应用DNA pooling发现GRIN2A基因多态性影响中国汉族慢性HBV感染者的疾病进展
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摘要
研究背景：HBV感染是一个严重的全球性公共健康问题,全世界大约有3.5亿慢性HBV感染者,每年与HBV感染相关的死亡人数超过100万例。HBV的全球发病率大约为5%,但其分布具有明显的地域差别,我国是乙型肝炎的高发地区,卫生部2008年公布的数据显示,我国1-59岁一般人群乙肝表面抗原携带率为7.18%。据此推断,我国约有9300万HBsAg携带者,其中有感染症状的慢性乙型肝炎患者占2000万。HBV感染的自然史包括病毒清除、慢性持续性HBV感染及HBV感染后出现的并发症,包括重症乙型肝炎、肝硬化和肝癌。持续性HBV感染是病毒、环境、宿主基因组等多因素、多基因的不平衡。影响慢性HBV感染者疾病进展的因素包括HBV基因组本身的变异,HBV感染者的年龄、性别、长期酗酒、合并丙型肝炎病毒(HCV)、丁型肝炎病毒(HDV)、人类免疫缺陷病毒(HIV)等的感染和宿主基因组的变异。尽管病毒因素包括病毒载量、HBV基因型、HBV-DNA自身的变异已被证实在乙型肝炎疾病进展中发挥重要作用,HBV感染的双胞胎研究、家族聚集性研究和民族研究强烈支持基因遗传易感性在持续性HBV感染及HBV感染疾病进展中的重要作用。
目的：为了探索影响中国汉族慢性HBV感染疾病进展的遗传易感基因,我们对中国汉族人进行两阶段的基因组关联分析研究,以便寻找影响中国汉族慢性HBV感染疾病进展的单核苷酸多态性(SNPs)位点,并进行大量人群验证,探索相关基因或遗传变异位点影响中国汉族HBV感染向重症乙型肝炎、肝硬化或肝癌转变的机制。
方法：第一阶段采用以DNA pooling为基础的Affymetrix全基因组SNP6.0芯片扫描,筛选影响HBV感染不同疾病进展的遗传易感的SNPs。第二阶段采用TaqMan探针个体基因分型的方法进行人群验证。人群验证为以医院为基础的病例对照研究,验证人群为以湖北省汉族人为代表的中国南方人群(1729例进展性HBV感染者vs.628例无症状HBV感染者)和以山东省汉族人为代表的中国北方人群(215例进展性HBV感染者vs.226例无症状HBV感染者)。HBV感染者入选标准为HBsAg阳性同时HBeAb阳性持续6个月以上,且不合并HCV、HDV和HIV的感染。第一批验证人群为湖北地区2357例乙型肝炎患者,他们是2007年9月至2010年3月收集的来自于武汉同济医院、武汉协和医院和湖北省中医医院的住院病人。病例组为1729例进展性HBV感染者,包括重症乙型肝炎患者261例、乙肝相关性肝硬化患者731例和乙肝相关性原发性肝癌患者737例；对照组为628例无症状HBV感染者。同时我们还收集了210例以社区为基础的健康人作为健康对照,健康对照要求血清HBV标志物全为阴性。第二批验证人群为山东地区441例慢性乙型肝炎患者,包括215例进展性HBV感染者和226例无症状HBV感染者。这些HBV感染者是2009年6月至2010年3月收集的青岛传染病医院和滨州医学院附属医院的住院病人。同时我们还收集了210例以社区为基础的健康人作为健康对照。为了减少年龄因素对HBV进展的影响,我们限制无症状HBV感染者和健康对照年龄均不小于35岁。挑选SNP位点进行深入研究的标准为Silhouette width大于0.7,同时最小等位基因频率(minor allele frequency MAF)大于0.05。根据HapMap计划公布的中国北京人和日本东京人的基因型频率可知,选择的10个SNP位点均为标签SNP (tagSNP)。采用TaqMan探针法,运用7900HT序列检测系统进行人群验证,SDS2.3软件阅读384孔板,统计各个SNPs基因型分布,将各个基因多态性位点基因型数据导入SPSS17.0软件,运用校正性别、年龄和饮酒状况的logistic回归进行关联分析。
结果：以校正性别、年龄和饮酒状况的logistic回归计算不同的遗传模型(dominant、recessive、additive models)分析结果。10个SNPs在湖北省2357例HBV感染者中关联分析显示,位于ARHGAP24基因上的遗传变异位点rs346473和rs346482、位于GRIN2A基因上的基因多态性位点rs11866328、位于BNC2基因上的SNP rs7861010和位于ASCC3基因上的SNP rs 12206945与乙型肝炎的疾病进展强相关。遗传变异位点rs346473,TT基因型携带者增加HBV感染者发生疾病进展的易感性(OR 1.849,95%CI 1.498-2.283, P=1.1×10-8; additive model);遗传变异位点rs346482, TT基因型携带者增加HBV感染者发生疾病进展的易感性(OR 1.516,95% CI 1.233.1.865,P=7.7×10-5; additive model);GRIN2A基因上的基因多态性位点rs11866328,携带GG纯合子的乙型肝炎患者易发生疾病进展(OR,1.645;95%CI,1.340-2.020;P=1.96×10-6；additive model);位于BNC2基因上的SNP rs7861010,GG基因型携带者发生疾病进展的发病风险增加(OR,1.305;95%CI,1.059-1.607;P=1.2×10-2;additive model)；ASCC3基因上的SNP rs12206945,A等位基因(AA+AG)携带的乙肝患者较携带GG基因型的乙肝患者更易发生疾病进展(OR,1.742;95%CI,1.210-2.509;P=3.0×10-3；dominant model).