Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
Department of Public Health Sciences, University of Virginia, Charlottesville, VA.
Diabetes Care. 2019 Mar;42(3):406-415. doi: 10.2337/dc18-1727. Epub 2019 Jan 18.
Genetic risk scores (GRS) have been developed that differentiate individuals with type 1 diabetes from those with other forms of diabetes and are starting to be used for population screening; however, most studies were conducted in European-ancestry populations. This study identifies novel genetic variants associated with type 1 diabetes risk in African-ancestry participants and develops an African-specific GRS.
We generated single nucleotide polymorphism (SNP) data with the ImmunoChip on 1,021 African-ancestry participants with type 1 diabetes and 2,928 control participants. HLA class I and class II alleles were imputed using SNP2HLA. Logistic regression models were used to identify genome-wide significant ( < 5.0 × 10) SNPs associated with type 1 diabetes in the African-ancestry samples and validate SNPs associated with risk in known European-ancestry loci ( < 2.79 × 10).
African-specific (HLA-*03:01-HLA-*02:01) and known European-ancestry HLA haplotypes (HLA-*03:01-HLA-*05:01-HLA-*02:01, HLA-*04:01-HLA-*03:01-HLA-*03:02) were significantly associated with type 1 diabetes risk. Among European-ancestry defined non-HLA risk loci, six risk loci were significantly associated with type 1 diabetes in subjects of African ancestry. An African-specific GRS provided strong prediction of type 1 diabetes risk (area under the curve 0.871), performing significantly better than a European-based GRS and two polygenic risk scores in independent discovery and validation cohorts.
Genetic risk of type 1 diabetes includes ancestry-specific, disease-associated variants. The GRS developed here provides improved prediction of type 1 diabetes in African-ancestry subjects and a means to identify groups of individuals who would benefit from immune monitoring for early detection of islet autoimmunity.
已经开发出了区分 1 型糖尿病患者和其他类型糖尿病患者的遗传风险评分(GRS),并开始用于人群筛查;然而,大多数研究都是在欧洲血统人群中进行的。本研究鉴定了与非洲血统参与者的 1 型糖尿病风险相关的新型遗传变异,并开发了一种非洲特异性 GRS。
我们在 1021 名 1 型糖尿病非洲裔参与者和 2928 名对照参与者中生成了单核苷酸多态性(SNP)数据,使用 SNP2HLA 对 HLA I 类和 II 类等位基因进行了推断。使用逻辑回归模型来识别在非洲裔样本中与 1 型糖尿病相关的全基因组显著(<5.0×10)SNP,并验证与已知欧洲血统基因座相关的风险 SNP(<2.79×10)。
非洲特异性(HLA-*03:01-HLA-*02:01)和已知的欧洲血统 HLA 单倍型(HLA-*03:01-HLA-*05:01-HLA-*02:01,HLA-*04:01-HLA-*03:01-HLA-*03:02)与 1 型糖尿病风险显著相关。在欧洲血统定义的非 HLA 风险基因座中,有 6 个风险基因座与非洲血统受试者的 1 型糖尿病显著相关。非洲特异性 GRS 为 1 型糖尿病风险提供了强有力的预测(曲线下面积 0.871),在独立发现和验证队列中的表现明显优于基于欧洲的 GRS 和两种多基因风险评分。
1 型糖尿病的遗传风险包括与种族特异性、疾病相关的变异。这里开发的 GRS 为非洲血统个体的 1 型糖尿病提供了更好的预测,并为识别受益于免疫监测以早期发现胰岛自身免疫的个体群体提供了一种方法。