocompatibility complex to susceptibility to ankylosing spondylitis [J]. Curr Opin Rheumatol,2008, 20:384-391.
[4]Breban M, Miceli-Richard C, Zinovieva E, et al. The genetics of spondyloarthropathies [J]. Joint Bone Spine,2006,73:355-362.
[5]Brown MA. Breakthroughs in genetic studies of ankylosing spondylitis [J]. Rheumatology,2008,47:132-137.
[6]Said-Nahal R, Miceli-Richard C, Berthelot JM, et al. The familial form of spondylarthropathy:a clinical study of 115 multiplex families [J]. Arthritis Rheum, 2000,43:1356-1365.
[7]van der Linden SM, Valkenburg HA, de Jongh BM, et al. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals [J]. Arthritis Rheum,1984,27: 361-368.
[8]Amor B, Feldmann JL, Delbarre F, et al. HLA antigen W27-a genetic link between ankylosing spondylitis and Reiter's syndrome [J]? N Engl J Med,1974,290:572-576.
[9]Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HLA-B27 [J]. Lancet,1973,1:904-907.
[10]BrownMA,Kennedy LG, MacGregor AJ, et al. Susceptibility to ankylosing spondylitis in twins:the role of genes, HLA, and the environment [J]. Arthritis Rheum,1997,40: 1823-1828.
[11]Braun J, BollowM, Remlinger G, et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors [J]. Arthritis Rheum,1998,41:58-67.
[12]Ebringer A,Wilson C. HLA molecules, bacteria and autoimmunity [J]. J Med Microbiol,2000,49:305-311.
[13]马海军,扈凤平.强直性脊柱炎遗传因素研究进展[J].中南大学学报(医学版), 2005,30:352-355.
[14]Muhammad AK, Alessandro M, Rosa S, et al. The pathogenetic role of HLA-B27 and its subtypes [J]. Autoimmunity Reviews,2007,6:183-189.
[15]Khan MA,Akkoc N. Etiopathogenic role of HLA-B27 alleles in ankylosing spondylitis [J]. APPLAR J Rheumatol,2005,8:146-153.
[16]Khan MA. HLA-B27 and its subtypes in world populations [J]. Curr Opin Rheumatol, 1995,7:263-269.
[17]Garcia-Fenrandez S, Gonzalez S, Mina Blanco A, et al. New insights regarding HLA-B27 diversity in the Asian population [J]. Tissue Antigens,2001,58:259-262.
[18]Vargas-Alarcon G, Londono JD, Hemandez-Pacheco G, et al. Effect of HLA-B and HLA-DR genes on susceptibility to and severity of spondyloarthropathies in mexican patients [J]. Ann Rheum Dis,2002,61:714-717.
[19]Sims AM, Wordsworth BP, Brown MA. Genetic susceptibility to ankylosing spondylitis [J]. Curr Mol Med,2004,4:13-20.
[20]MacLean IL, Iqball S, Woo P, et al. HLA-B27 subtypes in the spondarthropathies [J]. Clin Exp Immunol,1993,91:214-219.
[21]Reveille JD, Inman R, Khan M, et al. Family studies in ankylosing spondylitis: microsatellite analysis of 55 concordant sib pairs [J]. J Rheumatol,2000,27 (Suppl 59):5.
[22]Lopez-Larrea C, Sujirachato K, Mehra NK, et al. HLA-B27 subtypes in Asian patients with ankylosing spondylitis:evidence for new associations [J]. Tissue Antigens,1995, 45:169-176.
[23]Armas JB, Gonzalez S, Martinez-Borra J, et al. Susceptibility to ankylosing spondylitis is independent of the Bw4 and Bw6 epitopes of HLA-B27 alleles [J]. Tissue Antigens, 1999,53:237-243.
[24]Garcia F, Rognan D, Lamas JR, et al. An HLA-B27 polymorphism (B*2710) that is critical for T-cell recognition has limited effects on peptide specificity [J]. Tissue Antigens,1998,51:1-9.
[25]Garcia-Fernandez S, Gonzalez S, Mina Blanco A, et al. New insights regarding HLA-B27 diversity in the Asian population [J]. Tissue Antigens,2001,58:259-262.
[26]Tamouza R, Mansour I, Bouguacha N, et al. A new HLA-B-27 allele (B*2719) identified in a Lebanese patient affected with ankylosing spondylitis [J]. Tissue Antigens,2001,58:30-33.
[27]Hildebrand WH, Turnquist HR, Prilliman KR, et al. HLA class I polymorphism has a dual impact on ligand binding and chaperone interaction [J]. Hum Immunol,2002,63: 248-255.
[28]Gonzalez-Roces S, Alvarez MV, Gonzalez S, et al. HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis [J]. Tissue Antigens,1997,49: 116-123.
[29]Olivieri I, D'Angelo S, Scarano E, et al. The HLA-B*2709 subtype in a woman with early ankylosing spondylitis [J]. Arthritis Rheum,2007,56:2805-2807.
[30]Cauli A, Vacca A, Mameli A, et al. A Sardinian patient with ankylosing spondylitis and HLA-B*2709 co-occurring with HLA-B*1403 [J]. Arthritis Rheum,2007,56: 2807-2809.
[31]Madden DR, Gorga JC, Strominger JL, et al. The three dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC [J]. Cell,1992,70:1035-1048.
[32]Archer J, Keat A. Ankylosing spondylitis:time to focus on ankylosis [J]. J Rheumatol, 1999,26(4):761-764.
[33]Breban M, et al. T cells, but not thymic exposure to HLA-B27, are required for the inflammatory disease of HLA-B27 transgenic rats [J]. J Immunol,1996,156:794-803.
[34]Taurog JD. Spondylarthritis in HLAB27/human beta(2)-microglobulin-transgenic rats is not prevented by lack of CD8 [J]. Arthritis Rheum,2009,60:1977-1984.
[35]Allen RL, Callaghan CA, Mcmichael AJ, et al. Cutting edge:HLA-B27 can form a novel beta 22microglobulin2free heavy chain homodimer structure [J]. J Immunol, 1999,162(9):5045-5048.
[36]Kollnberger S. Cell-surface expression and immune receptor recognition of HLAB27 homodimers [J]. Arthritis Rheum,2002,46:2972-2982.
[37]Kollnberger S. Interaction of HLA-B27 homodimers with KIR3DL1 and KIR3DL2, unlike HLA-B27 heterotrimers, is independent of the sequence of bound peptid [J]. J Immunol,2007,37:1313-1322.
[38]Chan AT, Kollnberger SD, Wedderburn LR, et al. Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis [J]. Arthritis Rheum,2005,52:3586-3595.
[39]Smith JA, Turner MJ, DeLay ML, et al. Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-beta induction via X-box binding protein 1[J]. Eur J Immunol,2008,38:1194-1203.