我们发现位于ARHGAP24基因上的两个多态性位点(SNP rs346473和rs346482)存在强连锁不平衡(D’=0.99,r2=0.951),且与GG单倍型相比,单倍型TT携带者发展成进展性肝炎的几率增大1.980倍(95%CI,1.538-2.545;P=8.1×10-8).我们将在湖北省人群中与乙型肝炎进展强相关的三个多态性位点(位于GRIN2A基因上的基因多态性位点rs11866328、位于BNC2基因上的SNP rs7861010和位于ASCC3基因上的SNP rs12206945)在山东省人群中再次验证,校正年龄、性别和饮酒状况的logistic回归显示：位于GRIN2A基因上的基因多态性位点rs11866328的遗传变异仍然与疾病进展强相关(P=1.0×10-2；OR,1.727;95%CI,1.140-2.646 additive model),而SNP rs7861010和遗传变异位点rs12206945未见明显相关性。联合两次独立性研究,我们发现,在遗传变异位点rs11866328处,携带GG基因型的乙型肝炎患者对HBV感染的疾病进展高度易感(OR 1.684,95%CI 1.404-2.016,P=1.6×10-8).为了减少性别、年龄因素对HBV感染者发生疾病进展的影响,我们对该基因多态性位点进行了性别和年龄分层分析。性别分层分析可见,携带GG基因型的男性(OR,1.610;95%CI, 1.302-1.992；P=1.1×10-5;additive model).女性(OR,1.776；95%CI,1..253-2.525；P= 1.0x 10-3;additive model)患者发生HBV感染疾病进展的危险性均明显增高。35岁以上(包括35岁)年龄分层分析显示,年龄不小于35岁的携带GG纯合子的HBV感染者发生疾病进展的易感性增高(OR,1.634;95%CI,1.353-1.972;P=3.1×10-7;additive model)。运用HapMap报道的中国北京人和日本东京人基因型频率,我们发现遗传变异位点rs11866328在10kb区域内连锁不平衡(r2≥0.8)。
结论：基于DNA pooling的全基因组关联分析(genome wide association study GWAS)既可以降低全基因组关联分析花费,又被证明是一种有效的筛选候选基因及SNP的方法。它不需要预先根据一些尚未充分阐明的生物学基础来假设某些特定的基因或位点与某种疾病相关联,即不再需要在研究之前构建任何假设,是一种高效的筛选候选基因并进行关联分析的研究方法。我们对2798例中国汉族慢性HBV感染者两次独立性人群验证的结果显示位于GRIN2A基因上的SNP rs11866328可能是影响中国汉族HBV感染者疾病进展的易感遗传变异位点之一。
Background:Chronic hepatitis B virus (HBV) infection is a serious global public health problem. There are approximately 350 million people suffering from chronic HBV infection in the world and more than one million deaths annually attribute to HBV-related disease. The prevalence of chronic HBV infection is approximately 5% globally, but differs greatly from area to area. The prevalence of hepatitis B antigen (HBsAg) carriage is high in China (7.18%), that is there are 97 million HBsAg carriers in China and the number of chronic HBV carriers is 2 million in China. Most HBV carriers are considered to have been infected through maternal transmission in the neonatal period or infancy in high prevalent areas particularly in China. Persistent HBV infection has been considered a multifactorial and polygenic disequilibrium with viral, environmental, and host genetic components, including HBV genomic variability, age at infection, sex, chronic alcohol abuse, and co-infection with hepatitis C virus (HCV), hepatitis D virus (HDV) and human immunodeficiency virus (HIV). Though viral factors such as viral load, viral genotype and mutations in the viral genome itself are known risk factors for HBV infection, twin and ethical studies of HBV infection strongly support the role of genetic susceptibility to HBV persistence and the course of infection.
