Department of Human Genetics, Discovery Research, Roche Molecular Systems Inc., 4300 Hacienda Drive, Pleasanton, CA 94588, USA.
Genes Immun. 2009 Dec;10 Suppl 1(Suppl 1):S54-9. doi: 10.1038/gene.2009.92.
The Type I Diabetes Genetics Consortium (T1DGC) has collected thousands of multiplex and simplex families with type I diabetes (T1D) with the goal of identifying genes involved in T1D susceptibility. These families have been genotyped for the HLA class I and class II loci and, recently, for a genome-wide panel of single-nucleotide polymorphisms (SNPs). In addition, multiple SNPs in specific candidate genes have been genotyped in these families in an attempt to evaluate previously reported T1D associations, including the C883A (Pro-Thr) polymorphism in exon 2 of TCF7, a T-cell transcription factor. The TCF7 883A allele was associated with T1D in subjects with T1D not carrying the high-risk HLA genotype DR3/DR4. A panel of 11 SNPs in TCF7 was genotyped in 2092 families from 9 cohorts of the T1DGC. SNPs at two positions in TCF7 were associated with T1D. One associated SNP, C883A (rs5742913), was reported earlier to have a T1D association. A second SNP, rs17653687, represents a novel T1D susceptibility allele in TCF7. After stratification on the high T1D risk DR3/DR4 genotype, the variant (A) allele of C883A was significantly associated with T1D among non-DR3/DR4 cases (transmission=55.8%, P=0.004; OR=1.26) but was not significantly associated in the DR3/DR4 patient subgroup, replicating the earlier report. The reference A allele of intronic SNP rs17653687 was modestly associated with T1D in both DR3/DR4 strata (transmission=54.4% in DR3/DR4; P=0.03; transmission=52.9% in non-DR3/DR4; P=0.03). These results support the previously reported association of the non-synonymous Pro-Thr SNP in TCF7 with T1D, and suggest that other alleles at this locus may also confer risk.
I 型糖尿病遗传学联合会 (T1DGC) 收集了数千个具有 I 型糖尿病 (T1D) 的多基因和单基因家族，旨在鉴定与 T1D 易感性相关的基因。这些家族已对 HLA Ⅰ类和Ⅱ类基因座进行了基因分型，最近还对全基因组单核苷酸多态性 (SNP) 进行了基因分型。此外，还在这些家族中对特定候选基因的多个 SNP 进行了基因分型，以评估先前报道的 T1D 相关性，包括 T 细胞转录因子 TCF7 外显子 2 中的 C883A（脯氨酸-苏氨酸）多态性。TCF7 883A 等位基因与不携带高危 HLA 基因型 DR3/DR4 的 T1D 患者的 T1D 相关。在来自 T1DGC 的 9 个队列的 2092 个家族中，对 TCF7 的 11 个 SNP 进行了基因分型。TCF7 两个位置的 SNP 与 T1D 相关。一个相关的 SNP，C883A(rs5742913)，先前被报道与 T1D 相关。第二个 SNP，rs17653687，代表 TCF7 中的一个新的 T1D 易感等位基因。在对高 T1D 风险 DR3/DR4 基因型进行分层后，C883A 的变体 (A) 等位基因在非 DR3/DR4 病例中与 T1D 显著相关（传递率为 55.8%，P=0.004；OR=1.26），但在 DR3/DR4 患者亚组中无显著相关性，这与先前的报告一致。内含子 SNP rs17653687 的参考 A 等位基因在 DR3/DR4 两个亚组中均与 T1D 中度相关（DR3/DR4 中的传递率为 54.4%，P=0.03；非 DR3/DR4 中的传递率为 52.9%，P=0.03）。这些结果支持先前报道的 TCF7 中非同义脯氨酸-苏氨酸 SNP 与 T1D 的相关性，并表明该基因座的其他等位基因也可能具有风险。