[40]Colbert RA. HLA-B27 misfolding activates the IL-23/IL-17 axis via the unfolded protein response in transgenic rats:evidence for a novel mechanism of inflammation [J]. Arthritis Rheum,2007,1283:S515.
[41]Brown MA, Pile KD, Kennedy LG, et al. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom [J]. Ann Rheum Dis,1996, 5:268-270.
[42]Reveille JD. Major histocompatibility genes and ankylosing spondylitis [J]. Best Pract Res Clin Rheumatol,2006,20:601-609.
[43]Gran JT, Husby G, Hordvik M, et al. Prevalence of ankylosing spondylitis in males and females in a young middle-aged population of Tromso, northern Norway [J]. Ann Rheum Dis,1985,44:359-367.
[44]Robinson WP, van der Linden SM, Khan M A, et al. HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+patients [J]. Arthritis Rheum, 1989,32:1135-1141.
[45]Wei JC, Tsai WC, Lin HS, Tsai CY, Chou CT. HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients [J]. Rheumatology (Oxford),2004,43:839-842.
[46]Brown MA, Kennedy LG, Darke C, et al. HLA Class I and II associations of ankylosing spondylitis [J]. Arthritis Rheum,2009,60(Suppl):S437.
[47]Sims AM, Barnardo M, Herzberg I, et al. Non-B27 MHC associations of ankylosing spondylitis [J]. Genes Immun,2007,8:115-123.
[48]Aniko Vegvari a, Zoltan Szabo a, Sandor Szanto a, et al. The genetic background of ankylosing spondylitis [J]. Joint Bone Spine,76:623-628.
[49]Thomas GP, Brown MA. Genetics and genomics of ankylosing spondylitis [J]. Immunological Reviews,2010,233:162-180.
[50]Brown MA. Genetics and the pathogenesis of ankylosing spondylitis [J]. Current Opinion in Rheumatology,2009,21:318-323.
[51]Carter KW, Pluzhnikov A, Timms AE, et al. Combined analysis of three whole genome linkage scans for ankylosing spondylitis [J]. Rheumatology,2007,48: 763-771.
[52]McGarry F, Neilly J, Anderson N, et al. A polymorphism within the interleukin-1 receptor antagonist (IL-1Ra) gene is associated with ankylosing spondylitis [J]. Rheumatology,2001,40:1359-1364.
[53]van der Paardt M, Crusius JB, Garcia-Gonzalez MA, et al. Interleukin-1β and interleukin-1 receptor antagonist gene polymorphisms in ankylosing spondylitis [J]. Rheumatology,2002,41:1419-1423.
[54]Timms AE, Crane AM, Sims AM, et al. The interleukin-1 gene cluster contains a major susceptibility locus for ankylosing spondylitis [J]. Am J Hum Genet,2004,75: 587-595.
[55]Maksymowych WP, Rahman P, Reeve JP, et al. Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis:an analysis of three Canadian populations [J]. Arthritis Rheum,2006,54:974-985.
[56]Wu Z, Gu JR. A meta-analysis on interleukin-1 gene cluster polymorphism and genetic susceptibility for ankylosing spondylitis [J]. Zhonghua Yi Xue Za Zhi,2007, 87:433-437.
[57]Sims AM, Timms AE, Bruges-Armas J, et al. Prospective meta-analysis of IL-1 gene complex polymorphisms confirms associations with ankylosing spondylitis [J]. Ann Rheum Dis,2008,67:1305-1309.
[58]Gong WJ, Yang JQ, zhang L. Association of killer cell immunogloblin-like receptor gene polymorphisms with seronegative spondylarthropathies [J]. Section Genet Foreign Med Sci,2003,7:465-468.
[59]Chan T, Kollnberger SD, Wedderbum LR, et al. Expansion and enhanced survival of natural killer cells expressing the killer Immunoglobulin-like receptor KIR3DL2 in spondylarthritis [J]. Aathritis Rheumatism,2005,52:3586-3595.
[60]龚卫娟,杨珏琴,张磊.杀伤细胞免疫球蛋白样受体基因多态性与血清阴性脊柱关节病的关联性研究[J].国外医学遗传学分册,2001,24：35-38.
[61]Brown MA, Edwards S, Hoyle E, et al. Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis [J]. Hum Mol Genet,2000,9:1563-1566.
[62]Jaakkola E, Crane AM, Laiho K, et al. The effect of transforming growth factor β1 gene polymorphisms in ankylosing spondylitis [J]. Rheumatology,2004,43:32-38.
[63]Snelgrove T, Lim S, Greenwood C, et al. Association of toll-like receptor 4 variants and ankylosing spondylitis:a case-control study [J]. J Rheumatol,2007,34:368-370.
[64]The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J]. Nature,2007, 447:661-683.
[65]Wellcome Trust Case Control Consortium, The Australo-Anglo-American Spondylitis Consortium. A genome-wide scan of 14,000 non-synonymous coding SNP in 5,500 individuals [J]. Nat Genet,2007,39:1329-1336.
[66]Rahman P, Inman GD, Gladman DD, et al. Association of Interleukin-23 Receptor Variants With Ankylosing Spondylitis [J]. Arthritis Rheum,2008,58 (4):1020-1025.
[67]Rueda B, Orozco G, Raya E, et al. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis [J]. Ann Rheum Dis, 2008,67:1451-1454.
[68]Harvey D, Pointon JJ, Evans DM, et al. Investigating the genetic association between ERAP1 and ankylosing spondylitis. Human Molecular Genetics,2009,18 (21): 4204-4212.
[69]Maksymowych WP, Inman RD, Gladman DD, et al. Association of a specific ERAP1/ARTS1 haplotype with disease susceptibility in ankylosing spondylitis [J]. Arthritis Rheum,2009,60:1317-1323.
[70]Davidson SI, Wu X, Liu Y, et al. Association of ERAP1, but Not IL23R, With Ankylosing Spondylitis in a Han Chinese Population [J]. Arthritis Rheum,2009,60: 3263-3268.
[71]van der Paardt M, Crusius JB, Garcia-Gonzalez MA, et al. Susceptibility to ankylosing spondylitis:no evidence for the involvement of transforming growth factor beta 1 (TGFB1) gene polymorphisms [J]. Ann Rheum Dis,2005,64:616-619.
[72]Gergely P, Blazsek A, Weiszhar Z, et al. Lack of genetic association of the toll-like receptor 4 (TLR4) Asp299Gly and Thr399Ile polymorphisms with spondyloarthropathies in a Hungarian population [J]. Rheumatology,2006,45: 1194-1196.
[73]Brown MA. Non major-histocompatibility-complex genetics of ankylosing spondylitis [J]. Best Pract Res Clin Rheumatol,2006,20:611-621.
[74]Jacques C, Gosset M, Berenbaum F, et al. The role of IL1 and IL1-Ra in joint inflammation and cartilage degradation [J]. Vitam Horm,2006,74:371-403.
