Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects
Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects
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DOI：
10.1093/hmg/ddq078
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发表时间：
2010-05-15
影响因子：
3.5
通讯作者：
Hakonarson, Hakon
中科院分区：
文献类型：
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作者：
Wang, Kai;Baldassano, Robert;Hakonarson, Hakon
炎症性肠病，包括克罗恩病 (CD) 和溃疡性结肠炎 (UC) 以及 1 型糖尿病 (T1D)，都是可能具有共同易感途径的自身免疫性疾病。我们在 1689 名 CD 病例、777 名 UC 病例、989 名 T1D 病例和 6197 名具有欧洲血统的共同对照受试者队列中检查了这些疾病的已知易感位点，这些受试者均通过 Illumina HumanHap550 SNP 阵列进行了基因分型。我们确定了多个先前未报告或未经证实的疾病关联，包括已知的 CD 基因座（ICOSLG 和 TNFSF15）和赋予 UC 风险的 T1D 基因座（TNFAIP3）、赋予 T1D 风险的已知 UC 基因座（HERC2 和 IL26）以及赋予 CD 风险的已知 UC 基因座（IL10 和 CCNY）。此外，我们发现位于 PTPN22、IL27、IL18RAP 和 IL10 位点的 T1D 风险等位基因可以预防 CD。此外，主要组织相容性复合体 (MHC) 内 T1D 的最强风险等位基因可针对 CD 和 UC 提供强有力的保护；然而，考虑到 MHC 单倍型的多等位基因性质，需要对 MHC 基因座进行测序来解释这一观察结果。这些结果扩展了我们目前对易患自身免疫的遗传变异的认识，并表明许多参与自身免疫的基因座可能由于拮抗多效性效应而处于平衡选择之下。我们的分析表明，对不同疾病具有相反影响的变异可能有助于维持人群中常见的易感等位基因，使自身免疫性疾病特别适合通过全基因组关联研究进行遗传解剖。
Inflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC), and type 1 diabetes (T1D) are autoimmune diseases that may share common susceptibility pathways. We examined known susceptibility loci for these diseases in a cohort of 1689 CD cases, 777 UC cases, 989 T1D cases and 6197 shared control subjects of European ancestry, who were genotyped by the Illumina HumanHap550 SNP arrays. We identified multiple previously unreported or unconfirmed disease associations, including known CD loci (ICOSLG and TNFSF15) and T1D loci (TNFAIP3) that confer UC risk, known UC loci (HERC2 and IL26) that confer T1D risk and known UC loci (IL10 and CCNY) that confer CD risk. Additionally, we show that T1D risk alleles residing at the PTPN22, IL27, IL18RAP and IL10 loci protect against CD. Furthermore, the strongest risk alleles for T1D within the major histocompatibility complex (MHC) confer strong protection against CD and UC; however, given the multi-allelic nature of the MHC haplotypes, sequencing of the MHC locus will be required to interpret this observation. These results extend our current knowledge on genetic variants that predispose to autoimmunity, and suggest that many loci involved in autoimmunity may be under a balancing selection due to antagonistic pleiotropic effect. Our analysis implies that variants with opposite effects on different diseases may facilitate the maintenance of common susceptibility alleles in human populations, making autoimmune diseases especially amenable to genetic dissection by genome-wide association studies.