Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.
Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Okinawa 903-0215, Japan.
Hum Mol Genet. 2021 May 17;30(8):716-726. doi: 10.1093/hmg/ddab044.
Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (P < 1.0 × 10-4) in an independent case-control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stages 1 and 2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, P = 1.62 × 10-9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11-1.23, and rs140508424 within PALM2 on chromosome 9, P = 4.19 × 10-8, OR = 1.61, 95% CI 1.36-1.91. However, the association of these two loci was not replicated in Korean, European or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (P = 2.17 × 10-6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations.
一些报告表明，遗传易感性导致了糖尿病视网膜病变的发生和发展。我们旨在鉴定出日本 2 型糖尿病患者中导致糖尿病视网膜病变易感性的遗传基因座。我们对 8880 名日本 2 型糖尿病患者（4839 例视网膜病变患者和 4041 例对照者）、2217 名独立的日本 2 型糖尿病患者（693 例视网膜病变患者和 1524 名对照者）的 5790508 个单核苷酸多态性（SNP）进行了分析。这两项全基因组关联研究（GWAS）的结果结合了逆方差荟萃分析（第一阶段），随后对候选 SNP 基因座（P<1.0×10-4）进行了新的病例对照研究（第二阶段，2260 例和 723 例对照者）。在使用荟萃分析结合关联数据（第一阶段和第二阶段）后，两个基因座的关联达到了全基因组显著水平：位于 3 号染色体上的 STT3B 附近的 rs12630354，P=1.62×10-9，比值比（OR）=1.17，95%置信区间（CI）为 1.11-1.23，以及 9 号染色体上的 PALM2 内的 rs140508424，P=4.19×10-8，OR=1.61，95%CI 为 1.36-1.91。然而，这两个基因座的关联在韩国、欧洲或非裔美国人中并未得到复制。利用第一阶段 GWAS 数据进行的基于基因的分析确定了 EHD3 与糖尿病视网膜病变易感性相关（P=2.17×10-6）。总之，我们鉴定出了两个新的 SNP 基因座 STT3B 和 PALM2，以及一个新的基因 EHD3，它们赋予了糖尿病视网膜病变的易感性；然而，需要进一步的复制研究来验证这些关联。
