2 型糖尿病遗传变异与糖尿病视网膜病变风险。

Type 2 Diabetes Genetic Variants and Risk of Diabetic Retinopathy.

机构信息

Singapore Eye Research Institute, Singapore National Eye Centre, Singapore; Duke-NUS Medical School, Singapore.

Duke-NUS Medical School, Singapore.

出版信息

Ophthalmology. 2017 Mar;124(3):336-342. doi: 10.1016/j.ophtha.2016.11.016. Epub 2016 Dec 27.

DOI:10.1016/j.ophtha.2016.11.016

PMID:28038984

Abstract

PURPOSE

Genetic association studies to date have not identified any robust risk loci for diabetic retinopathy (DR). We hypothesized that individuals with more diabetes genetic risk alleles have a higher risk of developing DR.

DESIGN

Case-control genetic association study.

PARTICIPANTS

We evaluated the aggregate effects of multiple type 2 diabetes-associated genetic variants on the risk of DR among 1528 participants with diabetes from the Singapore Epidemiology of Eye Diseases Study, of whom 547 (35.8%) had DR.

METHODS

Participants underwent a comprehensive ocular examination, including dilated fundus photography. Retinal photographs were graded using the modified Airlie House classification system to assess the presence and severity of DR following a standardized protocol. We identified 76 previously discovered type 2 diabetes-associated single nucleotide polymorphisms (SNPs) and constructed multilocus genetic risk scores (GRSs) for each individual by summing the number of risk alleles for each SNP weighted by the respective effect estimates on DR. Two GRSs were generated: an overall GRS that included all 76 discovered type 2 diabetes-associated SNPs, and an Asian-specific GRS that included a subset of 55 SNPs previously found to be associated with type 2 diabetes in East and/or South Asian ancestry populations. Associations between the GRSs with DR were determined using logistic regression analyses. Discriminating ability of the GRSs was determined by the area under the receiver operating characteristic curve (AUC).

MAIN OUTCOME MEASURES

Odds ratios on DR.

RESULTS

Participants in the top tertile of the overall GRS were 2.56-fold more likely to have DR compared with participants in the lowest tertile. Participants in the top tertile of the Asian-specific GRS were 2.00-fold more likely to have DR compared with participants in the bottom tertile. Both GRSs were associated with higher DR severity levels. However, addition of the GRSs to traditional risk factors improved the AUC only modestly by 3% to 4%.

CONCLUSIONS

Type 2 diabetes-associated genetic loci were significantly associated with higher risks of DR, independent of traditional risk factors. Our findings may provide new insights to further our understanding of the genetic pathogenesis of DR.

摘要

目的

迄今为止，遗传关联研究并未发现任何与糖尿病视网膜病变（DR）相关的稳健风险基因座。我们假设，具有更多糖尿病遗传风险等位基因的个体发生 DR 的风险更高。

设计

病例对照遗传关联研究。

参与者

我们评估了来自新加坡眼病流行病学研究的 1528 名糖尿病患者的多种 2 型糖尿病相关遗传变异对 DR 风险的综合影响，其中 547 名（35.8%）患有 DR。

方法

参与者接受了全面的眼部检查，包括散瞳眼底照相。根据标准化方案，使用改良的 Airlie House 分类系统对视网膜照片进行分级，以评估 DR 的存在和严重程度。我们确定了 76 个先前发现的 2 型糖尿病相关单核苷酸多态性（SNP），并通过为每个 SNP 相加风险等位基因的数量，并根据每个 SNP 对 DR 的影响估计值对其进行加权，为每个个体构建多基因风险评分（GRS）。生成了两个 GRS：包含所有 76 个发现的与 2 型糖尿病相关的 SNP 的总体 GRS，以及包含先前在东亚和/或南亚人群中发现与 2 型糖尿病相关的 55 个 SNP 的亚组的亚洲特异性 GRS。使用逻辑回归分析确定 GRS 与 DR 之间的关联。通过接收者操作特征曲线下的面积（AUC）来确定 GRS 的判别能力。

主要观察指标

DR 的比值比。

结果

与最低三分位数的参与者相比，总体 GRS 最高三分位数的参与者发生 DR 的可能性高 2.56 倍。与最低三分位数的参与者相比，亚洲特异性 GRS 最高三分位数的参与者发生 DR 的可能性高 2.00 倍。两个 GRS 均与较高的 DR 严重程度水平相关。然而，将 GRS 添加到传统危险因素中仅适度地将 AUC 提高了 3%至 4%。