[75]Szekanecz Z, Koch AE. Cytokines.6th Edition [M]. Philadelphia:W.B. Saunders, 2001.275-290.
[76]Li J, Ge Z, Akey JM, et al. Lack of linkage of IL1RN genotypes with ankylosing spondylitis susceptibility [J]. Arthritis Rheum,2004,50:3047-3048.
[77]Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12 [J]. Immunity,2000,13(5):715-725.
[78]Langrish CL, McKenzie BS, Wilson NJ, et al. IL-12 and IL-23:master regulators of innate and adaptive immunity [J]. Immunol Rev,2004,202:96-105.
[79]Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene [J]. Science,2006,314:1461-1463.
[80]Cargill M, Schrodi SJ, Chang M, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasisrisk genes. Am J Hum Genet,2007,80:273-290.
[81]Farago B, Magyari L, Safrany E, et al. Functional variants of interleukin-23 receptor gene confer risk for rheumatoid arthritis but not for systemic sclerosis [J]. Ann Rheum Dis,2008,67:248-250.
[82]Cui X, Rouhani F, Hawari F, et al. An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding [J]. J Biol Chem,2003,278:28677-28685.
[83]Hammer GE, Kanaseki T, Shastri N. The final touches make perfect the peptide-MHC class I repertoire [J]. Immunity,2007,26:397-406.
[84]Lander E, Kruglyak L. Genetic dissection of complex traits:guidelines for interpreting and reporting linkage results [J]. Nat Genet,1995,11:241-247.
[85]Laval SH, Timms A, Edwards S, et al. Whole-genome screening in ankylosing spondylitis:evidence of non-MHC genetic-susceptibility loci [J]. Am J Hum Genet, 2001,68:918-926.
[86]Zhang G, Luo J, Bruckel J, et al. Genetic studies in familial ankylosing spondylitis susceptibility. Arthritis Rheum,2004,50:2246-2254.
[87]Brown MA, Pile KD,Kennedy GL, et al.Agenome-wide screen for susceptibility loci in ankylosing spondylitis [J]. Arthritis Rheum,1998,41:588-595.
[88]Brown MA, Brophy S, Bradbury L, et al. Identification of major loci controlling clinical manifestations of ankylosing spondylitis [J]. Arthritis Rheum,2003,48: 2234-2239.
[2]Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome [J]. Nature,2001,409(6822):860-921.
[3]Sieper J, Braun J, Rudwaleit M, et al. Ankylosing spondylitis:an overview [J]. Ann Rheum Dis,2002,61(Suppl 3):ⅲ8-ⅲ18.
[4]Brown J, B ollow M, Remlinger G, et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors [J]. Arthritis Rheum,1998,41:58-67.
[5]Gu MM, Yuan WT, Yang JQ, et al. A genomewide scan for the susceptibility gene loci to ankylosing spondylitis in Chinese populatin [J]. Acta Genetica Sinica,2004,3: 217-220.
[6]Brown MA. Breakthroughs in genetic studies of ankylosing spondylitis [J]. Rheumatology,2008,47:132-137.
[7]Said-Nahal R, Miceli-Richard C, Berthelot JM, et al. The familial form of spondylarthropathy:a clinical study of 115 multiplex families [J]. Arthritis Rheum, 2000,43:1356-1365.
[8]van der Linden SM, Valkenburg HA, de Jongh BM, et al. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals [J]. Arthritis Rheum,1984,27: 361-368.
[9]Braun J, BollowM, Remlinger G, et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors [J]. Arthritis Rheum,1998,41:58-67.
[10]Khan MA. Update on spondyloarthropathies [J]. Ann Intern Med,2002,136: 896-907.
[11]Amor B, Feldmann JL, Delbarre F, et al. HLA antigen W27-a genetic link between ankylosing spondylitis and Reiter's syndrome [J]? N Engl J Med,1974,290:572-576.
[12]Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HLA-B27 [J]. Lancet,1973,1:904-907.
[13]Brionez TF, Reveille JD. The contribution of genes outside the major histocompatibility complex to susceptibility to ankylosing spondylitis [J]. Curr Opin Rheumatol,2008,20:384-391.
[14]Breban M, Miceli-Richard C, Zinovieva E, et al. The genetics of spondyloarthropathies [J]. Joint Bone Spine,2006,73:355-362.
[15]Brown MA, Kennedy LG, Mac Gregor AJ, et al. Susceptibility to ankylosing spondylitis in twins:the role of genes, HLA, and the environment [J]. Arthritis Rheum, 1997,40:1823-1828.
[16]Muhammad AK, Alessandro M, Rosa S, et al. The pathogenetic role of HLA-B27 and its subtypes [J]. Autoimmunity Reviews,2007,6:183-189.
[17]Carter KW, Pluzhnikov A, Timms AE, et al. Combined analysis of three whole genome linkage scans for ankylosing spondylitis [J]. Rheumatology,2007,48: 763-771.
[18]The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J]. Nature,2007, 447:661-683.
[19]Wellcome Trust Case Control Consortium, The Australo-Anglo-American Spondylitis Consortium. A genome-wide scan of 14,000 non-synonymous coding SNP in 5,500 individuals [J]. Nat Genet,2007,39:1329-1336.
[1]Brown MA, Laval SH, Brophy S, et al. Recurrence risk modeling of the genetic susceptibility to ankylosing spondylitis [J]. Ann Rheum Dis,2000,59:883-886.
[2]Brewerton DA, Hart FD, NichollsA, et al. Ankylosing spondylitis and HLA-27 [J]. Lancet,1973,1:904-907.
[3]SchlossteinL, Terasaki PI, BluestoneR, et al. High Association of an HLA antigen, w27, with Ankylosing spondylitis [J]. New Ensl J Med,1973,288(14):704-706.
[4]Hammer RE, Maika SD, Richardson JA, et al. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m:an animal model of HLA-B27-associated human disorders [J]. Cell,1990,63:1099-1112.
[5]Tran TM, Dorris ML, Satumtira N, et al. Additional human beta2m curbs HLA-B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA-B27 transgenic rats [J]. Arthritis Rheum,2006,54:1317-1327.
[6]Madden DR, Gorga JC, Strominger JL, et al. The three dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC [J]. Cell,1992,70:1035-1048.
[7]Muhammad AK, Alessandro M, Rosa S, et al. The pathogenetic role of HLA-B27 and its subtypes [J]. Autoimmunity Reviews,2007,6:183-189.
[8]Sims AM, Wordsworth BP, Brown MA. Genetic susceptibility to ankylosing spondylitis [J]. Curr Mol Med,2004,4:13-20.
[9]Khan MA. Update on spondyloarthropathies [J]. Ann Intern Med,2002,136:896-907.
