The Low-Expression Variant of FABP4 is Associated with Cardiovascular Disease in Type 1 Diabetes

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 for the development of complications in type 1 diabetes, focusing on a functional, low-expression, variant (rs77878271) in the promoter of the FABP4 gene. For this, we assessed the risk of CVD, stroke, coronary artery disease (CAD), end-stage kidney disease (ESKD), and mortality using Cox proportional-hazard models for the FABP4 rs77878271 in 5,077 Finnish individuals with type 1 diabetes. The low-expression G-allele of rs77878271 increased the risk of CVD, independently 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% (p=0.04), CAD by 26% (p=0.006), and CVD by 17% (p=0.003). In Mendelian Randomization, a decrease in FABP4 increased CAD 2.4-fold. Hence, in contrast to the general population, the low-expression G-allele of rs77878271 increased CVD risk in type 1 diabetes, suggesting that genetically low FABP4 levels may be detrimental in the context of type 1 diabetes.