ORMDL3基因rs7216389位点多态性与哮喘相关性研究
摘要
目的：检测ORMDL3基因rs7216389位点多态性在中国江西地区汉族人群中的分布频率,探讨rs7216389位点多态性与支气管哮喘的关系。
方法：试验分二组：(1)哮喘组：哮喘病例患者80例,其中男性43例,女性37例；(2)对照组：同期的健康体检患者84例作为对照组,其中男性46例,女性38例。应用DNA提取试剂盒提取基因组DNA。采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)检测ORMDL3的基因型。将我国江西地区汉族人群与其他不同种族人群间的ORMDL3基因rs7216389位点等位基因频率进行了比较；还比较了两组之间各基因型及等位基因的分布频率。
结果：(1)哮喘组和对照组ORMDL3基因rs7216389位点3种基因型(TT、TC、CC)分布频数分别为30、36、14和18、40、26;采用χ2检验对不同基因型的分布观察值和期望值进行比较(哮喘组χ2=0.108；对照组χ2=0.097,P均>0.05),差异均无统计学意义；(2)健康对照组ORMDL3基因rs7216389位点等位基因频率在不同种族人群中比较差异有显著性差异(χ2=19.31,P<0.05);(3)在哮喘组ORMDL3基因rs7216389位点等位基因T与C的分布频率分别为60.0%和40.0%,在对照组为45.2%和54.8%,两组T与C等位基因频率差异比较亦有统计学意义(χ2=7.16,P<0.05);哮喘组中ORMDL3基因rs7216389位点3种基因型(TT、TC、CC)分布频率分别为37.5%、45.0%、17.5%；健康对照组分布频率分别为21.4%、47.6%、31.0%,3种基因型在两组分布频率差异比较有统计学意义(χ2=6.72,P<0.05)；(4)对ORMDL3基因rs7216389位点基因多态性与哮喘相关性进行单变量Logistic回归分析,结果表明相对CC基因型而言,TT+TC与TT基因型均能显著增加哮喘发生的概率[优势比(OR)值及95%可信区间(CI)分别为2.113(1.009-4.426)、3.095(1.292-7.417),P均<0.05]。
结论：(1)ORMDL3基因rs7216389位点多态性广泛存在于不同地域及种群中,包括江西地区汉族人群,且分布频率差异有显著性。(2)ORMDL3基因rs7216389位点多态性与江西地区汉族人群哮喘易感性相关,其T等位基因是哮喘病的易感基因。
Objective:To investigate the frequency and association of the allele polymorphism of ORMDL3 at rs7216389 locus in Han Chinese of Jiangxi.
Methods:The experiment is divided two groups:(1) The asthmatic group included 80 patients with asthma (43males, and 37 females); (2) The normal control group included 84 healthy individuals (46males, and 38 females). Using DNA extraction reagent box extract genome team DNA. rs7216389 locus allele in ORMDL3 gene was analyzed by Polymerase chain reaction-restriction Fragment length Polymorphism (PCR-RFLP) in both groups. Distribution of rs7216389 locus genotypes and frequency of rs7216389 locus allele were compared between the two groups. The frequency of rs7216389 locus allele in Han Chinese of Jiangxi was also compared with that in Puerto Ricans, Mexicans, German, British.
Results:(1) The frequencies of genotype of TT, TC and CC were respectively 30,36 and 14 in asthmatic subjects, which were in good agreement with Hardy-Weinberg equilibrium (χ2=0.108, P>0.05). The frequencies of genotype of TT, TC and CC were respectively 18,40 and 26 in normal control, which were in agreement with Hardy-Weinberg equilibrium (χ2=0.097, P>0.05). (2) Significant difference was found in the allele (T, C) frequency among populations in different ethnic populations (χ2=19.31, P<0.05). (3) In the asthmatic patients the frequencies of T and C of rs7216389 locus allele in ORMDL3 gene were 60.0% and 40.0%, respectively, and the genotype frequencies of (TT, TC, CC) were 37.5%、45.0% and 17.5%, respectively. In normal control the frequencies of locus allele were 45.2% and 54.8%, respectively, and the genotype frequencies of (TT, TC, CC) were 21.4%、47.6% and 31.0%, respectively. There was significant difference was observed between the asthmatics and normal controls (χ2 value were 6.72、7.16, respectively, all P<0.05). (4) The presence of TT+TC and TT genotypes can significantly increase the probability of asthma. The odds ratio (OR) of TT+TC and TT were 2.113 (1.009～4.426)、3.095 (1.292～7.417), respectively. When compared with CC genotype, all P<0.05.