[10]Paladini F, Taccari E, Fiorillo MT,, et al. Distribution of HLA-B27 subtypes in Sardinia and continental Italy and their association with spondylarthropathies [J]. Arthritis Rheum,2005,52:3319-3321.
[11]Ma HJ, Hu FP. Diversity of human leukocyte antigen-B27 alleles in Han population of Hunan province, southern China [J]. Tissue Antigens,2006,68:163-166.
[12]Chou CT, Chen JM, Chang MH, et al. HLA-B27 and its subtypes in 4 Taiwanese aborigine tribes:a comparison to Han Chinese patients with ankylosing spondylitis [J]. J Rheumatol,2003,30:321-325.
[13]Yang KL, Chen IH, Hsiao CK, et al. Polymorphism of HLA-B27 in Taiwanese Chinese. Tissue Antigens,2004,63:476-479.
[14]Dowing J, Coates E, Street J, et al. A High-Resolution Polymerase Chain Reaction-Sequence-Specific Primer HLA-B*27 Typing Set and Its Application in Routine HLA-B27 Testing [J]. Genet Test,2006,10:98-103.
[15]Downing J, Guttridge MG, Thompson J, et al. Five-locus HLA typing of haematopoietic stem cell donor volunteers by PCR using sequence specific primers [J]. Genet Test,2004,8:301-312.
[16]Van der Linden S, Valkenberg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis:a proposal for modification of the New York criteria [J]. Arthritis Rheum,1984,27:361-368.
[17]李一荣,胡丽华,陈凤花等.应用SYBR Green I实时荧光PCR法对中国汉族人群HLA-B27进行快速基因分型[J].临床血液学杂志,2008,21(5)：526-529.
[18]Sieper J, Braun J, Rudwaleit M, et al. Ankylosing spondylitis:an overview [J]. Ann Rheum Dis,2002,61(Suppl 3):ⅲ8-ⅲ18.
[19]Conde RA. Fxequeucy of the HLA-B27 alleles in Brazilieus patients with AS [J]. J Rhenmatol,2003,30(11):2512.
[20]Khan MA, Akkoc N. Etiopathogenic role of HLA-B27 alleles in ankylosing spondylitis [J]. APPLAR J Rheumatol,2005,8:146-153.
[21]Archer J, Keat A. Ankylosing spondylitis:time to focus on ankylosis [J]. J Rheumatol, 1999,26(4):761-764.
[22]Mclean L, Hammer R, Taurog J, et al. Immunosusceptibility genes in rheumatoid arthritis [J]. Hum Immunol,1996,51 (1):32-40.
[23]Allen RL, Callaghan CA, Mcmichael AJ, et al. Cutting edge:HLA-B27 can form a novel beta 22microglobulin2free heavy chain homodimer structure [J]. J Immunol, 1999,162(9):5045-5048.
[24]Reineli S, Dedier S, Asuni G, et al. Mutation of Cys-67 alters the thermodynamic stability of the human leukocyte antigen HLA-B2705 [J]. J Biol Chem,2001,276(21): 18472-18477.
[25]Khan MA. Update:the twenty subtypes of HLA-B27 [J]. Curr Opin Rheumatol,2000, 12:235-238.
[26]Blanco-Gelaz MA, Lopez-Vazquez A, Garcia-Fernandez Sl. Genetic variability, molecular evolution, and geographic diversity of HLA B27 [J]. Hum Immunol,2001, 62:1042-1050.
[27]Hill AVS, Allsopp CEM, Kwiatkowski D. HLA class I typing by PCR:HLA B27 and an African subtype [J]. Lancet,2001,337:640-642.
[28]Lopez-Larrea C, Sujirachato K, Mehra. NKHLA B27 subtypes in Asian patients with ankylosing spondylitis [J]. Tissue Antigens,1995,45:169-176.
[29]Toubert A, Tieng V, Boisgerault F. Subtypes of the HLA B27 molecule and association with spondyloarthropathies [J]. Ann Med Interne,1998,149(3):145.
[30]Chou CT, Chen JM, Chang MH, et al. HLA-B27 and its subtypes in 4 Taiwanese aborigine tribes:a comparison to Han Chinese patients with ankylosing spondylitis [J]. J Rheumatol,2003,30:321-325.
[31]Lopez-Larrea C, Sujirachato K, Mehra NK. HLA B27 subtypes in Asian patients with ankylosing spondylitis [J]. Tissue Antigens,1995,45:169-176.
[32]Garcia-Fernandez S, Gonzalez S, Mina Blanco A. New insights regarding HLA-B27 diversity in the Asian population [J]. Tissue Antigens,2001,58:259-262.
[33]Chen IH, Yang KL, Lee A, et al. Low frequency of HLA-B*2706 in Taiwanese patients with ankylosing spondylitis [J]. Eur J Immunogenet,2002,29:435-438.
[34]Lee SH, Choi IA, Lee YA, et al. Human leukocyte antigen-B*2705 is the predominant subtype in the Korean population with ankylosing spondylitis, unlike in other Asians. Rheumatol Int,2008,29:43-46.
[35]Birinci A, Bilgici A, Kuru O, et al. HLA-B27 polymorphism in Turkish patients with ankylosing spondylitis [J]. Rheumatol Int,2006,26:285-287.
[36]Fiorillo MT, Maragno M, Butler R, et al. CD8(+) T-cell autoreactivity to an HLA-B27-restricted selfepitope correlates with ankylosing spondylitis [J]. Arthritis Rheum,2005,52:3319-3321.
[37]Sesma L, Montserrat V, Lamas JR, et al. The peptide repertoires of HLA-B27 subtypes differentially associated to spondyloarthropathy(B*2704 and B*2706) differ by specific changes at three anchor positions [J]. J Biol Chem,2002,277(19): 16744-16779.
[38]Ramos M, Paradela A, Vazquez M, et al. Differential association of HLA-B*2705 and B*2709 to ankylosing spondylitis correlates with limited peptide subsets but not with altered cell surface stability [J]. J Biol Chem,2002,277(32):28749-28756.
[39]Choo SY, St John T, Orr HT. Molecular analysis of the variant alloantigen HLA-B27d(HLA-B*2703) identifies a unique single amino acid substitution [J]. Hum Immunol,1988,21:209-219.
[40]Gul A, Uyar FA, Inanc M. A weak association of HLA-B*2702 with Behcet's disease [J]. Genes Immun,2002,3:368-372.
[41]崔刘福,宋海澄,李宏芬等.HLA-B27等位基因与强直性脊柱炎的相关性研究[J].中华风湿病学杂志,2003,7(1)：55-56.
[1]Brown MA, Laval SH, Brophy S, et al. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis [J]. Ann Rheum Dis,2000,59:883-886.
[2]Brown MA, Kennedy LG, MacGregor AJ, et al. Susceptibility to ankylosing spondylitis in twins:the role of genes, HLA, and the environment [J]. Arthritis Rheum, 1997,40:1823-1828.
