Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Hum Mol Genet. 2010 May 15;19(10):2059-67. doi: 10.1093/hmg/ddq078. Epub 2010 Feb 22.
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.
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），都是自身免疫性疾病，可能具有共同的易感性途径。我们在一组 1689 例 CD 病例、777 例 UC 病例、989 例 T1D 病例和 6197 例欧洲血统的共享对照中检查了这些疾病的已知易感基因座，这些病例通过 Illumina HumanHap550 SNP 阵列进行了基因分型。我们发现了多个以前未报道或未经证实的疾病关联，包括已知的 CD 基因座（ICOSLG 和 TNFSF15）和 T1D 基因座（TNFAIP3），它们会增加 UC 的风险，已知的 UC 基因座（HERC2 和 IL26）会增加 T1D 的风险，已知的 UC 基因座（IL10 和 CCNY）会增加 CD 的风险。此外，我们还表明，位于 PTPN22、IL27、IL18RAP 和 IL10 基因座的 T1D 风险等位基因可预防 CD。此外，MHC 内与 T1D 最强相关的风险等位基因可强烈预防 CD 和 UC；然而，鉴于 MHC 单倍型的多等位基因性质，需要对 MHC 基因座进行测序才能解释这一观察结果。这些结果扩展了我们对易患自身免疫性疾病的遗传变异的现有认识，并表明参与自身免疫的许多基因座可能由于拮抗多效性而处于平衡选择之下。我们的分析意味着对不同疾病有相反影响的变体可能有助于在人类群体中维持常见的易感性等位基因，从而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分析。