Conclusions:(1) The rs7216389 locus genetic polymorphism was found to exist widely in different ethnic populations, including the Han Chinese of Jiangxi, and the significance difference in the distribution frequency was observed. (2) The rs7216389 locus genetic polymorphism is associated with susceptibility of asthma in Han Chinese of Jiangxi, the T allele in ORMDL3 gene was found to be a susceptibility gene in asthma.
方法：试验分二组：(1)哮喘组：哮喘病例患者80例,其中男性43例,女性37例；(2)对照组：同期的健康体检患者84例作为对照组,其中男性46例,女性38例。应用DNA提取试剂盒提取基因组DNA。采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)检测ORMDL3的基因型。将我国江西地区汉族人群与其他不同种族人群间的ORMDL3基因rs7216389位点等位基因频率进行了比较；还比较了两组之间各基因型及等位基因的分布频率。
结果：(1)哮喘组和对照组ORMDL3基因rs7216389位点3种基因型(TT、TC、CC)分布频数分别为30、36、14和18、40、26;采用χ2检验对不同基因型的分布观察值和期望值进行比较(哮喘组χ2=0.108；对照组χ2=0.097,P均>0.05),差异均无统计学意义；(2)健康对照组ORMDL3基因rs7216389位点等位基因频率在不同种族人群中比较差异有显著性差异(χ2=19.31,P<0.05);(3)在哮喘组ORMDL3基因rs7216389位点等位基因T与C的分布频率分别为60.0%和40.0%,在对照组为45.2%和54.8%,两组T与C等位基因频率差异比较亦有统计学意义(χ2=7.16,P<0.05);哮喘组中ORMDL3基因rs7216389位点3种基因型(TT、TC、CC)分布频率分别为37.5%、45.0%、17.5%；健康对照组分布频率分别为21.4%、47.6%、31.0%,3种基因型在两组分布频率差异比较有统计学意义(χ2=6.72,P<0.05)；(4)对ORMDL3基因rs7216389位点基因多态性与哮喘相关性进行单变量Logistic回归分析,结果表明相对CC基因型而言,TT+TC与TT基因型均能显著增加哮喘发生的概率[优势比(OR)值及95%可信区间(CI)分别为2.113(1.009-4.426)、3.095(1.292-7.417),P均<0.05]。
结论：(1)ORMDL3基因rs7216389位点多态性广泛存在于不同地域及种群中,包括江西地区汉族人群,且分布频率差异有显著性。(2)ORMDL3基因rs7216389位点多态性与江西地区汉族人群哮喘易感性相关,其T等位基因是哮喘病的易感基因。
Objective:To investigate the frequency and association of the allele polymorphism of ORMDL3 at rs7216389 locus in Han Chinese of Jiangxi.
Methods:The experiment is divided two groups:(1) The asthmatic group included 80 patients with asthma (43males, and 37 females); (2) The normal control group included 84 healthy individuals (46males, and 38 females). Using DNA extraction reagent box extract genome team DNA. rs7216389 locus allele in ORMDL3 gene was analyzed by Polymerase chain reaction-restriction Fragment length Polymorphism (PCR-RFLP) in both groups. Distribution of rs7216389 locus genotypes and frequency of rs7216389 locus allele were compared between the two groups. The frequency of rs7216389 locus allele in Han Chinese of Jiangxi was also compared with that in Puerto Ricans, Mexicans, German, British.