[3]Sims AM, Wordsworth BP, Brown MA. Genetic susceptibility to ankylosing spondylitis [J]. Curr Mol Med,2004,4:13-20.
[4]Reveille JD, Ball EJ, Khan MA. HLA-B27 and genetic predisposing factors in spondyloarthropathies [J]. Curr Opin Rheumatol,2001,13:265-272.
[5]Khan MA, Mathieu A, Sorrentino R, et al. The pathogenetic role of HLA-B27 and its subtypes [J]. Autoimmun Rev,2007,6:183-189.
[6]Kuon W, Kuhne M, Busch DH, et al. Identification of novel human aggrecan T cell epitopes in HLA-B27 transgenic mice associated with spondyloarthropathy [J]. J Immunol,2004,173 (8):4859-4866.
[7]Atagunduz P, Appel H, Kuon W, et al. HLA-B27-restricted CD8+ T cell response to cartilagederived self peptides in ankylosing spondylitis [J]. Arthritis Rheum,2005,52: 892-901.
[8]Ishida Y, Agata Y, Ahibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death [J]. EMBOJ, 1992,11:3887-3895.
[9]Magnusson V, Lindqvist AK, Castillejo-Lopez C, et al. Fine mapping of the SLEB2 locus involved in susceptibility to systemic lupus erythematosus [J]. Genomics,2000, 70:307-314.
[10]Shinohara T, Taniwaki M, Ishida Y, et al. Structure and chromosomal localization of the human PD-1 gene (PDCD1) [J]. Genomics,1994,23:704-706.
[11]Okazaki T, Wang J. PD-1/PD-L pathways and autoimmunity [J]. Autoimmunity, 2005,38:353-357.
[12]Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity [J]. Annu Rev Immunol,2008,26:677-704.
[13]Gregersen PK, Behrens TW. Genetics of autoimmune diseases-disorders of immune homeostasis[J]. Nat Rev Genet,2006,7:917-928.
[14]Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection [J]. Nat Immunol,2007,8: 239-245.
[15]Keir ME, Francisco LM, Sharpe AH. PD-1 and its ligands in T-cell immunity [J]. Curr Opin Immunol,2007,19:309-314.
[16]Ferreiros-Vidal I, Gomez-Reino JJ, Barros F, et al. Association of PDCD1 with susceptibility to systemic lupus erythematosus:evidence of population-specific effects [J]. Arthritis Rheum,2004,50:2590-2597.
[17]Johansson M, Arlestig L, Moller B, rt al. Association of a PDCD1 polymorphism with renal manifestations in systemic lupus erythematosus [J]. Arthritis Rheum,2005,52: 1665-1669.
[18]Nielsen C, Laustrup H, Voss A, et al. A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients [J]. Lupus,2004,13:510-516.
[19]Wang Q, Ye D, Yin J, Li X, et al. Programmed cell death 1 genotypes are associated with susceptibility to systemic lupus erythematosus among Chinese [J]. Arch Dermatol Res,2008,300:91-93.
[20]Velazquez-Cruz R, Orozco L, Espinosa-Rosales F, et al. Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus [J]. Eur J Hum Genet,2007,15:336-341.
[21]Prokunina L, Castillejo-Lopez C, Oberg F, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans [J]. Nat Genet,2002,32:666-669.
[22]Thorburn CM, Prokunina-Olsson L, Sterba KA, et al. Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort [J]. Genes Immun,2007,8:279-287.
[23]Wang SC, Chen YJ, Ou TT, et al. Programmed Death-1 Gene Polymorphisms in Patients With Systemic Lupus Erythematosus in Taiwan [J]. J Clin Immunol,2006, 26(6):506-511.
[24]Kong EK, Prokunina-Olsson L, Wong WH, et al. A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese [J]. Arthritis Rheum,2005, 52:1058-1062.
[25]Lin SC, Yen JH, Tsai JJ, et al. Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus [J]. Arthritis Rheum,2004,50:770-775.
[26]Prokunina L, Padyukov L, Bennet A, et al. Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope [J]. Arthritis Rheum,2004,50:1770-1773.
[27]Nielsen C, Hansen D, Husby S, et al. Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes [J]. Tissue Antigens,2003,62:492-497.
[28]Ronghua Ni, Kenji I, Kenichi M, et al. PD-1 gene haplotype is associated with the development of type 1 diabetes mellitus in Japanese children [J]. Hum Genet,2007, 121:223-232.
[29]Kroner A, Mehling M, Hemmer B, et al. A PD-1 polymorphism is associated with disease progression in multiple sclerosis [J]. Ann Neurol,2005,58:50-57.
[30]Lee SH, Lee YA, Woo DH, et al. Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population [J]. Arthritis Res Ther,2006,8:R163.
[31]Van der Linden S, Valkenberg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis:a proposal for modification of the New York criteria [J]. Arthritis Rheum,1984,27:361-368.
[32]Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci [J]. Cell Res,2005,15:97-98.
[33]Li Z, Zhang Z, He Z, et al. A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers:update of the SHEsis (http://analysis.bio-x.cn) [J]. Cell Res,2009,19(4):519-523.
[34]Finger LR, Pu J, Wasserman R, et al. The human PD-1 gene:compplete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors [J]. Gene,1997,197:177-187.
[35]Saunders PA, Hendrycks VR, LidinskyWA, et al. PD-L2:PD-1 involvement in T cell proliferation, cytokine p roduction, and integrinmediated adhesion [J]. Eur J Immunol, 2005,35:3561-3569.
[36]Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation [J]. Nat Immunol,2001,2:261-268.
[37]Ravetch JV, Lanier LL. Immune inhibitory receptors [J]. Science,2000,290:84-89.
[38]Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation [J]. T Exp Med,2000,192:1027-1034.
[39]Dong H, Zhu G, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion [J]. Nat Med,1999,5: 1365-1369.
[40]Tseng SY, Otsuji M, Gorski K, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cell [J]. J Exp Med,2001,193:839-846.
[41]Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor [J]. Immunity,1999,11:141-151.
[42]Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice [J]. Science,2001,291:319-322.
[43]Ansari MJ, Salama AD, Chitnis T, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic(NOD) mice [J]. J Exp Med,2003, 198:63-69.
[44]Iwamoto T, Ikari K, Inoue E, et al. Failure to confirm association between PDCD1 polymorphisms and rheumatoid arthritis in a Japanese population [J]. J Hum Genet, 2007,52:557-560.
[45]Fawwaz S, Nikamo P, Torn C, et al. No evidence of association of the PDCD1 gene with Type 1 diabetes [J]. Diabet Med,2007,24:1473-1477.
