全基因组关联分析搜寻中国人群白癜风免疫相关基因
摘要
研究背景白癜风是一种皮肤和毛发黑素细胞选择性破坏导致的色素脱失性皮肤病,为最常见的色素脱失性疾病,该病患病率约为0.1-2.9%。白癜风发病机制不明,目前存在多种发病机制假说。遗传与环境因素相互作用导致自身免疫性黑素细胞自毁是其主要发病假说。白癜风发病受遗传因素影响,通过连锁分析和候选基因关联已发现大量白癜风易感基因。但这两种遗传研究方法存在一定的局限性。如全基因组连锁研究应用的微卫星标记信息量有限,所定位区域往往较大,很难从其中找出真正的易感基因。同时,全基因组连锁研究主要是针对家系研究,因而所发现的疾病易感位点是否能够代表散发病例尚不清楚。对于候选基因研究,其选取候选基因主要根据研究者们认为最有可能导致疾病发生的易感基因,故不可避免的存在着局限性,不可能全面搜寻到白癜风的易感基因。随着人类基因组计划(HGP)和人类基因组单体型图计划(HapMap)的相继完成以及高通量基因分型技术的飞速发展和分型费用的降低,使得在大规模人群中开展全基因组关联研究(genome-wide association study, GWAS)成为可能。这种研究方法对全基因组范围内的SNP进行总体的分析,能够更有效的发现和疾病有关联的基因。近年来全基因组关联分析为研究复杂疾病易感基因的主要方法。中国汉族人和高加索人白癜风全基因组关联分析研究共发现了9个白癜风易感基因/位点:TYR, C1QTNF6, RERE, LPP, UBASH3A, GZMB, PTPN22和6q27, 10p15.1。绝大多数基因/位点是免疫相关基因,其中7个位点与其他自身免疫性疾病全基因组关联分析报道的位点重合。本研究基于本课题组一期白癜风全基因组关联分析,增加全基因组关联分析初筛样本量,使用候选基因选点方法进一步搜寻中国汉族人白癜风易感基因。
目的利用GWAS研究方法构建中国人群白癜风病例-对照的全基因组关联分析数据库;用候选基因法筛选与白癜风可能关联的变异位点,并在多个人群中进行验证,鉴定白癜风易感基因/位点并探讨白癜风与其他自身免疫性疾病的关系。
方法
(1)在中国汉族人群中,首先利用Illumina Human 610-Quad全基因组SNP分型芯片(50,000 SNPs)对1,149白癜风病例和1,701对照进行SNP分型。进行数据质控,去除不合格样本。
(2)验证阶段:①验证第一阶段:经过严格的数据质控和统计分析,从全基因组关联分析所发表的所有自身免疫性疾病中(包括白癜风)查找被验证的最显著的SNP,根据人群对应的HapMap参照人群的多态结构,找到最显著SNP所在的连锁不平衡区域,然后在连锁不平衡区域中找到我们白癜风初筛结果中最显著的SNP进行验证,共选择45个SNPs,使用Sequenom平台在一个独立的中国人群中进行验证[2,827个病例和3,876个对照];②验证第二阶段:从验证第一阶段中选取了12个SNPs,进一步加大样本量使用Sequenom进行验证(2,913个病例和6,448个对照)。之后,将上述附加的对照和之前已分型的对照数据及病例进行合并分析,发现了3个SNPs达到全基因组显著关联性水平,1个SNP达到提示性的全基因组关联水平。③验证第三阶段:将验证第二阶段的12个SNP在新疆人群中验证(713病例-758对照)。
(3)对17例患者的皮损和非皮损部位取皮,进行表达谱芯片分析。
(4)利用公共数据库进行表达量的分析,寻找区域内与SNP最可能相关的基因。
结果(1)经过多种严格的数据质控后,本课题组构建了一个包括1,117患者/1,701对照493,909个常染色体SNPs的白癜风全基因组关联分析数据库。该数据库无明显的人群分层,并且病例-对照样本匹配良好。(2)通过在中国汉族人群和新疆维吾尔人群的验证,本研究发现12q13为新的白癜风易感位点(汉族:rs10876864, P=8.07×10~(-12);新疆维吾尔人群:rs10876864, P=1.01×10~(-2))。该区域也是1型糖尿病、斑秃等自身免疫性疾病的易感位点,可能包含了10个已知基因,eQTL分析表明RPS26最可能为相关基因,此基因与T细胞代谢相关。表达谱芯片结果提示此区域SILV, CDK2,SUOX,IKZF4, RPS26为相关基因。(3) 10q23区域汉族人群白癜风患者全基因组关联分析提示存在强关联信号(rs638893, P=2.47×10~(-9)),此区域包含基因为PHLDB1, TREH,DDX6,此区域曾被报道与SLE发病相关。表达谱芯片分析结果提示PHLDB1为白癜风相关基因。(4) 11q23区域为新的白癜风易感区域(rs1417210,P=1.83×10~(-8)),包含基因为SLC29A3,CDH23。(6)对已往报道的欧洲人白癜风全基因组关联分析结果进行验证,发现3q28在中国人群中为提示相关位点(rs9851967,P=8.57×10~(-8))。
结论本研究在中国人群中进行了一项大样本量的GWAS,通过在多个独立中国人群中进行验证,报道了3个新白癜风易感位点(12q13,11q23和10q23),同时讨论了白癜风与其他自身免疫性疾病之间的关系。强调了免疫因素在白癜风发病过程中的重要性,为揭示白癜风发病机制提供了新的线索。
Background Generalized vitiligo is an acquired, non-contagious disorder in which progressive, patchy loss of pigmentation of skin and often overlying hair, and mucous membranes, results from loss of melanocytes from the involved areas. It is one of the most common pigmentary disorders affecting about 0.09%-2.7% of Chinese Han population. Although many different etiologic hypotheses have been suggest for vitiligo, the most compelling of which involves a combination of environment and genetic factors interacting to contribute to autoimmune melanocyte destruction. Vitiligo is strongly influenced by genetic factors. In the past years, researches mainly used linkage studies, candidate genes studies or other research strategies to search vitiligo susceptibility genes and some progress was made. However, there are limitations in these