Results:(1) The frequencies of genotype of TT, TC and CC were respectively 30,36 and 14 in asthmatic subjects, which were in good agreement with Hardy-Weinberg equilibrium (χ2=0.108, P>0.05). The frequencies of genotype of TT, TC and CC were respectively 18,40 and 26 in normal control, which were in agreement with Hardy-Weinberg equilibrium (χ2=0.097, P>0.05). (2) Significant difference was found in the allele (T, C) frequency among populations in different ethnic populations (χ2=19.31, P<0.05). (3) In the asthmatic patients the frequencies of T and C of rs7216389 locus allele in ORMDL3 gene were 60.0% and 40.0%, respectively, and the genotype frequencies of (TT, TC, CC) were 37.5%、45.0% and 17.5%, respectively. In normal control the frequencies of locus allele were 45.2% and 54.8%, respectively, and the genotype frequencies of (TT, TC, CC) were 21.4%、47.6% and 31.0%, respectively. There was significant difference was observed between the asthmatics and normal controls (χ2 value were 6.72、7.16, respectively, all P<0.05). (4) The presence of TT+TC and TT genotypes can significantly increase the probability of asthma. The odds ratio (OR) of TT+TC and TT were 2.113 (1.009～4.426)、3.095 (1.292～7.417), respectively. When compared with CC genotype, all P<0.05.
Conclusions:(1) The rs7216389 locus genetic polymorphism was found to exist widely in different ethnic populations, including the Han Chinese of Jiangxi, and the significance difference in the distribution frequency was observed. (2) The rs7216389 locus genetic polymorphism is associated with susceptibility of asthma in Han Chinese of Jiangxi, the T allele in ORMDL3 gene was found to be a susceptibility gene in asthma.
引文
[1]Masoli M, Fabian D, Holt S, et al. The global burden of asthma:xecutive summary of the GINA Dissemination Committee report.Allergy,2004,59(5):469-478.
[2]Tattersfield AE, Knox AJ, Britton JR, et al. Asthma.Lancet,2002,360(9342):1313-1322.
[3]Los H, Koppelman GH, Postma DS.The importance of genetic influences in asthma. Eur ResPir J,1999,14(5):1210-1227.
[4]Duffy DL, Martin NG, Battistutta D, et al. Geneties of asthma and hay fever in Australian twins. Am Rev Respir Dis,1990,142(6):1351-1358.
[5]Nieminen MM, Kaprio J, Koskenvuo M. A Population-based study of bronchial asthma in adult twin pairs. Chest,1991,100(1):70-75.
[6]Hopp RJ, Bewtra AK, Watt GD, et al. Genetic analysis of allergic disease in twins. Allergy Clin Immunol,1984,73(2):265-270.
[7]Weiss ST, Raby BA, Rogers A, et al. Asthma genetics and genomics 2009. Curr Opin Genet Dev,2009,19(3):279-282.
[8]Holloway JW, Koppelman GH.17q21 variants and asthma-questions and answers. N Engl J Med,2008,359(6):2043-2045.
[9]Dominique J, Verlaan, Soizik Berlivet S, et al. Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Am J Hum Genet,2009,85(3):377-393.
[10]Hjelmqvist L, Tuson M, Marfany G. et al. ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol,2002,3(6):research 0027.1-research0027.16.
[11]Tavendale R, Macgregor DF, Mukhopadhyay S, et al. A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. Allergy Clin Immunol,2008,121(4):860-863.
[12]Gerard CR, Cesar Fandos, Fanny RM, et al. et al. The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum Mol Genet,2010,19(1):111-121.
[13]Galanter J, Choudhry S, Eng C, et al. ORMDL3 gene is associated with asthma in three ethnically diverse populations. Am J Respir Crit Care Med,2008,177(11):1194-1200.
[14]Mahn K, Hirst SJ, Ying S, et al. Ca2+ homeostasis and structural and functional remodelling of airway smooth muscle in asthma. Thorax,2010,65(5):547-552.