Aims:The objective of this study was to identify novel susceptibility loci to HBV progression in Han Chinese chronic HBV carriers, we conducted a two-stage genome-wide association study for HBV infection and progression in Han Chinese population.
Methods:Affymetrix Genome-Wide Human Mapping SNP6.0 Array with DNA pooling was used in the screening stage, and ten high-ranked single nucleotide polymorphisms (SNPs) were included in this panel. All HBV carriers were genotyped by using TaqMan method in the second stage. A total of 2798 unrelated Han Chinese HBV carriers were recruited from Hubei province (n=2357) in south of China (Wuhan Tongji hospital, Wuhan Union hospital and Traditional Chinese Medicine hospital of Hubei province) and Shandong province (n=441) in north of China (Qingdao hospital for Infection Disease and the Affiliated hospital of Binzhou Medical College) between September 2007 and March 2010 in our hospital-based case-control study. All HBV carriers were positive for both HBsAg and antibody to HBV core antigen of the immunoglobulin G type for at least 6 months. Among the 2798 HBV carriers,854 asymptomatic HBV carriers (AsC) (628 from Hubei province and 226 from Shandong province) and 1944 progressed HBV carriers (1729 from Hubei and 215 from Shandong) were included. Of the 1944 progressed HBV carriers,263 individuals were patients with fulminant hepatitis B (FHB),786 subjects with liver cirrhosis (LC) and 895 were patients with hepatocellular carcinoma (HCC). The 420 unrelated healthy Han Chinese were recruited as naive control (210 from Hubei and 210 from Shandong), who were HBV serum markers negative and no HB vaccination history. The AsC and naive controls were all over 35 years old to provide adequate time for symptoms to manifest. All subjects had no serologic evidence for co-infection with HCV, HDV and HIV. The criteria for selection of SNPs for further investigation was Silhouette width exceeding 0.7 and minor allele frequency (MAF)> 0.05. They were all tagSNPs using data from the International HapMap project (www. hapmap.org; CHB+JPT population). TaqMan 7900HT Sequence Detection System (Applied Biosystems, Foster City, Calif.) was used for genotyping according to the manufacture's instruction. Statistical analysis was performed using SPSS software (version 17.0; SPSS Inc, Chicago, IL).χ2 tests were used to examine the differences in clinical characteristics of participants. The adjusted Odds ratio (OR) and 95% confidence interval (95% CI) were tested by multivariable unconditional logistic regression under genetic models with adjustment for gender, age and alcohol consumption.