studies. For example, there are few microsatellite markers in linkage studies and the targeted region is large, which is why it is often difficult to identify the real susceptibility genes. Meanwhile, the genome linkage method is a family-based approach, which identified the diseases susceptibility locus. Whether it can represent the sporadic cases is unknown. Similar to candidate genes studies, researchers often selected candidate genes based on available data which suggest an implication of this gene in the disease. So, there are some limitations in candidate genes study, which could not uncover susceptibility genes of vitiligo with a genome wide coverage. In recent years, completion of the Human Genome Project (HGP) and the Human Genome Haplotype Mapping Project (HapMap) facilitated the rapid development of high-throughput gene genotyping technologies and the reduction of genotyping costs, which made genome-wide association study become possible in large-scale approaches. The method of genome wide SNP analysis is highly effective to uncover disease susceptibility genes. GWAS is one of the most effective ways currently described to identify susceptibility genes of complex diseases. The success of a large number of GWAS shows a strong efficiency to uncover susceptibility genes of complex diseases, and GWAS of vitiligo in Chinese Han and Caucasian have identified a spectrum of new associated genes/loci: TYR, C1QTNF6, RERE, LPP, UBASH3A, GZMB, PTPN22 and 6q27, 10p15.1. Most of these loci were immune related loci, seven of them have been reported associate with other autoimmune diseases.
Object To explore the susceptibility variants for vitiligo, we carried out a candidate gene study in Chinese populations.
Methods (1) We conducted a genome-wide association study of generalized vitiligo in Chinese Han population by genotyping 1,149 cases and 1,701 controls using Illumina Human 610-Quad BeadChips. We took the most promising SNPs for replication in Chinese Han (5,740 cases and 10,324 controls) and Chinese Uygur (713 cases and 758 controls) using Sequenom MassArray.
(2) Replication stage:①Replication in the first stage: After quality control and statistical analysis, we selected 67 SNPs for replication in two independent samples of Chinese Han (2,827 cases and 3,876 controls) by using the Sequenom(?) MassARRAY research platform.②Replication in the second stage: we further genotyped the most promising 12 (of the 45 selected) SNPs that showed supportive association evidence in the initial validation study in additional 2,913cases and 6,448 controls using Sequenom(?) MassARRAY research platform. Then, for statistical analysis we combined GWAS, replication of the first stage and replication of the second stage together and found 3 SNPs reached genome-wide significance. In addition, one promising SNP showed a genome-wide association barely below significance.③Replication in the third stage: 12 most significant SNPs of the 45 SNPs were further genotyped in Chinese Uygur (713 cases and 758 controls) by using TaqMan assays.