[15]Noguchi E, Yokouchi Y, Zhang J, et al. Positional identification of an asthma susceptibility gene on chromosome 5q33. Am J Respir Crit Care Med,2005,172(18):183-188.
[16]Allen M, Heinzmann A, Ponting CP, et al. Positional cloning of a novel gene influencing asthma from chromosome 2p14. Nat Genet,2003,35(12):258-263.
[17]Laitinen T, Polvi B, Rydman P, et al. Characterization of a common susceptibility locus for asthma-related traits. Science,2004,304(16):300-304.
[18]Nicolae D, Cox NJ, Lester LA, et al. Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet,2005, 76(2):349-357.
[19]Van Eerdewegh P, Little RD, Dupuis D, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature,2002,418(24):426-430.
[20]Zhang Y, Leaves NL, Anderson GG, et al. Positional cloning of a quantitative trait locus on chromosome 13q14 that influence immunoglobulin E levels and asthma. Nat Genet,2003, 34(15):181-186.
[21]Hu N, Wang C, Tang ZZ, et al. Genome-wide association study in esophageal cancer using GeneChip mapping 10k array. Cancer Res,2005,65(9):2541-2546.
[22]Ozaki K, Tanaka T. Genome-wide association study to identify SNPs conferring risk of myocardial infarction and their functional analyses. Cell Mol Life Sci,2005,62(19): 1804-1813.
[23]Moffatt MF, Kabesch M, Liang L, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature,2007,448(7152):470-473.
[24]Leung TF, Sy HY, Ng MCY, et al. Asthma and atopy are associated with chromosome 17q21 markers in Chinese children. Allergy,2009,64(4):621-628.
[25]中华医学会呼吸病学分会哮喘学组.支气管哮喘防治指南.中华结核和呼吸杂志,2008,31(3)：177-185.
[26]Campbell H, Rudan I. Interpretation of genetic association studies in complex disease. Pharmacogenomics,2002,2(3):349-360.
[27]Burchard EG, Ziv E, Coyle N, et al. The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med,2003,348(12):1170-1175.
[28]Bouzigon E, Corda E, Aschard H, et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med,2008,359(7):1985-1994.
[29]Halapi E, Gudbjartsson DF, Jonsdottir GM, et al. A sequence variant on 17q21 is associated with age at onset and severity of asthma. Eur J Hum Genet,2010,18(8):902-908.
[30]Bisgaard H, Bφnnelykke K, Sleiman PM, et al. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am J Respir Crit Care Med,2009,179(14):179-185.
[31]Hirota T, Harada M, Sakashita M, et al. Genetic polymorphism regulating ORM1-like 3 (Saccharomy cescerevisiae) expression is associated with childhood atopic asthma in a Japanese population. Allergy Clin Immunol,2008,121(4):769-770.
[32]Wu H, Romieu I, Sienra-Monge JJ, et al. Genetic variation in ORM1-Like3(ORMDL3) and gasdermin-like(GSDML) and childhood asthma. Allergy,2009,64(4):629-635.