Results:In Hubei population, on the basis of multivariable logistic regression with adjustment for gender, age and alcohol consumption, variant rs346473 in the ARHGAP24 gene, SNP rs11866328 in the GRIN2A gene, SNP rs7861010 in the BNC2 gene and variant rs12206945 in the ASCC3 gene were found having increased susceptibility with disease progression of HBV infection in south of China (1729 progressed HBV carriers vs 628 AsC). At variant rs346473 in the ARHGAP24 gene, TT genotype carriers were found having significant associations with disease progression of HBV infection (OR 1.849,95% CI 1.498-2.283, P=1.1 x 10-8; additive model). At variant rs346482 in the ARHGAP24 gene, TT genotype carriers were found having significant associations with disease progression of HBV infection (OR 1.516,95% CI 1.233-1.865, P=7.7×10-5; additive model). SNP rs11866328 in the GRIN2A gene, subjects bearing GG homozygote were susceptive to HBV progression compared with GT heterozygote carriers (OR,1.645; 95% CI, 1.340-2.020; P=1.96×10-6; additive model). HBV patients carrying GG genotype at SNP rs7861010 in the BNC2 gene displayed a strong correlation with disease progression of HBV infection (OR,1.305; 95% CI,1.059-1.607; P=1.2×10-2; additive model). Variant rs12206945 in the ASCC3 gene, A allele carriers performed an elevated effect for disease progression of HBV infection (OR,1.742; 95% CI,1.210-2.509; P=3.0×10-3; dominant model). Using genotypes of 420 naive controls, we defined these two SNPs (rs346482 and rs346473) in strong linkage disequilibrium with D'=0.99 and r2= 0.951 generated by software HaploView 4.1.When haplotype CC was chosen as a baseline, haplotype TT displayed a significant increased risk for developing into progressed hepatitis (OR,1.980; 95% CI,1.538-2.545; P= 8.1×10-8). To validate the results of the association test, we carried out a replication using population recruited from Shandong province (215 progressed HBV carriers vs.226 AsC) in north of China. The three noticeably correlated SNPs (rs11866328, rs7861010 and rs12206945) were genotyped using the same TaqMan assay. SNP rs11866328 in the tenth intron of GRIN2A gene was confirmed to have an elevated effect on diverse outcomes of HBV infection (OR 1.727; 95% CI,1.140-2.646; P= 1.0×10-2; additive model). Combining all population, subjects bearing GG homozygote of rs11866328 had an increased susceptibility to HBV progression (OR 1.684,95%CI 1.404-2.016, P=1.6×10-8). In stratification analysis of SNP rs11866328 in all studied HBV carriers, the results remained significant in male patients (OR,1.610; 95% CI,1.302-1.992; P= 1.1×10-5; additive model), female patients (OR,1.776; 95% CI,1.253-2.525; P= 1.0×10-3; additive model) and patients 35 years or older (OR,1.634; 95% CI,1.353-1.972; P= 3.1×10-7; additive model). Using data from the International HapMap project (www.hapmap.org; CHB+JPT population) and HaploView (version 4.1) software, we found SNP rs11866328 having linkage disequilibrium (LD) within a 10kb region with r2≥0.8
Conclusions Performing Genome-wide association (GWA) studies on pools of DNA samples has been shown to be an efficient method to select candidate susceptibility loci for follow-up by individual genotyping. SNP rs11866328 in the GRIN2A gene could be a part of the genetic variants underlying the susceptibility of individuals to disease progression of chronic HBV infection.
目的：为了探索影响中国汉族慢性HBV感染疾病进展的遗传易感基因,我们对中国汉族人进行两阶段的基因组关联分析研究,以便寻找影响中国汉族慢性HBV感染疾病进展的单核苷酸多态性(SNPs)位点,并进行大量人群验证,探索相关基因或遗传变异位点影响中国汉族HBV感染向重症乙型肝炎、肝硬化或肝癌转变的机制。