[46]Meng Q, Liu X, Yang P, et al. PDCD1 genes may protect against extraocular manifestations in Chinese Han patients with Vogt-Koyanagi-Harada syndrome [J]. Mol Vis,2009,15:386-392.
[47]Akey J, Jin L, Xiong M. Haplotypes vs single marker linkage disequilibrium tests: what do we gain [J]? Eur J Hum Genet,2001,9(4):291-300.
[48]Zollner S, von Haeseler A. A coalescent approach to study linkage disequilibrium between single-nucleotide polymorphisms [J]. Am J Hum Genet,2000,66(2): 615-628.
[1]Braun J, Sieper J. Ankylosing spondylitis [J]. Lancet,2007,369:1379-1390.
[2]Brown MA. Breakthroughs in genetic studies of ankylosing spondylitis [J]. Rheumatology,2008,47:132-137.
[3]Trinchieri G, Pflanz S, Kastelein RA. The IL-12 family of heterodimeric cytokines:new players in the regulation of T cell responses [J]. Immunity,2003,19:641-644.
[4]Parham C, Chirica M, Timans J, et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbetal and a novel cytokine receptor subunit, IL-23R [J]. J Immunol,2002,168:5699-5708.
[5]Cua DJ, Sherlock J, Chen Y et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain [J]. Nature,2003,421:744-748.
[6]Murphy CA, Langrish CL, Chen Y et al. Divergent pro-and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation [J]. J Exp Med,2003,198: 1951-1957.
[7]Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage [J]. Nat Med,2007,13:139-145.
[8]Cargill M, Schrodi SJ, Chang M et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes [J]. Am J Hum Genet,2007,80:273-290.
[9]Duerr RH, Taylor KD, Brant SR et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene [J]. Science,2006,314:1461-1463.
[10]Nunez C, Dema B, Cenit MC et al. IL23R:a susceptibility locus for celiac disease and multiple sclerosis [J]? Genes Immun,2008,9:289-293.
[11]Burton PR, Calyton DG, Cardon LR, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants [J]. Nat Genet, 2007,39:1329-1337.
[12]Rahman P, Inman RD, Gladman DD, et al. Association of interleukin-23 receptor variants with ankylosing spondylitis [J]. Arthritis Rheum,2008,58:1020-1025.
[13]Rueda B, Orozco G, Raya E, et al. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis [J]. Ann Rheum Dis, 2008,67:1451-1454.
[14]杨清锐,张源潮,孙红胜等.强直性脊柱炎与肿瘤坏死因子α基因启动子一308位点多态性关联研究的Meta分析[J].中华风湿病学杂志,2007,6(11)：365-369.
[15]Salanti G, Sanderson S, Higgins JP. Obstacles and opportunities in meta-analysis of genetic association studies [J]. Genet Med,2005,7:13-20.
[16]Karaderi T, Harvey D, Farrar C, et al. Association between the interleukin 23 receptor and ankylosing spondylitis is confirmed by a new UK case-control study and meta-analysis of published series [J]. Rheumatology,2009,48:386-389.
[17]Safrany E, Pazar. B, Csongei V, et al. Variants of the IL23R Gene are Associated with Ankylosing Spondylitis but not with Sjogren Syndrome in Hungarian Population Samples [J]. Scandinavian Journal of Immunology,2009,70:68-74.
[18]王新卫,黄进贤,林智明等.白细胞介素-23R单核苷酸多态性与中国汉族人群强直性脊柱炎的关联分析[J].中华风湿病学杂志,2008,10(12)：670-672.
[19]Brown MA. Non-major-histocompatibility-complex genetics of ankylosing spondylitis [J]. Best Pract Res Clin Rheumatol,2006,20:611-621.
[20]Glass GV. Primary, secondary, and meta analysis of research [J]. Education Research, 1976,6(5):3.
[21]方积乾,陆盈.Meta分析.现代医学统计学[M].北京：人民卫生出版社,2002,150-209.
[22]钟文昭,吴一龙,谷力加.Review Manager-临床医生通向meta分析的桥梁[J].循证医学,2003,3(4)：234-246.
[1]van der Linden SM, van der Heijde D, Maksymowych WP. Ankylosing spondylitis [J]. 8th edition. Philadelphia:Saunders-Elsevier,2008.1169-1190.
[2]曾宪国.强直性脊柱炎死亡原因分析[J].海南医学,2006,17(2)：57-58.
[3]Brionez TF, Reveille JD. The contribution of genes outside the major histocompatibility complex to susceptibility to ankylosing spondylitis [J]. Curr Opin Rheumatol,2008, 20:384-391.
[4]Breban M, Miceli-Richard C, Zinovieva E, et al. The genetics of spondyloarthropathies [J]. Joint Bone Spine,2006,73:355-362.
[5]Brown MA. Breakthroughs in genetic studies of ankylosing spondylitis [J]. Rheumatology,2008,47:132-137.
[6]Said-Nahal R, Miceli-Richard C, Berthelot JM, et al. The familial form of spondylarthropathy:a clinical study of 115 multiplex families [J]. Arthritis Rheum, 2000,43:1356-1365.
[7]van der Linden SM, Valkenburg HA, de Jongh BM, et al. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals [J]. Arthritis Rheum,1984,27: 361-368.
[8]Amor B, Feldmann JL, Delbarre F, et al. HLA antigen W27-a genetic link between ankylosing spondylitis and Reiter's syndrome [J]? N Engl J Med,1974,290:572-576.
[9]Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HLA-B27 [J]. Lancet,1973,1:904-907.
[10]BrownMA,Kennedy LG, MacGregor AJ, et al. Susceptibility to ankylosing spondylitis in twins:the role of genes, HLA, and the environment [J]. Arthritis Rheum,1997,40: 1823-1828.
[11]Braun J, BollowM, Remlinger G, et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors [J]. Arthritis Rheum,1998,41:58-67.
[12]Ebringer A,Wilson C. HLA molecules, bacteria and autoimmunity [J]. J Med Microbiol,2000,49:305-311.
[13]马海军,扈凤平.强直性脊柱炎遗传因素研究进展[J].中南大学学报(医学版), 2005,30:352-355.
[14]Muhammad AK, Alessandro M, Rosa S, et al. The pathogenetic role of HLA-B27 and its subtypes [J]. Autoimmunity Reviews,2007,6:183-189.
[15]Khan MA,Akkoc N. Etiopathogenic role of HLA-B27 alleles in ankylosing spondylitis [J]. APPLAR J Rheumatol,2005,8:146-153.
[16]Khan MA. HLA-B27 and its subtypes in world populations [J]. Curr Opin Rheumatol, 1995,7:263-269.
[17]Garcia-Fenrandez S, Gonzalez S, Mina Blanco A, et al. New insights regarding HLA-B27 diversity in the Asian population [J]. Tissue Antigens,2001,58:259-262.