(3) RNA from 17 pairs of full-thickness vitiligo skin biopsies were used in DNA microarray analysis.
(4) We also analysis the relationship between SNPs and genes in the loci.
Results (1) After stringent quality control, 493,909 SNPs were analyzed in 1,117 cases and 1,701 controls by using Cochran-Armitage trend test to assess the genotype-phenotype association. (2) We identified one novel locus at 12q13 associated with vitiligo both in Chinese Han (rs10876864, P=8.07×10~(-12)) and Chinese Uygur (rs10876864, P= P=1.01×10~(-2)), which been reported to confer risk to several autoimmune disease, such as type 1 diabetes (T1D) and alopecia areata (AA). (3) We also identified one association evidence at 10q23 in Chinese Han (rs638893, P=2.47×10~(-9)), this region have been reported to be associate with SLE. There are three genes in this region: PHLDB1, TREH,DDX6, PHLDB1 showed the differential expression between vitiligo and normal skin. (4) there are two genes in the region of 11q23: SLC29A3,CDH23 the most significant SNP was rs1417210 (P=1.83×10~(-8)),we can not find the association between SNP rs1417210 and any gene of this region. (5) We also performed a repetation of previous reported vitiligo associated genes. Only one locus at 3q28 provided suggestive evidence (rs9851967, P=8.57×10~(-8))
Conclusions We have performed a large scale GWAS for vitiligo in Chinese population, with replication in three independent Chinese population groups. Our study identifies three novel susceptibility loci at 12q13, 10q23, 11q23. In particular, it highlighted potential pathogenic overlap between vitiligo and other autoimmune diseases.
目的利用GWAS研究方法构建中国人群白癜风病例-对照的全基因组关联分析数据库;用候选基因法筛选与白癜风可能关联的变异位点,并在多个人群中进行验证,鉴定白癜风易感基因/位点并探讨白癜风与其他自身免疫性疾病的关系。
方法
(1)在中国汉族人群中,首先利用Illumina Human 610-Quad全基因组SNP分型芯片(50,000 SNPs)对1,149白癜风病例和1,701对照进行SNP分型。进行数据质控,去除不合格样本。
(2)验证阶段:①验证第一阶段:经过严格的数据质控和统计分析,从全基因组关联分析所发表的所有自身免疫性疾病中(包括白癜风)查找被验证的最显著的SNP,根据人群对应的HapMap参照人群的多态结构,找到最显著SNP所在的连锁不平衡区域,然后在连锁不平衡区域中找到我们白癜风初筛结果中最显著的SNP进行验证,共选择45个SNPs,使用Sequenom平台在一个独立的中国人群中进行验证[2,827个病例和3,876个对照];②验证第二阶段:从验证第一阶段中选取了12个SNPs,进一步加大样本量使用Sequenom进行验证(2,913个病例和6,448个对照)。之后,将上述附加的对照和之前已分型的对照数据及病例进行合并分析,发现了3个SNPs达到全基因组显著关联性水平,1个SNP达到提示性的全基因组关联水平。③验证第三阶段:将验证第二阶段的12个SNP在新疆人群中验证(713病例-758对照)。
(3)对17例患者的皮损和非皮损部位取皮,进行表达谱芯片分析。
(4)利用公共数据库进行表达量的分析,寻找区域内与SNP最可能相关的基因。
结果(1)经过多种严格的数据质控后,本课题组构建了一个包括1,117患者/1,701对照493,909个常染色体SNPs的白癜风全基因组关联分析数据库。该数据库无明显的人群分层,并且病例-对照样本匹配良好。(2)通过在中国汉族人群和新疆维吾尔人群的验证,本研究发现12q13为新的白癜风易感位点(汉族:rs10876864, P=8.07×10~(-12);新疆维吾尔人群:rs10876864, P=1.01×10~(-2))。该区域也是1型糖尿病、斑秃等自身免疫性疾病的易感位点,可能包含了10个已知基因,eQTL分析表明RPS26最可能为相关基因,此基因与T细胞代谢相关。表达谱芯片结果提示此区域SILV, CDK2,SUOX,IKZF4, RPS26为相关基因。(3) 10q23区域汉族人群白癜风患者全基因组关联分析提示存在强关联信号(rs638893, P=2.47×10~(-9)),此区域包含基因为PHLDB1, TREH,DDX6,此区域曾被报道与SLE发病相关。表达谱芯片分析结果提示PHLDB1为白癜风相关基因。(4) 11q23区域为新的白癜风易感区域(rs1417210,P=1.83×10~(-8)),包含基因为SLC29A3,CDH23。(6)对已往报道的欧洲人白癜风全基因组关联分析结果进行验证,发现3q28在中国人群中为提示相关位点(rs9851967,P=8.57×10~(-8))。
结论本研究在中国人群中进行了一项大样本量的GWAS,通过在多个独立中国人群中进行验证,报道了3个新白癜风易感位点(12q13,11q23和10q23),同时讨论了白癜风与其他自身免疫性疾病之间的关系。强调了免疫因素在白癜风发病过程中的重要性,为揭示白癜风发病机制提供了新的线索。
