Diverse effect of MC4R risk alleles on obesity-related traits over a lifetime: Evidence from a well-designed cohort study.

This population-based longitudinal study is the first investigation that assesses the association of common MC4R SNPs with the obesity-related parameters over time and determines the effect of risk alleles during the three adulthood life periods (early, middle, and late) in a large Iranian cohort, a population with a unique genetic make-up that has been understudied and relatively unexplored. We obtained the genotype of 5370 unrelated adults who participated in the ongoing Tehran Cardiometabolic Genetic Study (TCGS) cohort project for the common MC4R SNPs. Linear regression and linear mixed model analyses were performed to examine the effect of MC4R polymorphisms on maximum BMI and other obesity-related factors over time. We recognized that several SNPs associated with the maximum BMI and the increased BMI, waist circumference, and waist-hip ratio across Iranian adults over a lifetime. Interestingly, we found that rs9954571-A has a yet unreported protective role against obesity-related factors, including BMI, waist circumference, waist-hip ratio, and triglyceride level. Additionally, a survey of the impact of the MC4R risk score throughout the adulthood life periods indicated that the MC4R risk score is influenced both the elevated BMI and waist circumference only during the early adulthood period. Our findings can expand our knowledge about the MC4R genetic variant's contributions to adulthood obesity and highlight the importance of evaluating the genetic components affecting obesity over a lifetime, which could be considered for obesity clinical screening and treatment.