Fat Mass and Obesity Associated (FTO) and Melanocortin 4 Receptor (MC4R) Gene Variants as Prognostic Markers of Obesity in Quetta City

Background: Obesity is a complex condition caused by environmental and hereditary factors. Single nucleotide polymorphisms (SNPs) in the FTO (rs9939609) and melanocortin-4-receptor (MC4R) (rs17782313) genes have been strongly linked to an increased risk of obesity. This study sought to determine the relationship between these polymorphisms and their combined effects on the risk of obesity in Quetta, Pakistan. Methods: A total of 250 individuals (150 obese and 100 non-obese) aged 18–65 were recruited from Sardar Bahadur Khan Women’s University, Bolan Medical Complex Hospital, and the overall Quetta population. Anthropometric measurements, lifestyle characteristics, and demographic information were gathered using standardized questionnaires. The fat mass and obesity associated FTO rs9939609 and Melanocortin-4-receptor MC4R rs17782313 genes were genotyped using the amplification refractory mutation system polymerase chain reaction method. Results: Both SNPs were associated with obesity across multiple genetic models. For FTO rs9939609, the risk variant significantly increased obesity susceptibility under co-dominant (odds ratio [OR] = 4.13, p = 0.010), recessive (OR = 3.44, p = 0.011), and dominant (OR = 1.91, p = 0.013) models; Similarly, the MC4R rs17782313 variant demonstrated robust association in co-dominant (OR = 3.33 and 3.64, p = 0.009), recessive (OR = 3.37, p = 0.002), and dominant models (OR = 1.88, p = 0.037). Both SNPs deviated from Hardy-Weinberg equilibrium in the obese group, indicating possible selection pressure; risk genotypes were also significantly associated with higher body mass index, weight, and waist-hip ratio ( p < 0.05). Furthermore, combined genotype analysis revealed that the MC4R/FTO variant combination TT/AA (OR = 0.19, p = 0.006) and CC/AT (OR = 0.12, p = 0.002) were significantly predictive of obesity status compared to the wild-type baseline. Conclusion: This study shows a clear correlation between the higher incidence of obesity in Quetta, Pakistan, and the FTO rs9939609 and MC4R rs17782313 polymorphisms. These results of the study play an important role in genetic screening for the evaluation of obesity risk and play an essential role in research related to the role of genetic variables in public health initiatives aimed at preventing obesity.