Background. Diabetic retinopathy (DR) risk has been shown to vary depending on ethnic backgrounds, and thus, it is worthy that underrepresented populations are analyzed for the potential identification of DR-associated genetic variants. We conducted a case-control study for the identification of DR-risk variants in Mexican population. Methods. We ascertained 60 type 2 diabetes mellitus (T2DM) patients. Cases () were patients with advanced proliferative DR (PDR) with less than 15 years after a T2DM diagnosis while controls () were patients with no DR 15 years after the diagnosis of T2DM. Exome sequencing was performed in all patients, and the frequency of rare variants was compared. In addition, the frequency of variants occurring in a set of 169 DR-associated genes were compared. Results. Statistically significant differences were identified for rare missense and splice variants and for rare splice variants occurring more than once in either group. A strong statistical difference was observed when the number of rare missense variants with an aggregated prediction of pathogenicity and occurring more than once in either group was compared (). Moreover, 8 variants identified more than once in either group, occurring in previously identified DR-associated genes were recognized. The p.Pro234Ser KIR2DS4 variant showed a strong protective effect ( [0.001–0.36]; ). Conclusions. Our study showed an enrichment of rare splice acceptor/donor variants in patients with PDR and identified a potential protective variant in KIR2DS4. Although statistical significance was not reached, our results support the replication of 8 previously identified DR-associated genes.

中文翻译：

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在极端表型中应用外显子组测序鉴定糖尿病视网膜病变风险的遗传变异

背景。糖尿病视网膜病变 (DR) 风险已被证明因种族背景而异，因此，值得对代表性不足的人群进行分析，以潜在识别 DR 相关的遗传变异。我们进行了一项病例对照研究，以鉴定墨西哥人群中的 DR 风险变异。方法。我们确定了 60 名 2 型糖尿病 (T2DM) 患者。案例（)是诊断 T2DM 后不到 15 年的晚期增殖性 DR (PDR) 患者，而对照组 (）是诊断 T2DM 15 年后没有出现 DR 的患者。对所有患者进行外显子组测序，并比较罕见变异的频率。此外，还比较了一组 169 个 DR 相关基因中出现的变异频率。结果。对于罕见的错义和剪接变体以及在任一组中出现多次的罕见剪接变体，都发现了统计学上的显着差异。当比较具有致病性聚合预测且在任一组中出现超过一次的罕见错义变异的数量时，观察到强烈的统计差异（）。此外，在之前鉴定的 DR 相关基因中出现的 8 个变异在任一组中都被多次鉴定出。p.Pro234Ser KIR2DS4 变体表现出很强的保护作用（[0.001–0.36]；）。 结论。我们的研究显示 PDR 患者中罕见剪接受体/供体变异的富集，并鉴定了KIR2DS4中潜在的保护性变异。尽管未达到统计学显着性，但我们的结果支持 8 个先前鉴定的 DR 相关基因的复制。