方法：第一阶段采用以DNA pooling为基础的Affymetrix全基因组SNP6.0芯片扫描,筛选影响HBV感染不同疾病进展的遗传易感的SNPs。第二阶段采用TaqMan探针个体基因分型的方法进行人群验证。人群验证为以医院为基础的病例对照研究,验证人群为以湖北省汉族人为代表的中国南方人群(1729例进展性HBV感染者vs.628例无症状HBV感染者)和以山东省汉族人为代表的中国北方人群(215例进展性HBV感染者vs.226例无症状HBV感染者)。HBV感染者入选标准为HBsAg阳性同时HBeAb阳性持续6个月以上,且不合并HCV、HDV和HIV的感染。第一批验证人群为湖北地区2357例乙型肝炎患者,他们是2007年9月至2010年3月收集的来自于武汉同济医院、武汉协和医院和湖北省中医医院的住院病人。病例组为1729例进展性HBV感染者,包括重症乙型肝炎患者261例、乙肝相关性肝硬化患者731例和乙肝相关性原发性肝癌患者737例；对照组为628例无症状HBV感染者。同时我们还收集了210例以社区为基础的健康人作为健康对照,健康对照要求血清HBV标志物全为阴性。第二批验证人群为山东地区441例慢性乙型肝炎患者,包括215例进展性HBV感染者和226例无症状HBV感染者。这些HBV感染者是2009年6月至2010年3月收集的青岛传染病医院和滨州医学院附属医院的住院病人。同时我们还收集了210例以社区为基础的健康人作为健康对照。为了减少年龄因素对HBV进展的影响,我们限制无症状HBV感染者和健康对照年龄均不小于35岁。挑选SNP位点进行深入研究的标准为Silhouette width大于0.7,同时最小等位基因频率(minor allele frequency MAF)大于0.05。根据HapMap计划公布的中国北京人和日本东京人的基因型频率可知,选择的10个SNP位点均为标签SNP (tagSNP)。采用TaqMan探针法,运用7900HT序列检测系统进行人群验证,SDS2.3软件阅读384孔板,统计各个SNPs基因型分布,将各个基因多态性位点基因型数据导入SPSS17.0软件,运用校正性别、年龄和饮酒状况的logistic回归进行关联分析。
结果：以校正性别、年龄和饮酒状况的logistic回归计算不同的遗传模型(dominant、recessive、additive models)分析结果。10个SNPs在湖北省2357例HBV感染者中关联分析显示,位于ARHGAP24基因上的遗传变异位点rs346473和rs346482、位于GRIN2A基因上的基因多态性位点rs11866328、位于BNC2基因上的SNP rs7861010和位于ASCC3基因上的SNP rs 12206945与乙型肝炎的疾病进展强相关。遗传变异位点rs346473,TT基因型携带者增加HBV感染者发生疾病进展的易感性(OR 1.849,95%CI 1.498-2.283, P=1.1×10-8; additive model);遗传变异位点rs346482, TT基因型携带者增加HBV感染者发生疾病进展的易感性(OR 1.516,95% CI 1.233.1.865,P=7.7×10-5; additive model);GRIN2A基因上的基因多态性位点rs11866328,携带GG纯合子的乙型肝炎患者易发生疾病进展(OR,1.645;95%CI,1.340-2.020;P=1.96×10-6；additive model);位于BNC2基因上的SNP rs7861010,GG基因型携带者发生疾病进展的发病风险增加(OR,1.305;95%CI,1.059-1.607;P=1.2×10-2;additive model)；ASCC3基因上的SNP rs12206945,A等位基因(AA+AG)携带的乙肝患者较携带GG基因型的乙肝患者更易发生疾病进展(OR,1.742;95%CI,1.210-2.509;P=3.0×10-3；dominant model).我们发现位于ARHGAP24基因上的两个多态性位点(SNP rs346473和rs346482)存在强连锁不平衡(D’=0.99,r2=0.951),且与GG单倍型相比,单倍型TT携带者发展成进展性肝炎的几率增大1.980倍(95%CI,1.538-2.545;P=8.1×10-8).我们将在湖北省人群中与乙型肝炎进展强相关的三个多态性位点(位于GRIN2A基因上的基因多态性位点rs11866328、位于BNC2基因上的SNP rs7861010和位于ASCC3基因上的SNP rs12206945)在山东省人群中再次验证,校正年龄、性别和饮酒状况的logistic回归显示：位于GRIN2A基因上的基因多态性位点rs11866328的遗传变异仍然与疾病进展强相关(P=1.0×10-2；OR,1.727;95%CI,1.140-2.646 additive model),而SNP rs7861010和遗传变异位点rs12206945未见明显相关性。联合两次独立性研究,我们发现,在遗传变异位点rs11866328处,携带GG基因型的乙型肝炎患者对HBV感染的疾病进展高度易感(OR 1.684,95%CI 1.404-2.016,P=1.6×10-8).为了减少性别、年龄因素对HBV感染者发生疾病进展的影响,我们对该基因多态性位点进行了性别和年龄分层分析。性别分层分析可见,携带GG基因型的男性(OR,1.610;95%CI, 1.302-1.992；P=1.1×10-5;additive model).女性(OR,1.776；95%CI,1..253-2.525；P= 1.0x 10-3;additive model)患者发生HBV感染疾病进展的危险性均明显增高。35岁以上(包括35岁)年龄分层分析显示,年龄不小于35岁的携带GG纯合子的HBV感染者发生疾病进展的易感性增高(OR,1.634;95%CI,1.353-1.972;P=3.1×10-7;additive model)。运用HapMap报道的中国北京人和日本东京人基因型频率,我们发现遗传变异位点rs11866328在10kb区域内连锁不平衡(r2≥0.8)。
结论：基于DNA pooling的全基因组关联分析(genome wide association study GWAS)既可以降低全基因组关联分析花费,又被证明是一种有效的筛选候选基因及SNP的方法。它不需要预先根据一些尚未充分阐明的生物学基础来假设某些特定的基因或位点与某种疾病相关联,即不再需要在研究之前构建任何假设,是一种高效的筛选候选基因并进行关联分析的研究方法。我们对2798例中国汉族慢性HBV感染者两次独立性人群验证的结果显示位于GRIN2A基因上的SNP rs11866328可能是影响中国汉族HBV感染者疾病进展的易感遗传变异位点之一。
