Data_Sheet_1_Neuronal Dysfunction Is Linked to the Famine-Associated Risk of Proliferative Retinopathy in Patients With Type 2 Diabetes.pdf

Persons with type 2 diabetes born in the regions of famine exposures have disproportionally elevated risk of vision-threatening proliferative diabetic retinopathy (PDR) in adulthood. However, the underlying mechanisms are not known. In the present study, we aimed to investigate the plausible molecular factors underlying progression to PDR. To study the association of genetic variants with PDR under the intrauterine famine exposure, we analyzed single nucleotide polymorphisms (SNPs) that were previously reported to be associated with type 2 diabetes, glucose, and pharmacogenetics. Analyses were performed in the population from northern Ukraine with a history of exposure to the Great Ukrainian Holodomor famine [the Diagnostic Optimization and Treatment of Diabetes and its Complications in the Chernihiv Region (DOLCE study), n = 3,583]. A validation of the top genetic findings was performed in the Hong Kong diabetes registry (HKDR, n = 730) with a history of famine as a consequence of the Japanese invasion during WWII. In DOLCE, the genetic risk for PDR was elevated for the variants in ADRA2A, PCSK9, and CYP2C19*2 loci, but reduced at PROX1 locus. The association of ADRA2A loci with the risk of advanced diabetic retinopathy in famine-exposed group was further replicated in HKDR. The exposure of embryonic retinal cells to starvation for glucose, mimicking the perinatal exposure to famine, resulted in sustained increased expression of Adra2a and Pcsk9, but decreased Prox1. The exposure to starvation exhibited a lasting inhibitory effects on neurite outgrowth, as determined by neurite length. In conclusion, a consistent genetic findings on the famine-linked risk of ADRA2A with PDR indicate that the nerves may likely to be responsible for communicating the effects of perinatal exposure to famine on the elevated risk of advanced stages of diabetic retinopathy in adults. These results suggest the possibility of utilizing neuroprotective drugs for the prevention and treatment of PDR.

在饥荒暴露地区的2型糖尿病患者，成年后发生威胁视力的增殖性糖尿病视网膜病变（PDR）的风险显著增加。然而，其潜在机制尚不明确。在本研究中，我们旨在探究导致PDR进展的可能分子因素。为研究遗传变异在子宫内饥荒暴露下与PDR的相关性，我们分析了先前报道与2型糖尿病、血糖和药代遗传学相关的单核苷酸多态性（SNPs）。分析在具有乌克兰大饥荒暴露史的乌克兰北部人群中进行[切尔尼戈夫地区的糖尿病诊断优化和治疗及其并发症（DOLCE研究），n=3,583]。在香港糖尿病登记处（HKDR，n=730）对二战期间日本侵略造成的饥荒历史进行了顶级遗传发现的验证。在DOLCE中，ADRA2A、PCSK9和CYP2C19*2位点的变异导致PDR的遗传风险升高，而PROX1位点的风险降低。ADRA2A位点与饥荒暴露组晚期糖尿病视网膜病变风险的关联在香港糖尿病登记处中得到进一步证实。胚胎视网膜细胞暴露于葡萄糖饥饿，模拟围产期饥荒暴露，导致Adra2a和Pcsk9的持续表达增加，而Prox1表达减少。饥饿暴露对神经突起生长的抑制效应持久存在，如神经突起长度所示。总之，与饥荒相关的ADRA2A风险的一致遗传发现表明，神经可能负责传递围产期饥荒暴露对成人晚期糖尿病视网膜病变高风险的影响。这些结果提示了利用神经保护药物预防和治疗PDR的可能性。