The Low-Expression Variant of Fatty Acid-Binding Protein 4 Favors Reduced Manifestations of Atherosclerotic Disease and Increased Plaque Stability
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 (ER) 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 (MI, 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 (CPs, P=0.060). Consistently, the variant allele homozygotes showed 8-fold lower odds for MI (P=0.019, OR=0.12, 95% CI 0.003-0.801). Within the CPs, 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 CPs was associated with lipid accumulation, intraplaque haemorrhages, plaque ulcerations and phosphoactivated ER 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 ER stress signalling, and attenuation of apoptosis, lipid burden and inflammation.
- ER stress
- coronary artery disease
- carotid stenosis
- Received December 5, 2013.
- Revision received June 10, 2014.
- Accepted June 25, 2014.