Background:Chronic hepatitis B virus (HBV) infection is a serious global public health problem. There are approximately 350 million people suffering from chronic HBV infection in the world and more than one million deaths annually attribute to HBV-related disease. The prevalence of chronic HBV infection is approximately 5% globally, but differs greatly from area to area. The prevalence of hepatitis B antigen (HBsAg) carriage is high in China (7.18%), that is there are 97 million HBsAg carriers in China and the number of chronic HBV carriers is 2 million in China. Most HBV carriers are considered to have been infected through maternal transmission in the neonatal period or infancy in high prevalent areas particularly in China. Persistent HBV infection has been considered a multifactorial and polygenic disequilibrium with viral, environmental, and host genetic components, including HBV genomic variability, age at infection, sex, chronic alcohol abuse, and co-infection with hepatitis C virus (HCV), hepatitis D virus (HDV) and human immunodeficiency virus (HIV). Though viral factors such as viral load, viral genotype and mutations in the viral genome itself are known risk factors for HBV infection, twin and ethical studies of HBV infection strongly support the role of genetic susceptibility to HBV persistence and the course of infection.
Aims:The objective of this study was to identify novel susceptibility loci to HBV progression in Han Chinese chronic HBV carriers, we conducted a two-stage genome-wide association study for HBV infection and progression in Han Chinese population.
Methods:Affymetrix Genome-Wide Human Mapping SNP6.0 Array with DNA pooling was used in the screening stage, and ten high-ranked single nucleotide polymorphisms (SNPs) were included in this panel. All HBV carriers were genotyped by using TaqMan method in the second stage. A total of 2798 unrelated Han Chinese HBV carriers were recruited from Hubei province (n=2357) in south of China (Wuhan Tongji hospital, Wuhan Union hospital and Traditional Chinese Medicine hospital of Hubei province) and Shandong province (n=441) in north of China (Qingdao hospital for Infection Disease and the Affiliated hospital of Binzhou Medical College) between September 2007 and March 2010 in our hospital-based case-control study. All HBV carriers were positive for both HBsAg and antibody to HBV core antigen of the immunoglobulin G type for at least 6 months. Among the 2798 HBV carriers,854 asymptomatic HBV carriers (AsC) (628 from Hubei province and 226 from Shandong province) and 1944 progressed HBV carriers (1729 from Hubei and 215 from Shandong) were included. Of the 1944 progressed HBV carriers,263 individuals were patients with fulminant hepatitis B (FHB),786 subjects with liver cirrhosis (LC) and 895 were patients with hepatocellular carcinoma (HCC). The 420 unrelated healthy Han Chinese were recruited as naive control (210 from Hubei and 210 from Shandong), who were HBV serum markers negative and no HB vaccination history. The AsC and naive controls were all over 35 years old to provide adequate time for symptoms to manifest. All subjects had no serologic evidence for co-infection with HCV, HDV and HIV. The criteria for selection of SNPs for further investigation was Silhouette width exceeding 0.7 and minor allele frequency (MAF)> 0.05. They were all tagSNPs using data from the International HapMap project (www. hapmap.org; CHB+JPT population). TaqMan 7900HT Sequence Detection System (Applied Biosystems, Foster City, Calif.) was used for genotyping according to the manufacture's instruction. Statistical analysis was performed using SPSS software (version 17.0; SPSS Inc, Chicago, IL).χ2 tests were used to examine the differences in clinical characteristics of participants. The adjusted Odds ratio (OR) and 95% confidence interval (95% CI) were tested by multivariable unconditional logistic regression under genetic models with adjustment for gender, age and alcohol consumption.