Background Generalized vitiligo is an acquired, non-contagious disorder in which progressive, patchy loss of pigmentation of skin and often overlying hair, and mucous membranes, results from loss of melanocytes from the involved areas. It is one of the most common pigmentary disorders affecting about 0.09%-2.7% of Chinese Han population. Although many different etiologic hypotheses have been suggest for vitiligo, the most compelling of which involves a combination of environment and genetic factors interacting to contribute to autoimmune melanocyte destruction. Vitiligo is strongly influenced by genetic factors. In the past years, researches mainly used linkage studies, candidate genes studies or other research strategies to search vitiligo susceptibility genes and some progress was made. However, there are limitations in these studies. For example, there are few microsatellite markers in linkage studies and the targeted region is large, which is why it is often difficult to identify the real susceptibility genes. Meanwhile, the genome linkage method is a family-based approach, which identified the diseases susceptibility locus. Whether it can represent the sporadic cases is unknown. Similar to candidate genes studies, researchers often selected candidate genes based on available data which suggest an implication of this gene in the disease. So, there are some limitations in candidate genes study, which could not uncover susceptibility genes of vitiligo with a genome wide coverage. In recent years, completion of the Human Genome Project (HGP) and the Human Genome Haplotype Mapping Project (HapMap) facilitated the rapid development of high-throughput gene genotyping technologies and the reduction of genotyping costs, which made genome-wide association study become possible in large-scale approaches. The method of genome wide SNP analysis is highly effective to uncover disease susceptibility genes. GWAS is one of the most effective ways currently described to identify susceptibility genes of complex diseases. The success of a large number of GWAS shows a strong efficiency to uncover susceptibility genes of complex diseases, and GWAS of vitiligo in Chinese Han and Caucasian have identified a spectrum of new associated genes/loci: TYR, C1QTNF6, RERE, LPP, UBASH3A, GZMB, PTPN22 and 6q27, 10p15.1. Most of these loci were immune related loci, seven of them have been reported associate with other autoimmune diseases.
Object To explore the susceptibility variants for vitiligo, we carried out a candidate gene study in Chinese populations.
Methods (1) We conducted a genome-wide association study of generalized vitiligo in Chinese Han population by genotyping 1,149 cases and 1,701 controls using Illumina Human 610-Quad BeadChips. We took the most promising SNPs for replication in Chinese Han (5,740 cases and 10,324 controls) and Chinese Uygur (713 cases and 758 controls) using Sequenom MassArray.
(2) Replication stage:①Replication in the first stage: After quality control and statistical analysis, we selected 67 SNPs for replication in two independent samples of Chinese Han (2,827 cases and 3,876 controls) by using the Sequenom(?) MassARRAY research platform.②Replication in the second stage: we further genotyped the most promising 12 (of the 45 selected) SNPs that showed supportive association evidence in the initial validation study in additional 2,913cases and 6,448 controls using Sequenom(?) MassARRAY research platform. Then, for statistical analysis we combined GWAS, replication of the first stage and replication of the second stage together and found 3 SNPs reached genome-wide significance. In addition, one promising SNP showed a genome-wide association barely below significance.③Replication in the third stage: 12 most significant SNPs of the 45 SNPs were further genotyped in Chinese Uygur (713 cases and 758 controls) by using TaqMan assays.
