Diabetic retinopathy and other diabetes complications arise more commonly among individuals of African ancestry compared with other ancestry groups. To gain insight into genetic factors influencing the risk of diabetes complications, particularly among individuals of African ancestry, Breeyear et al. performed multi-ancestry genome-wide association analyses, comprising 68,169 individuals with diabetic retinopathy (cases) and 129,188 individuals with diabetes who did not have diabetic retinopathy (controls). They identified nine loci associated with diabetic retinopathy at genome-wide significance, including a coding variant in G6PD that reached significance both in the combined analysis across all ancestry groups and in the non-Hispanic African subgroup. This G6PD variant, which confers glucose-6-phosphate dehydrogenase deficiency, has previously been associated with protection against severe malaria and is present at a higher frequency in populations of African ancestry. In the current study, this G6PD variant was found to be associated with higher plasma glucose levels, which mediate the effect of this variant on increased risk of diabetic retinopathy. Phenome-wide analyses across two biobanks provided additional evidence that this G6PD variant confers increased risk of other diabetes complications, including diabetic nephropathy. These findings suggest a fitness trade-off at G6PD between protection from severe malaria and risk of other adverse health outcomes.

Original reference: Nat. Med. https://doi.org/10.1038/s41591-024-03089-1 (2024)

与其他血统群体相比，非洲血统的个体更容易出现糖尿病视网膜病变和其他糖尿病并发症。为了深入了解影响糖尿病并发症风险的遗传因素，尤其是非洲血统的个体，Breeyear 等人。进行了多祖先全基因组关联分析，其中包括 68,169 名糖尿病视网膜病变患者（病例）和 129,188 名未患有糖尿病视网膜病变的糖尿病患者（对照）。他们确定了 9 个与糖尿病视网膜病变相关的全基因组显着性位点，其中包括G6PD中的一个编码变体，该变体在所有血统群体和非西班牙裔非洲亚组的综合分析中均具有显着意义。这种导致葡萄糖-6-磷酸脱氢酶缺乏的G6PD变体以前被认为与预防严重疟疾有关，并且在非洲血统人群中出现的频率较高。在当前的研究中，发现这种G6PD变体与较高的血浆葡萄糖水平相关，从而介导该变体对糖尿病视网膜病变风险增加的影响。两个生物库的全表型组分析提供了额外的证据，表明这种G6PD变异会增加其他糖尿病并发症（包括糖尿病肾病）的风险。这些发现表明， G6PD在预防严重疟疾和其他不良健康结果的风险之间存在健康权衡。

Original reference: Nat. Med. https://doi.org/10.1038/s41591-024-03089-1 (2024)