[18]Vargas-Alarcon G, Londono JD, Hemandez-Pacheco G, et al. Effect of HLA-B and HLA-DR genes on susceptibility to and severity of spondyloarthropathies in mexican patients [J]. Ann Rheum Dis,2002,61:714-717.
[19]Sims AM, Wordsworth BP, Brown MA. Genetic susceptibility to ankylosing spondylitis [J]. Curr Mol Med,2004,4:13-20.
[20]MacLean IL, Iqball S, Woo P, et al. HLA-B27 subtypes in the spondarthropathies [J]. Clin Exp Immunol,1993,91:214-219.
[21]Reveille JD, Inman R, Khan M, et al. Family studies in ankylosing spondylitis: microsatellite analysis of 55 concordant sib pairs [J]. J Rheumatol,2000,27 (Suppl 59):5.
[22]Lopez-Larrea C, Sujirachato K, Mehra NK, et al. HLA-B27 subtypes in Asian patients with ankylosing spondylitis:evidence for new associations [J]. Tissue Antigens,1995, 45:169-176.
[23]Armas JB, Gonzalez S, Martinez-Borra J, et al. Susceptibility to ankylosing spondylitis is independent of the Bw4 and Bw6 epitopes of HLA-B27 alleles [J]. Tissue Antigens, 1999,53:237-243.
[24]Garcia F, Rognan D, Lamas JR, et al. An HLA-B27 polymorphism (B*2710) that is critical for T-cell recognition has limited effects on peptide specificity [J]. Tissue Antigens,1998,51:1-9.
[25]Garcia-Fernandez S, Gonzalez S, Mina Blanco A, et al. New insights regarding HLA-B27 diversity in the Asian population [J]. Tissue Antigens,2001,58:259-262.
[26]Tamouza R, Mansour I, Bouguacha N, et al. A new HLA-B-27 allele (B*2719) identified in a Lebanese patient affected with ankylosing spondylitis [J]. Tissue Antigens,2001,58:30-33.
[27]Hildebrand WH, Turnquist HR, Prilliman KR, et al. HLA class I polymorphism has a dual impact on ligand binding and chaperone interaction [J]. Hum Immunol,2002,63: 248-255.
[28]Gonzalez-Roces S, Alvarez MV, Gonzalez S, et al. HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis [J]. Tissue Antigens,1997,49: 116-123.
[29]Olivieri I, D'Angelo S, Scarano E, et al. The HLA-B*2709 subtype in a woman with early ankylosing spondylitis [J]. Arthritis Rheum,2007,56:2805-2807.
[30]Cauli A, Vacca A, Mameli A, et al. A Sardinian patient with ankylosing spondylitis and HLA-B*2709 co-occurring with HLA-B*1403 [J]. Arthritis Rheum,2007,56: 2807-2809.
[31]Madden DR, Gorga JC, Strominger JL, et al. The three dimensional structure of HLA-B27 at 2.1 A resolution suggests a general mechanism for tight peptide binding to MHC [J]. Cell,1992,70:1035-1048.
[32]Archer J, Keat A. Ankylosing spondylitis:time to focus on ankylosis [J]. J Rheumatol, 1999,26(4):761-764.
[33]Breban M, et al. T cells, but not thymic exposure to HLA-B27, are required for the inflammatory disease of HLA-B27 transgenic rats [J]. J Immunol,1996,156:794-803.
[34]Taurog JD. Spondylarthritis in HLAB27/human beta(2)-microglobulin-transgenic rats is not prevented by lack of CD8 [J]. Arthritis Rheum,2009,60:1977-1984.
[35]Allen RL, Callaghan CA, Mcmichael AJ, et al. Cutting edge:HLA-B27 can form a novel beta 22microglobulin2free heavy chain homodimer structure [J]. J Immunol, 1999,162(9):5045-5048.
[36]Kollnberger S. Cell-surface expression and immune receptor recognition of HLAB27 homodimers [J]. Arthritis Rheum,2002,46:2972-2982.
[37]Kollnberger S. Interaction of HLA-B27 homodimers with KIR3DL1 and KIR3DL2, unlike HLA-B27 heterotrimers, is independent of the sequence of bound peptid [J]. J Immunol,2007,37:1313-1322.
[38]Chan AT, Kollnberger SD, Wedderburn LR, et al. Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis [J]. Arthritis Rheum,2005,52:3586-3595.
[39]Smith JA, Turner MJ, DeLay ML, et al. Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-beta induction via X-box binding protein 1[J]. Eur J Immunol,2008,38:1194-1203.
[40]Colbert RA. HLA-B27 misfolding activates the IL-23/IL-17 axis via the unfolded protein response in transgenic rats:evidence for a novel mechanism of inflammation [J]. Arthritis Rheum,2007,1283:S515.
[41]Brown MA, Pile KD, Kennedy LG, et al. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom [J]. Ann Rheum Dis,1996, 5:268-270.
[42]Reveille JD. Major histocompatibility genes and ankylosing spondylitis [J]. Best Pract Res Clin Rheumatol,2006,20:601-609.
[43]Gran JT, Husby G, Hordvik M, et al. Prevalence of ankylosing spondylitis in males and females in a young middle-aged population of Tromso, northern Norway [J]. Ann Rheum Dis,1985,44:359-367.
[44]Robinson WP, van der Linden SM, Khan M A, et al. HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+patients [J]. Arthritis Rheum, 1989,32:1135-1141.
[45]Wei JC, Tsai WC, Lin HS, Tsai CY, Chou CT. HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients [J]. Rheumatology (Oxford),2004,43:839-842.
[46]Brown MA, Kennedy LG, Darke C, et al. HLA Class I and II associations of ankylosing spondylitis [J]. Arthritis Rheum,2009,60(Suppl):S437.
[47]Sims AM, Barnardo M, Herzberg I, et al. Non-B27 MHC associations of ankylosing spondylitis [J]. Genes Immun,2007,8:115-123.
[48]Aniko Vegvari a, Zoltan Szabo a, Sandor Szanto a, et al. The genetic background of ankylosing spondylitis [J]. Joint Bone Spine,76:623-628.
[49]Thomas GP, Brown MA. Genetics and genomics of ankylosing spondylitis [J]. Immunological Reviews,2010,233:162-180.
[50]Brown MA. Genetics and the pathogenesis of ankylosing spondylitis [J]. Current Opinion in Rheumatology,2009,21:318-323.
[51]Carter KW, Pluzhnikov A, Timms AE, et al. Combined analysis of three whole genome linkage scans for ankylosing spondylitis [J]. Rheumatology,2007,48: 763-771.
[52]McGarry F, Neilly J, Anderson N, et al. A polymorphism within the interleukin-1 receptor antagonist (IL-1Ra) gene is associated with ankylosing spondylitis [J]. Rheumatology,2001,40:1359-1364.