(3) RNA from 17 pairs of full-thickness vitiligo skin biopsies were used in DNA microarray analysis.
(4) We also analysis the relationship between SNPs and genes in the loci.
Results (1) After stringent quality control, 493,909 SNPs were analyzed in 1,117 cases and 1,701 controls by using Cochran-Armitage trend test to assess the genotype-phenotype association. (2) We identified one novel locus at 12q13 associated with vitiligo both in Chinese Han (rs10876864, P=8.07×10~(-12)) and Chinese Uygur (rs10876864, P= P=1.01×10~(-2)), which been reported to confer risk to several autoimmune disease, such as type 1 diabetes (T1D) and alopecia areata (AA). (3) We also identified one association evidence at 10q23 in Chinese Han (rs638893, P=2.47×10~(-9)), this region have been reported to be associate with SLE. There are three genes in this region: PHLDB1, TREH,DDX6, PHLDB1 showed the differential expression between vitiligo and normal skin. (4) there are two genes in the region of 11q23: SLC29A3,CDH23 the most significant SNP was rs1417210 (P=1.83×10~(-8)),we can not find the association between SNP rs1417210 and any gene of this region. (5) We also performed a repetation of previous reported vitiligo associated genes. Only one locus at 3q28 provided suggestive evidence (rs9851967, P=8.57×10~(-8))
Conclusions We have performed a large scale GWAS for vitiligo in Chinese population, with replication in three independent Chinese population groups. Our study identifies three novel susceptibility loci at 12q13, 10q23, 11q23. In particular, it highlighted potential pathogenic overlap between vitiligo and other autoimmune diseases.
引文
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31 Birlea SA, Gowan K, Fain PR et al. Genome-Wide Association Study of Generalized Vitiligo in an Isolated European Founder Population Identifies SMOC2, in Close Proximity to IDDM8. J. Invest. Dermatol. 2009.
32 Jin Y, Birlea SA, Fain PR et al. Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo. N. Engl. J. Med. 2010.
33杨国亮,王侠生等.现代皮肤病学, 1 edn.上海:上海医科大学出版社. 1996.
34 Taieb A, Picardo M. The definition and assessment of vitiligo: a consensus report of the Vitiligo European Task Force. Pigment Cell Res. 2007; 20: 27-35.
35 Wang K, Li M, Bucan M. Pathway-Based Approaches for Analysis of Genomewide Association Studies. Am J Hum Genet 2007; 81.
1. Davies, A. J. Immunological tolerance and the autoimmune response. Autoimmun. Rev. 7, 538–543 (2008).
2. Broide, D. New perspectives on mechanisms underlying chronic allergic inflammation and asthma in 2007. J. Allergy Clin. Immunol. 122, 475–480 (2008).
3. Cho, J. H. The genetics and immunopathogenesis of inflammatory bowel disease.Nature Rev. Immunol. 8, 458–466 (2008).
4. Somers, E. C., Thomas, S. L., Smeeth, L. & Hall, A. J. Autoimmune diseases co-occurring within individuals and within families: a systematic review. Epidemiology17, 202–217 (2006).
5. Barera, G. et al. Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study. Pediatrics 109, 833–838 (2002).
6. Xavier, R. J. & Rioux, J. D. Genome-wide association studies: a new window into immune-mediated diseases. Nature Rev. Immunol. 8, 631–643 (2008).
7. Fernando, M. M. et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 4, e1000024 (2008).
8. Duffy, D. L. Genetic determinants of diabetes are similarly associated with other immune-mediated diseases. Curr. Opin. Allergy Clin. Immunol. 7, 468–474 (2007).
9. Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).
10. Becker, K. G. et al. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc. Natl Acad. Sci. USA 95, 9979–9984 (1998).
11. Becker, K. G. The common variants/multiple disease hypothesis of common complex genetic disorders. Med. Hypotheses 62, 309–317 (2004).
