Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA.
Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA.
Diabetes. 2014 Dec;63(12):4360-8. doi: 10.2337/db13-1785. Epub 2014 Jul 9.
Single nucleotide polymorphisms (SNPs) located in the chromosomal region 16p13.13 have been previously associated with risk for several autoimmune diseases, including type 1 diabetes. To identify and localize specific risk variants for type 1 diabetes in this region and understand the mechanism of their action, we resequenced a 455-kb region in type 1 diabetic patients and unaffected control subjects, identifying 93 novel variants. A panel of 939 SNPs that included 46 of these novel variants was genotyped in 3,070 multiplex families with type 1 diabetes. Forty-eight SNPs, all located in CLEC16A, provided a statistically significant association (P < 5.32 × 10(-5)) with disease, with rs34306440 being most significantly associated (P = 5.74 × 10(-6)). The panel of SNPs used for fine mapping was also tested for association with transcript levels for each of the four genes in the region in B lymphoblastoid cell lines. Significant associations were observed only for transcript levels of DEXI, a gene with unknown function. We examined the relationship between the odds ratio for type 1 diabetes and the magnitude of the effect of DEXI transcript levels for each SNP in the region. Among SNPs significantly associated with type 1 diabetes, the common allele conferred an increased risk for disease and corresponded to lower DEXI expression. Our results suggest that the primary mechanism by which genetic variation at CLEC16A contributes to the risk for type 1 diabetes is through reduced expression of DEXI.
位于染色体 16p13.13 上的单核苷酸多态性 (SNP) 先前与包括 1 型糖尿病在内的几种自身免疫性疾病的风险相关。为了在该区域中鉴定和定位 1 型糖尿病的特定风险变体，并了解其作用机制，我们对 1 型糖尿病患者和未受影响的对照受试者中的 455-kb 区域进行了重新测序，鉴定出 93 个新变体。939 个 SNP 的面板，其中包括 46 个这些新变体，在 3070 个具有 1 型糖尿病的多重家庭中进行了基因分型。48 个 SNP，全部位于 CLEC16A 中，与疾病呈统计学显著关联（P < 5.32 × 10(-5)），其中 rs34306440 相关性最强（P = 5.74 × 10(-6)）。用于精细映射的 SNP 面板也在 B 淋巴母细胞系中用于检测该区域中四个基因的每个基因的转录水平的关联。仅观察到转录水平与 DEXI 的显著关联，DEXI 是一个具有未知功能的基因。我们检查了 1 型糖尿病的优势比与该区域中每个 SNP 的 DEXI 转录水平的影响程度之间的关系。在与 1 型糖尿病显著相关的 SNP 中，常见等位基因赋予疾病更高的风险，并且与 DEXI 表达降低相对应。我们的结果表明，CLEC16A 遗传变异导致 1 型糖尿病风险的主要机制是通过降低 DEXI 的表达。