[53]van der Paardt M, Crusius JB, Garcia-Gonzalez MA, et al. Interleukin-1β and interleukin-1 receptor antagonist gene polymorphisms in ankylosing spondylitis [J]. Rheumatology,2002,41:1419-1423.
[54]Timms AE, Crane AM, Sims AM, et al. The interleukin-1 gene cluster contains a major susceptibility locus for ankylosing spondylitis [J]. Am J Hum Genet,2004,75: 587-595.
[55]Maksymowych WP, Rahman P, Reeve JP, et al. Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis:an analysis of three Canadian populations [J]. Arthritis Rheum,2006,54:974-985.
[56]Wu Z, Gu JR. A meta-analysis on interleukin-1 gene cluster polymorphism and genetic susceptibility for ankylosing spondylitis [J]. Zhonghua Yi Xue Za Zhi,2007, 87:433-437.
[57]Sims AM, Timms AE, Bruges-Armas J, et al. Prospective meta-analysis of IL-1 gene complex polymorphisms confirms associations with ankylosing spondylitis [J]. Ann Rheum Dis,2008,67:1305-1309.
[58]Gong WJ, Yang JQ, zhang L. Association of killer cell immunogloblin-like receptor gene polymorphisms with seronegative spondylarthropathies [J]. Section Genet Foreign Med Sci,2003,7:465-468.
[59]Chan T, Kollnberger SD, Wedderbum LR, et al. Expansion and enhanced survival of natural killer cells expressing the killer Immunoglobulin-like receptor KIR3DL2 in spondylarthritis [J]. Aathritis Rheumatism,2005,52:3586-3595.
[60]龚卫娟,杨珏琴,张磊.杀伤细胞免疫球蛋白样受体基因多态性与血清阴性脊柱关节病的关联性研究[J].国外医学遗传学分册,2001,24：35-38.
[61]Brown MA, Edwards S, Hoyle E, et al. Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis [J]. Hum Mol Genet,2000,9:1563-1566.
[62]Jaakkola E, Crane AM, Laiho K, et al. The effect of transforming growth factor β1 gene polymorphisms in ankylosing spondylitis [J]. Rheumatology,2004,43:32-38.
[63]Snelgrove T, Lim S, Greenwood C, et al. Association of toll-like receptor 4 variants and ankylosing spondylitis:a case-control study [J]. J Rheumatol,2007,34:368-370.
[64]The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J]. Nature,2007, 447:661-683.
[65]Wellcome Trust Case Control Consortium, The Australo-Anglo-American Spondylitis Consortium. A genome-wide scan of 14,000 non-synonymous coding SNP in 5,500 individuals [J]. Nat Genet,2007,39:1329-1336.
[66]Rahman P, Inman GD, Gladman DD, et al. Association of Interleukin-23 Receptor Variants With Ankylosing Spondylitis [J]. Arthritis Rheum,2008,58 (4):1020-1025.
[67]Rueda B, Orozco G, Raya E, et al. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis [J]. Ann Rheum Dis, 2008,67:1451-1454.
[68]Harvey D, Pointon JJ, Evans DM, et al. Investigating the genetic association between ERAP1 and ankylosing spondylitis. Human Molecular Genetics,2009,18 (21): 4204-4212.
[69]Maksymowych WP, Inman RD, Gladman DD, et al. Association of a specific ERAP1/ARTS1 haplotype with disease susceptibility in ankylosing spondylitis [J]. Arthritis Rheum,2009,60:1317-1323.
[70]Davidson SI, Wu X, Liu Y, et al. Association of ERAP1, but Not IL23R, With Ankylosing Spondylitis in a Han Chinese Population [J]. Arthritis Rheum,2009,60: 3263-3268.
[71]van der Paardt M, Crusius JB, Garcia-Gonzalez MA, et al. Susceptibility to ankylosing spondylitis:no evidence for the involvement of transforming growth factor beta 1 (TGFB1) gene polymorphisms [J]. Ann Rheum Dis,2005,64:616-619.
[72]Gergely P, Blazsek A, Weiszhar Z, et al. Lack of genetic association of the toll-like receptor 4 (TLR4) Asp299Gly and Thr399Ile polymorphisms with spondyloarthropathies in a Hungarian population [J]. Rheumatology,2006,45: 1194-1196.
[73]Brown MA. Non major-histocompatibility-complex genetics of ankylosing spondylitis [J]. Best Pract Res Clin Rheumatol,2006,20:611-621.
[74]Jacques C, Gosset M, Berenbaum F, et al. The role of IL1 and IL1-Ra in joint inflammation and cartilage degradation [J]. Vitam Horm,2006,74:371-403.
[75]Szekanecz Z, Koch AE. Cytokines.6th Edition [M]. Philadelphia:W.B. Saunders, 2001.275-290.
[76]Li J, Ge Z, Akey JM, et al. Lack of linkage of IL1RN genotypes with ankylosing spondylitis susceptibility [J]. Arthritis Rheum,2004,50:3047-3048.
[77]Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12 [J]. Immunity,2000,13(5):715-725.
[78]Langrish CL, McKenzie BS, Wilson NJ, et al. IL-12 and IL-23:master regulators of innate and adaptive immunity [J]. Immunol Rev,2004,202:96-105.
[79]Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene [J]. Science,2006,314:1461-1463.
[80]Cargill M, Schrodi SJ, Chang M, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasisrisk genes. Am J Hum Genet,2007,80:273-290.
[81]Farago B, Magyari L, Safrany E, et al. Functional variants of interleukin-23 receptor gene confer risk for rheumatoid arthritis but not for systemic sclerosis [J]. Ann Rheum Dis,2008,67:248-250.
[82]Cui X, Rouhani F, Hawari F, et al. An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding [J]. J Biol Chem,2003,278:28677-28685.
[83]Hammer GE, Kanaseki T, Shastri N. The final touches make perfect the peptide-MHC class I repertoire [J]. Immunity,2007,26:397-406.
[84]Lander E, Kruglyak L. Genetic dissection of complex traits:guidelines for interpreting and reporting linkage results [J]. Nat Genet,1995,11:241-247.
[85]Laval SH, Timms A, Edwards S, et al. Whole-genome screening in ankylosing spondylitis:evidence of non-MHC genetic-susceptibility loci [J]. Am J Hum Genet, 2001,68:918-926.
[86]Zhang G, Luo J, Bruckel J, et al. Genetic studies in familial ankylosing spondylitis susceptibility. Arthritis Rheum,2004,50:2246-2254.
[87]Brown MA, Pile KD,Kennedy GL, et al.Agenome-wide screen for susceptibility loci in ankylosing spondylitis [J]. Arthritis Rheum,1998,41:588-595.
[88]Brown MA, Brophy S, Bradbury L, et al. Identification of major loci controlling clinical manifestations of ankylosing spondylitis [J]. Arthritis Rheum,2003,48: 2234-2239.