The Low-Expression Variant of FABP4 Is Associated With Cardiovascular Disease in Type 1 Diabetes

Area of Science:

• Genetics
• Cardiology
• Endocrinology

Background:

• Fatty acid binding protein 4 (FABP4) is a key player in cardiometabolic disorders.
• Preclinical studies show FABP4 inhibition or deletion improves metabolic health and protects against atherosclerosis.
• Cardiovascular disease (CVD) is a major complication in type 1 diabetes (T1D).

Purpose of the Study:

• To investigate the role of a specific FABP4 promoter variant (rs77878271) associated with low gene expression in T1D complications.
• To assess the association between the FABP4 rs77878271 variant and the risk of CVD, stroke, coronary artery disease (CAD), end-stage kidney disease, and mortality in T1D patients.

Main Methods:

• Utilized Cox proportional hazards models in a large cohort of Finnish individuals with T1D (n=5,077).
• Assessed the risk of various cardiovascular and kidney outcomes associated with the FABP4 rs77878271 low-expression G allele.
• Validated findings through replication in Danish and additional Finnish T1D cohorts, followed by a meta-analysis and Mendelian randomization study.

Main Results:

• The low-expression G allele of FABP4 rs77878271 was significantly associated with an increased risk of CVD in individuals with T1D.
• Meta-analysis revealed that each G allele copy increased the risk of stroke by 26%, CAD by 26%, and overall CVD by 17%.
• Mendelian randomization indicated a 2.4-fold increased risk of CAD with a one-unit decrease in FABP4 levels.

Conclusions:

• Contrary to findings in the general population, the low-expression G allele of FABP4 rs77878271 elevates CVD risk in the context of type 1 diabetes.
• Genetically determined low FABP4 levels may be detrimental for cardiovascular health in patients with T1D.
• These findings highlight a potential genotype-specific therapeutic target for managing CVD risk in T1D.