[1]Weiss ST et al. Asthma genetics and genomics 2009. Curr Opin Genet Dev,2009,19: 279-282
[2]Holloway JW et al.17q21 variants and asthma-questions and answers. NEngl JMed,2008, 359:2043-2045
[3]Moffatt MF et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature,2007,448:470-473
[4]Tavendale R et al. A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. J Allergy Clin Immunol,2008,121: 860-863
[5]Dominique J et al. Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Am J Hum Genet,2009,85: 377-393
[6]Hjelmqvist L et al. ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol,2002,3:research0027.1-research0027.16
[7]Gerard CR et al. The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum Mol Genet,2010,19:111-121
[8]Galanter J et al. ORMDL3 gene is associated with asthma in three ethnically diverse populations. Am JRespir Crit Care Med,2008,177:1194-1200
[9]Mahn K et al. Ca2+ homeostasis and structural and functional remodelling of airway smooth muscle in asthma. Thorax,2010,65:547-552
[10]Bouzigon E et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med,2008,359:1985-1994
[11]Halapi E et al. A sequence variant on 17q21 is associated with age at onset and severity of asthma. Eur J Hum Genet,2010, doi:10.1038/ejhg.2010.38
[12]Bisgaard H et al. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am J Respir Crit Care Med,2009,179: 179-185
[13]Hirota T et al. Genetic polymorphism regulating ORM1-like 3 (Saccharomyces cerevisiae) expression is associated with childhood atopic asthma in a Japanese population. J Allergy Clin Immunol,2008,121:769-770
[14]Wu H et al. Genetic variation in ORM1-Like3(ORMDL3) and gasdermin-like(GSDML) and childhood asthma. Allergy,2009,64:629-635
[15]Burchard EG et al. The importance of race and ethnic background in biomedical research and clinical practice. NEngl J Med,2003,348:1170-1175
[16]Duan S W et al. Genetic Architecture of Transcript-Level Variation in Humans. Am J Hum Genet,2008,82:1101-1113
[17]Salam MT et al. Microsomal epoxide hydrolase, glutathione S-transferase PI, traffic and childhood asthma. Thorax,2007,62:1050-1057
[18]Leung TF et al. Asthma and atopy are associated with chromosome 17q21 markers in Chinese children. Allergy,2009,64:621-628
[19]Weiland SK et al. Phase II of the International Study of Asthma and Allergies in Childhood (ISAAC II):rationale and methods. Eur Respir J,2004,24:406-412
[2]Tattersfield AE, Knox AJ, Britton JR, et al. Asthma.Lancet,2002,360(9342):1313-1322.
[3]Los H, Koppelman GH, Postma DS.The importance of genetic influences in asthma. Eur ResPir J,1999,14(5):1210-1227.
[4]Duffy DL, Martin NG, Battistutta D, et al. Geneties of asthma and hay fever in Australian twins. Am Rev Respir Dis,1990,142(6):1351-1358.
[5]Nieminen MM, Kaprio J, Koskenvuo M. A Population-based study of bronchial asthma in adult twin pairs. Chest,1991,100(1):70-75.
[6]Hopp RJ, Bewtra AK, Watt GD, et al. Genetic analysis of allergic disease in twins. Allergy Clin Immunol,1984,73(2):265-270.
[7]Weiss ST, Raby BA, Rogers A, et al. Asthma genetics and genomics 2009. Curr Opin Genet Dev,2009,19(3):279-282.
[8]Holloway JW, Koppelman GH.17q21 variants and asthma-questions and answers. N Engl J Med,2008,359(6):2043-2045.
[9]Dominique J, Verlaan, Soizik Berlivet S, et al. Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Am J Hum Genet,2009,85(3):377-393.
[10]Hjelmqvist L, Tuson M, Marfany G. et al. ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol,2002,3(6):research 0027.1-research0027.16.
[11]Tavendale R, Macgregor DF, Mukhopadhyay S, et al. A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. Allergy Clin Immunol,2008,121(4):860-863.
[12]Gerard CR, Cesar Fandos, Fanny RM, et al. et al. The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum Mol Genet,2010,19(1):111-121.
[13]Galanter J, Choudhry S, Eng C, et al. ORMDL3 gene is associated with asthma in three ethnically diverse populations. Am J Respir Crit Care Med,2008,177(11):1194-1200.
[14]Mahn K, Hirst SJ, Ying S, et al. Ca2+ homeostasis and structural and functional remodelling of airway smooth muscle in asthma. Thorax,2010,65(5):547-552.
[15]Noguchi E, Yokouchi Y, Zhang J, et al. Positional identification of an asthma susceptibility gene on chromosome 5q33. Am J Respir Crit Care Med,2005,172(18):183-188.
[16]Allen M, Heinzmann A, Ponting CP, et al. Positional cloning of a novel gene influencing asthma from chromosome 2p14. Nat Genet,2003,35(12):258-263.