12. Schreiber, S., Rosenstiel, P., Albrecht, M., Hampe, J. & Krawczak, M. Genetics of Crohn disease, an archetypal inflammatory barrier disease. Nature Rev. Genet. 6, 376–388 (2005).
13. Frazer, K. A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).
14. Manolio, T. A., Brooks, L. D. & Collins, F. S. A HapMap harvest of insights into the genetics of common disease. J. Clin. Invest 118, 1590–1605 (2008).
15. Alper, C. A. et al. The haplotype structure of the human major histocompatibility complex. Hum. Immunol. 67, 73–84 (2006).
16. Nejentsev, S. et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450, 887–892 (2007).
17. Bettelli, E., Korn, T., Oukka, M. & Kuchroo, V. K. Induction and effector functions of TH17 cells. Nature 453, 1051–1057 (2008).
18. Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature Genet. 40, 955–962 (2008).
19. Cargill, M. et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).
20. Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nature Genet. 40, 1319–1323 (2008).
21. Brusko, T. M., Putnam, A. L. & Bluestone, J. A. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol. Rev. 223, 371–390 (2008).
22. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).
23. Sadlack, B. et al. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol. 25, 3053–3059 (1995).
24. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).
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28. Lowe, C. E. et al. Large-scale genetic fine mapping and genotype–phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nature Genet. 39, 1074–1082 (2007).
29. Todd, J. A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. 39, 857–864 (2007).
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32 Jin Y, Birlea SA, Fain PR et al. Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo. N. Engl. J. Med. 2010.
33杨国亮,王侠生等.现代皮肤病学, 1 edn.上海:上海医科大学出版社. 1996.
34 Taieb A, Picardo M. The definition and assessment of vitiligo: a consensus report of the Vitiligo European Task Force. Pigment Cell Res. 2007; 20: 27-35.
35 Wang K, Li M, Bucan M. Pathway-Based Approaches for Analysis of Genomewide Association Studies. Am J Hum Genet 2007; 81.
1. Davies, A. J. Immunological tolerance and the autoimmune response. Autoimmun. Rev. 7, 538–543 (2008).
2. Broide, D. New perspectives on mechanisms underlying chronic allergic inflammation and asthma in 2007. J. Allergy Clin. Immunol. 122, 475–480 (2008).
3. Cho, J. H. The genetics and immunopathogenesis of inflammatory bowel disease.Nature Rev. Immunol. 8, 458–466 (2008).
4. Somers, E. C., Thomas, S. L., Smeeth, L. & Hall, A. J. Autoimmune diseases co-occurring within individuals and within families: a systematic review. Epidemiology17, 202–217 (2006).
5. Barera, G. et al. Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study. Pediatrics 109, 833–838 (2002).
6. Xavier, R. J. & Rioux, J. D. Genome-wide association studies: a new window into immune-mediated diseases. Nature Rev. Immunol. 8, 631–643 (2008).
7. Fernando, M. M. et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 4, e1000024 (2008).
8. Duffy, D. L. Genetic determinants of diabetes are similarly associated with other immune-mediated diseases. Curr. Opin. Allergy Clin. Immunol. 7, 468–474 (2007).
9. Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).
10. Becker, K. G. et al. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc. Natl Acad. Sci. USA 95, 9979–9984 (1998).
11. Becker, K. G. The common variants/multiple disease hypothesis of common complex genetic disorders. Med. Hypotheses 62, 309–317 (2004).
12. Schreiber, S., Rosenstiel, P., Albrecht, M., Hampe, J. & Krawczak, M. Genetics of Crohn disease, an archetypal inflammatory barrier disease. Nature Rev. Genet. 6, 376–388 (2005).
13. Frazer, K. A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).
14. Manolio, T. A., Brooks, L. D. & Collins, F. S. A HapMap harvest of insights into the genetics of common disease. J. Clin. Invest 118, 1590–1605 (2008).
15. Alper, C. A. et al. The haplotype structure of the human major histocompatibility complex. Hum. Immunol. 67, 73–84 (2006).
16. Nejentsev, S. et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450, 887–892 (2007).
17. Bettelli, E., Korn, T., Oukka, M. & Kuchroo, V. K. Induction and effector functions of TH17 cells. Nature 453, 1051–1057 (2008).
18. Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature Genet. 40, 955–962 (2008).
19. Cargill, M. et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).
20. Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nature Genet. 40, 1319–1323 (2008).
21. Brusko, T. M., Putnam, A. L. & Bluestone, J. A. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol. Rev. 223, 371–390 (2008).
22. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).
23. Sadlack, B. et al. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol. 25, 3053–3059 (1995).
24. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).
25. Yamanouchi, J. et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nature Genet. 39, 329–337 (2007).
26. The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3000 shared controls. Nature 447, 661–678 (2007).
27. Burton, P. R. et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nature Genet. 39, 1329–1337 (2007).
28. Lowe, C. E. et al. Large-scale genetic fine mapping and genotype–phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nature Genet. 39, 1074–1082 (2007).
29. Todd, J. A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. 39, 857–864 (2007).
30. van Heel, D. A. et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nature Genet. 39, 827–829 (2007).
31. Vella, A. et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76, 773–779 (2005).
32. Fina, D. et al. Interleukin-21 contributes to the mucosal T helper cell type 1 response in celiac disease. Gut 57, 887–892 (2008).
33. Fina, D., Caruso, R., Pallone, F. & Monteleone, G. Interleukin-21 (IL-21) controls inflammatory pathways in the gut. Endocr. Metab Immune. Disord. Drug Targets. 7, 288–291 (2007).
34. Monteleone, G., Pallone, F. & Macdonald, T. T. Interleukin-21: a critical regulator of the balance between effector and regulatory T-cell responses. Trends Immunol. 29, 290–294 (2008).
35. Jiang, H. & Chess, L. Regulation of immune responses by T cells. N. Engl. J. Med.354, 1166–1176 (2006).
36. Ohashi, P. S. T-cell signalling and autoimmunity: molecular mechanisms of disease.Nature Rev. Immunol. 2, 427–438 (2002).
37. Harley, J. B. et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nature Genet. 40, 204–210 (2008).
38. Hunt, K. A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nature Genet. 40, 395–402 (2008).
39. Kavvoura, F. K. et al. Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis. J. Clin. Endocrinol. Metab. 92, 3162–3170 (2007).
40. Anjos, S. & Polychronakos, C. Mechanisms of genetic susceptibility to type I diabetes: beyond HLA. Mol. Genet. Metab. 81, 187–195 (2004).
41. Vang, T., Miletic, A. V., Bottini, N. & Mustelin, T. Protein tyrosine phosphatase PTPN22 in human autoimmunity. Autoimmunity 40, 453–461 (2007).
42. Vang, T. et al. Protein tyrosine phosphatases in autoimmunity. Annu. Rev. Immunol.26, 29–55 (2008).
43. Fitau, J., Boulday, G., Coulon, F., Quillard, T. & Charreau, B. The adaptor molecule Lnk negatively regulates tumor necrosis factor-alpha-dependent VCAM-1 expression in endothelial cells through inhibition of the ERK1 and -2 pathways. J. Biol. Chem.281, 20148–20159 (2006).
44. Li, Y., He, X., Schembri-King, J., Jakes, S. & Hayashi, J. Cloning and characterization of human Lnk, an adaptor protein with pleckstrin homology and Srchomology 2 domains that can inhibit T cell activation. J. Immunol. 164, 5199–5206 (2000).
45. Isenberg, D. A., Manson, J. J., Ehrenstein, M. R. & Rahman, A. Fifty years of anti-ds DNA antibodies: are we approaching journey's end? Rheumatology 46, 1052–1056 (2007).
46. Rahman, A. & Isenberg, D. A. Systemic lupus erythematosus. N. Engl. J. Med. 358, 929–939 (2008).
47. Vojdani, A. Antibodies as predictors of complex autoimmune diseases. Int. J. Immunopathol. Pharmacol. 21, 267–278 (2008).
48. van der Helm-van Mil A. H., Huizinga, T. W., de Vries, R. R. & Toes, R. E. Emerging patterns of risk factor make-up enable subclassification of rheumatoid arthritis.Arthritis Rheum. 56, 1728–1735 (2007).
49. Raychaudhuri, S. et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nature Genet. 40, 1216–1223 (2008).
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