Results:In Hubei population, on the basis of multivariable logistic regression with adjustment for gender, age and alcohol consumption, variant rs346473 in the ARHGAP24 gene, SNP rs11866328 in the GRIN2A gene, SNP rs7861010 in the BNC2 gene and variant rs12206945 in the ASCC3 gene were found having increased susceptibility with disease progression of HBV infection in south of China (1729 progressed HBV carriers vs 628 AsC). At variant rs346473 in the ARHGAP24 gene, TT genotype carriers were found having significant associations with disease progression of HBV infection (OR 1.849,95% CI 1.498-2.283, P=1.1 x 10-8; additive model). At variant rs346482 in the ARHGAP24 gene, TT genotype carriers were found having significant associations with disease progression of HBV infection (OR 1.516,95% CI 1.233-1.865, P=7.7×10-5; additive model). SNP rs11866328 in the GRIN2A gene, subjects bearing GG homozygote were susceptive to HBV progression compared with GT heterozygote carriers (OR,1.645; 95% CI, 1.340-2.020; P=1.96×10-6; additive model). HBV patients carrying GG genotype at SNP rs7861010 in the BNC2 gene displayed a strong correlation with disease progression of HBV infection (OR,1.305; 95% CI,1.059-1.607; P=1.2×10-2; additive model). Variant rs12206945 in the ASCC3 gene, A allele carriers performed an elevated effect for disease progression of HBV infection (OR,1.742; 95% CI,1.210-2.509; P=3.0×10-3; dominant model). Using genotypes of 420 naive controls, we defined these two SNPs (rs346482 and rs346473) in strong linkage disequilibrium with D'=0.99 and r2= 0.951 generated by software HaploView 4.1.When haplotype CC was chosen as a baseline, haplotype TT displayed a significant increased risk for developing into progressed hepatitis (OR,1.980; 95% CI,1.538-2.545; P= 8.1×10-8). To validate the results of the association test, we carried out a replication using population recruited from Shandong province (215 progressed HBV carriers vs.226 AsC) in north of China. The three noticeably correlated SNPs (rs11866328, rs7861010 and rs12206945) were genotyped using the same TaqMan assay. SNP rs11866328 in the tenth intron of GRIN2A gene was confirmed to have an elevated effect on diverse outcomes of HBV infection (OR 1.727; 95% CI,1.140-2.646; P= 1.0×10-2; additive model). Combining all population, subjects bearing GG homozygote of rs11866328 had an increased susceptibility to HBV progression (OR 1.684,95%CI 1.404-2.016, P=1.6×10-8). In stratification analysis of SNP rs11866328 in all studied HBV carriers, the results remained significant in male patients (OR,1.610; 95% CI,1.302-1.992; P= 1.1×10-5; additive model), female patients (OR,1.776; 95% CI,1.253-2.525; P= 1.0×10-3; additive model) and patients 35 years or older (OR,1.634; 95% CI,1.353-1.972; P= 3.1×10-7; additive model). Using data from the International HapMap project (www.hapmap.org; CHB+JPT population) and HaploView (version 4.1) software, we found SNP rs11866328 having linkage disequilibrium (LD) within a 10kb region with r2≥0.8
Conclusions Performing Genome-wide association (GWA) studies on pools of DNA samples has been shown to be an efficient method to select candidate susceptibility loci for follow-up by individual genotyping. SNP rs11866328 in the GRIN2A gene could be a part of the genetic variants underlying the susceptibility of individuals to disease progression of chronic HBV infection.
引文
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