We analyzed the effects of the common BMI-increasing
melanocortin 4 receptor (MC4R) rs17782313-C allele with a minor allele frequency of 0.22-0.25 on (1)
cardiovascular disease outcomes in two large population-based cohorts (Copenhagen City Heart Study and Copenhagen General Population Study, n = 106,018; and UK Biobank, n = 357,426) and additionally in an elderly population at risk for
cardiovascular disease (n = 5241), and on (2)
atherosclerotic plaque phenotypes in samples of patients who underwent
endarterectomy (n = 1439). Using regression models, we additionally analyzed whether potential associations were modified by sex or explained by changes in body mass index. We confirmed the BMI-increasing effects of +0.22 kg/m2 per additional copy of the C allele (p < 0.001). However, we found no evidence for an association of common MC4R genetic variation with
coronary artery disease (HR 1.03; 95% CI 0.99, 1.07), ischemic
vascular disease (HR 1.00; 95% CI 0.98, 1.03),
myocardial infarction (HR 1.01; 95% CI 0.94, 1.08 and 1.02; 0.98, 1.07) or
stroke (HR 0.93; 95% CI 0.85, 1.01), nor with any
atherosclerotic plaque phenotype. Thus, common MC4R genetic variation, despite increasing BMI, does not affect
cardiovascular disease risk in the general population or in populations at risk for
cardiovascular disease.