Low-Expression Variant of Fatty Acid–Binding Protein 4 Favors Reduced Manifestations of Atherosclerotic Disease and Increased Plaque Stability

Abstract

Background— Fatty acid–binding protein 4 (FABP4 or aP2 in mice) has been identified as a key regulator of core aspects of cardiometabolic disorders, including lipotoxic endoplasmic reticulum stress in macrophages. A functional promoter polymorphism ( rs77878271 ) of human FABP4 gene has been described resulting in reduced FABP4 transcription. Methods and Results— We investigated the effects of this low-expression variant of FABP4 on cardiovascular morbidity and carotid atherosclerosis on a population level (n=7491) and in patient cohorts representing endarterectomized patients with advanced carotid atherosclerosis (n=92) and myocardial infarction (n=3432). We found that the low-expression variant was associated with decreased total cholesterol levels ( P =0.006) with the largest reduction in variant allele homozygotes. Obese variant allele carriers also showed reduced carotid intima-media thickness ( P =0.010) and lower prevalence of carotid plaques ( P =0.060). Consistently, the variant allele homozygotes showed 8-fold lower odds for myocardial infarction ( P =0.019; odds ratio, 0.12; 95% confidence interval, 0.003–0.801). Within the carotid plaques, the variant allele was associated with a 3.8-fold reduction in FABP4 transcription ( P =0.049) and 2.7-fold reduction in apoptosis (activated caspase 3; P =0.043). Furthermore, the variant allele was enriched to patients with asymptomatic carotid stenosis ( P =0.038). High FABP4 expression in the carotid plaques was associated with lipid accumulation, intraplaque hemorrhages, plaque ulcerations, and phosphoactivated endoplasmic reticulum stress markers. Conclusions— Our results reveal FABP4 rs77878271 as a novel variant affecting serum total cholesterol levels and cardiovascular risk. A therapeutic regimen reducing FABP4 expression within the atherosclerotic plaque may promote lesion stability through modulation of endoplasmic reticulum stress signaling, and attenuation of apoptosis, lipid burden, and inflammation.