[17]Laitinen T, Polvi B, Rydman P, et al. Characterization of a common susceptibility locus for asthma-related traits. Science,2004,304(16):300-304.
[18]Nicolae D, Cox NJ, Lester LA, et al. Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet,2005, 76(2):349-357.
[19]Van Eerdewegh P, Little RD, Dupuis D, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature,2002,418(24):426-430.
[20]Zhang Y, Leaves NL, Anderson GG, et al. Positional cloning of a quantitative trait locus on chromosome 13q14 that influence immunoglobulin E levels and asthma. Nat Genet,2003, 34(15):181-186.
[21]Hu N, Wang C, Tang ZZ, et al. Genome-wide association study in esophageal cancer using GeneChip mapping 10k array. Cancer Res,2005,65(9):2541-2546.
[22]Ozaki K, Tanaka T. Genome-wide association study to identify SNPs conferring risk of myocardial infarction and their functional analyses. Cell Mol Life Sci,2005,62(19): 1804-1813.
[23]Moffatt MF, Kabesch M, Liang L, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature,2007,448(7152):470-473.
[24]Leung TF, Sy HY, Ng MCY, et al. Asthma and atopy are associated with chromosome 17q21 markers in Chinese children. Allergy,2009,64(4):621-628.
[25]中华医学会呼吸病学分会哮喘学组.支气管哮喘防治指南.中华结核和呼吸杂志,2008,31(3)：177-185.
[26]Campbell H, Rudan I. Interpretation of genetic association studies in complex disease. Pharmacogenomics,2002,2(3):349-360.
[27]Burchard EG, Ziv E, Coyle N, et al. The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med,2003,348(12):1170-1175.
[28]Bouzigon E, Corda E, Aschard H, et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med,2008,359(7):1985-1994.
[29]Halapi E, Gudbjartsson DF, Jonsdottir GM, et al. A sequence variant on 17q21 is associated with age at onset and severity of asthma. Eur J Hum Genet,2010,18(8):902-908.
[30]Bisgaard H, Bφnnelykke K, Sleiman PM, et al. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am J Respir Crit Care Med,2009,179(14):179-185.
[31]Hirota T, Harada M, Sakashita M, et al. Genetic polymorphism regulating ORM1-like 3 (Saccharomy cescerevisiae) expression is associated with childhood atopic asthma in a Japanese population. Allergy Clin Immunol,2008,121(4):769-770.
[32]Wu H, Romieu I, Sienra-Monge JJ, et al. Genetic variation in ORM1-Like3(ORMDL3) and gasdermin-like(GSDML) and childhood asthma. Allergy,2009,64(4):629-635.
[1]Weiss ST et al. Asthma genetics and genomics 2009. Curr Opin Genet Dev,2009,19: 279-282
[2]Holloway JW et al.17q21 variants and asthma-questions and answers. NEngl JMed,2008, 359:2043-2045
[3]Moffatt MF et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature,2007,448:470-473
[4]Tavendale R et al. A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. J Allergy Clin Immunol,2008,121: 860-863
[5]Dominique J et al. Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Am J Hum Genet,2009,85: 377-393
[6]Hjelmqvist L et al. ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol,2002,3:research0027.1-research0027.16
[7]Gerard CR et al. The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum Mol Genet,2010,19:111-121
[8]Galanter J et al. ORMDL3 gene is associated with asthma in three ethnically diverse populations. Am JRespir Crit Care Med,2008,177:1194-1200
[9]Mahn K et al. Ca2+ homeostasis and structural and functional remodelling of airway smooth muscle in asthma. Thorax,2010,65:547-552
[10]Bouzigon E et al. Effect of 17q21 variants and smoking exposure in early-onset asthma. N Engl J Med,2008,359:1985-1994
[11]Halapi E et al. A sequence variant on 17q21 is associated with age at onset and severity of asthma. Eur J Hum Genet,2010, doi:10.1038/ejhg.2010.38
[12]Bisgaard H et al. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am J Respir Crit Care Med,2009,179: 179-185
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