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.

这项基于人群的纵向研究是第一次评估常见MC4R SNP 与肥胖相关参数随时间推移的关联，并确定风险等位基因在成年期的三个时期（早期、中期和晚期）的影响。伊朗队列，一个具有独特基因构成的人群，尚未得到充分研究和相对未探索。我们获得了参与针对常见MC4R SNP正在进行的德黑兰心脏代谢遗传研究 (TCGS) 队列项目的 5370 名无关成年人的基因型。进行线性回归和线性混合模型分析以检查MC4R的效果随着时间的推移，最大 BMI 和其他肥胖相关因素的多态性。我们认识到，几个 SNP 与伊朗成年人一生中的最大 BMI 和增加的 BMI、腰围和腰臀比相关。有趣的是，我们发现 rs9954571-A 对肥胖相关因素（包括 BMI、腰围、腰臀比和甘油三酯水平）具有尚未报道的保护作用。此外，一项关于MC4R风险评分在整个成年期影响的调查表明，MC4R风险评分仅在成年早期受到升高的 BMI 和腰围的影响。我们的发现可以扩展我们对MC4R 的了解 遗传变异对成年肥胖的贡献，并强调了评估影响终生肥胖的遗传成分的重要性，这可以考虑用于肥胖临床筛查和治疗。