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

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posted on 09.07.2021, 15:25 by Emma H. Dahlström, Jani Saksi, Carol Forsblom, Nicoline Uglebjerg, Nina Mars, Lena M. Thorn, Valma Harjutsalo, Peter Rossing, Tarunveer S. Ahluwalia, Perttu J Lindsberg, Niina Sandholm, Per-Henrik Groop, FinnDiane Study Group
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.

Funding

This work was supported by grants from Folkhälsan Research Foundation, Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Helsinki University Hospital Research Funds (EVO), Finnish Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, the Novo Nordisk Foundation (NNF OC0013659), Dorothea Olivia, Karl Walther och Jarl Walther Perklén Foundation, Medical Society of Finland (Finska Läkaresällskapet), Academy of Finland (299200, 316664, and for N.M: 331671), EFSD award supported by EFSD/Sanofi European Diabetes Research Programme in Macrovascular Complications, Waldemar von Frenckell Foundation, Jane and Aatos Erkko Foundation, Sigrid Jusélius Foundation, Nylands Nation and the Otto Malm Foundation. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb, Genentech Inc., Merck Sharp & Dohme Corp, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, and Novartis Pharma AG.

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