The Center for Applied Genomics, The Children's Hospital Philadelphia, Philadelphia, Pennsylvania, United States of America.
PLoS Genet. 2011 Sep;7(9):e1002293. doi: 10.1371/journal.pgen.1002293. Epub 2011 Sep 29.
Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly revealed dozens of genetic contributors to the pathogenesis of T1D, with the most recent meta-analysis identifying in excess of 40 loci. To identify additional genetic loci for T1D susceptibility, we examined associations in the largest meta-analysis to date between the disease and ∼2.54 million SNPs in a combined cohort of 9,934 cases and 16,956 controls. Targeted follow-up of 53 SNPs in 1,120 affected trios uncovered three new loci associated with T1D that reached genome-wide significance. The most significantly associated SNP (rs539514, P = 5.66×10⁻¹¹) resides in an intronic region of the LMO7 (LIM domain only 7) gene on 13q22. The second most significantly associated SNP (rs478222, P = 3.50×10⁻⁹ resides in an intronic region of the EFR3B (protein EFR3 homolog B) gene on 2p23; however, the region of linkage disequilibrium is approximately 800 kb and harbors additional multiple genes, including NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC, and DNMT3A. The third most significantly associated SNP (rs924043, P = 8.06×10⁻⁹ lies in an intergenic region on 6q27, where the region of association is approximately 900 kb and harbors multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP, and PCD2. These latest associated regions add to the growing repertoire of gene networks predisposing to T1D.
全球约有 2 亿人受糖尿病影响，其中约 10%受 1 型糖尿病（T1D）影响。全基因组关联研究（GWAS）的应用已经强有力地揭示了数十个与 T1D 发病机制相关的遗传因素，最近的荟萃分析确定了超过 40 个位点。为了确定 T1D 易感性的其他遗传位点，我们在迄今为止最大的荟萃分析中，在一个包含 9934 例病例和 16956 例对照的联合队列中，检查了疾病与约 254 万个单核苷酸多态性（SNP）之间的关联。对 1120 个受影响三胞胎中的 53 个 SNP 进行了靶向随访，发现了三个与 T1D 相关的新位点，达到了全基因组显著性。最显著相关的 SNP（rs539514，P=5.66×10⁻¹¹）位于 13q22 上的 LMO7（LIM 域只有 7）基因的内含子区域。第二显著相关的 SNP（rs478222，P=3.50×10⁻⁹）位于 2p23 上的 EFR3B（蛋白 EFR3 同源物 B）基因的内含子区域；然而，连锁不平衡区域约为 800kb，并且包含多个其他基因，包括 NCOA1、C2orf79、CENPO、ADCY3、DNAJC27、POMC 和 DNMT3A。第三显著相关的 SNP（rs924043，P=8.06×10⁻⁹）位于 6q27 的基因间区域，关联区域约为 900kb，包含多个基因，包括 WDR27、C6orf120、PHF10、TCTE3、C6orf208、LOC154449、DLL1、FAM120B、PSMB1、TBP 和 PCD2。这些最新相关区域增加了导致 T1D 的基因网络不断增加的储备。
