Dahlström Emma H, Saksi Jani, Forsblom Carol, Uglebjerg Nicoline, Mars Nina, Thorn Lena M, Harjutsalo Valma, Rossing Peter, Ahluwalia Tarunveer S, Lindsberg Perttu J, Sandholm Niina, Groop Per-Henrik
Folkhälsan Research Center, Helsinki, Finland.
Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Diabetes. 2021 Oct;70(10):2391-2401. doi: 10.2337/db21-0056. Epub 2021 Jul 9.
Fatty acid binding protein 4 (FABP4) is implicated in the pathogenesis of cardiometabolic disorders. Pharmacological inhibition or genetic deletion of FABP4 improves cardiometabolic health and protects against atherosclerosis in preclinical models. As cardiovascular disease (CVD) is common in type 1 diabetes, we examined the role of FABP4 in the development of complications in type 1 diabetes, focusing on a functional, low-expression variant (rs77878271) in the promoter of the gene. For this, we assessed the risk of CVD, stroke, coronary artery disease (CAD), end-stage kidney disease, and mortality using Cox proportional hazards models for the rs77878271 in 5,077 Finnish individuals with type 1 diabetes. The low-expression G allele of rs77878271 increased the risk of CVD, independent of confounders. Findings were tested for replication in 852 Danish and 3,678 Finnish individuals with type 1 diabetes. In the meta-analysis, each G allele increased the risk of stroke by 26% ( = 0.04), CAD by 26% ( = 0.006), and CVD by 17% ( = 0.003). In Mendelian randomization, a 1-SD unit decrease in FABP4 increased risk of CAD 2.4-fold. Hence, in contrast with the general population, among patients with type 1 diabetes the low-expression G allele of rs77878271 increased CVD risk, suggesting that genetically low FABP4 levels may be detrimental in the context of type 1 diabetes.
脂肪酸结合蛋白4（FABP4）与心脏代谢紊乱的发病机制有关。在临床前模型中，对FABP4进行药理抑制或基因敲除可改善心脏代谢健康并预防动脉粥样硬化。由于心血管疾病（CVD）在1型糖尿病中很常见，我们研究了FABP4在1型糖尿病并发症发展中的作用，重点关注该基因启动子中的一个功能性低表达变体（rs77878271）。为此，我们使用Cox比例风险模型评估了5077名芬兰1型糖尿病患者中rs77878271的CVD、中风、冠状动脉疾病（CAD）、终末期肾病和死亡风险。rs77878271的低表达G等位基因增加了CVD风险，与混杂因素无关。在852名丹麦和3678名芬兰1型糖尿病患者中对研究结果进行了重复验证。在荟萃分析中，每个G等位基因使中风风险增加26%（P = 0.04），CAD风险增加26%（P = 0.006），CVD风险增加17%（P = 0.003）。在孟德尔随机化分析中，FABP4降低1个标准差单位会使CAD风险增加2.4倍。因此，与普通人群不同，在1型糖尿病患者中，rs77878271的低表达G等位基因增加了CVD风险，这表明在1型糖尿病背景下，FABP4基因水平低可能是有害的。
