OBJECTIVE Individuals with diabetes who carry genetic variants that lower hemoglobin A1c (HbA1c) independently of glycemia may have higher real, but undetected, hyperglycemia compared with those without these variants despite achieving similar HbA1c targets, potentially placing them at greater risk for diabetes-related complications. We sought to determine whether these genetic variants, aggregated in a polygenic score, and the large-effect African ancestry–specific missense variant in G6PD (rs1050828) that lower HbA1c were associated with higher retinopathy risk. RESEARCH DESIGN AND METHODS Using data from 29,828 type 2 diabetes cases of genetically inferred African American/African British and European ancestries, we calculated ancestry-specific nonglycemic HbA1c polygenic scores (ngA1cPS) composed of 122 variants associated with HbA1c at genome-wide significance, but not with glucose. We tested the association of the ngA1cPS and the G6PD variant with retinopathy, adjusting for measured HbA1c and retinopathy risk factors. RESULTS Participants in the bottom quintile of the ngA1cPS showed between 20% and 50% higher retinopathy prevalence, compared with those above this quintile, despite similar levels of measured HbA1c. The adjusted meta-analytic odds ratio for the bottom quintile was 1.31 (95% CI 1.0, 1.73; P = 0.05) in African ancestry and 1.31 (95% CI 1.15, 1.50; P = 6.5 × 10−5) in European ancestry. Among individuals of African ancestry with HbA1c below 7% units, retinopathy prevalence was higher in individuals below, compared with above, the 50th percentile of the ngA1cPS regardless of sex or G6PD carrier status. CONCLUSIONS Genetic effects need to be considered to personalize HbA1c targets and improve outcomes of people with diabetes from diverse ancestries.

中文翻译：

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血红蛋白 A1c 遗传学和遗传推断的非裔美国人/非洲裔英国人和欧洲血统个体患糖尿病视网膜病变风险的差异


目的 携带独立于血糖而降低糖化血红蛋白 （HbA1c） 的遗传变异的糖尿病患者，与没有这些变异的人相比，可能具有更高的实际但未被发现的高血糖，尽管达到了相似的 HbA1c 目标，这可能使他们面临更大的糖尿病相关并发症风险。我们试图确定这些聚合在多基因评分中的遗传变异以及 G6PD （rs1050828） 中较低 HbA1c 的大效应非洲血统特异性错义变异是否与较高的视网膜病变风险相关。研究设计和方法 使用来自 29,828 例遗传推断的非裔美国人/非裔英国人和欧洲血统的 2 型糖尿病病例的数据，我们计算了血统特异性非血糖 HbA1c 多基因评分 （ngA1cPS），该评分由 122 个与 HbA1c 相关的全基因组显着性变体组成，但不与葡萄糖相关。我们测试了 ngA1cPS 和 G6PD 变体与视网膜病变的相关性，调整了测量的 HbA1c 和视网膜病变危险因素。结果 尽管测得的 HbA1c 水平相似，但与高于该五分位数的参与者相比，ngA1cPS 底部五分位数的参与者视网膜病变患病率高出 20% 至 50%。底部五分位数的调整后荟萃分析比值比为 1.31 （95% CI 1.0， 1.73;P = 0.05） 和 1.31 （95% CI 1.15， 1.50;P = 6.5 × 10−5） 在欧洲血统中。在 HbA1c 低于 7% 单位的非洲血统个体中，与上述相比，低于 ngA1cPS 第 50 个百分位的个体的视网膜病变患病率更高，无论性别或 G6PD 携带者状态如何。结论 需要考虑遗传效应以个性化 HbA1c 靶标并改善来自不同血统的糖尿病患者的预后。