Melanocortin-4 receptor gene and physical activity in the Québec Family Study

Physical inactivity is a risk factor for numerous chronic diseases. Low compliance with interventions to increase activity suggests involvement of biological systems.

To examine whether sequence variants in genes encoding neuropeptides and receptors in the arcuate and paraventricular nucleus of the hypothalamus contribute to variations in physical activity level in the Québec Family Study.

We genotyped polymorphisms in the melanocortin-4 receptor (MC4R), melanocortin-3 receptor (MC3R), neuropeptide-Y (NPY), neuropeptide-Y Y1 receptor (NPY Y1R), cocaine- and amphetamine-regulated transcript (CART), agouti-related protein (AGRP), and pro-opiomelanocortin (POMC) genes in 669 subjects (age (X+/-s.d.): parents: 52+/-3.4 y; offspring: 28+/-8.7 y). Total physical activity, moderate-to-strenuous activity, and inactivity phenotypes were estimated from a three-day record. The past year's physical activity level was assessed from a questionnaire. Associations between the physical activity phenotypes and the polymorphisms were analyzed using the MIXED model (SAS).

The MC4R-C-2745T variant showed significant associations with physical activity phenotypes. The lowest moderate-to-strenuous activity scores (P = 0.005) and the highest inactivity scores (P = 0.01) emerged in the T/T genotype. Exclusion of obese subjects increased the association. For inactivity, the association of the MC4R-C-2745T variant was strongest in the offspring (P = 0.002). The T/T offspring had both the highest inactivity score and the lowest body mass index. The CART-A1475G variant modified the associations with MC4R-C-2745T; T/T homozygotes had the lowest activity scores when they also had the A/A CART-A1475G genotype. No significant associations were observed with polymorphisms in the other neuropeptides.

These findings suggest that DNA sequence variation at the MC4R gene locus may contribute to the propensity to be sedentary.