Issei Yoshiuchi
Background: Human adaptation to environmental changes in food supply, lifestyle, and geography may have initiated the selection of genes associated with the metabolism of glucose, lipids, carbohydrates, and energy. Obesity is significantly associated with type 2 diabetes mellitus, metabolic syndrome, hypertension, stroke, and cardiovascular diseases. The worldwide prevalence of obesity and type 2 diabetes is increasing steadily. Obesity and type 2 diabetes are highly heritable diseases that cause serious health problems. The melanocortin-4 receptor gene is one of the major obesity genes, and common genetic variations near the melanocortin-4 receptor gene were found to be associated with obesity, type 2 diabetes, and insulin resistance. We aimed to uncover evidence of selection at melanocortin-4 receptor gene loci using single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes and obesity.
Methods: We analyzed melanocortin-4 receptor gene loci in HapMap populations to detect selection using a 3-step test: Wright’s F-statistics (Fst) as a measure of population differentiation, the long-range haplotype (LRH) test to obtain evidence of positive selection by testing haplotypes, and integrated haplotype score (iHS).
Results: We observed one body mass index (BMI)-associated SNP (rs7227255) and one type 2 diabetesassociated SNP (rs11873305) that exhibited high Fst values, and showed high population differentiation and natural selection at the melanocortin-4 receptor gene loci.
Conclusion: This is the first report that SNPs associated with type 2 diabetes and obesity exhibited high Fst values in one-gene loci. Most of the SNPs associated with type 2 diabetes and obesity that were reported did not demonstrate high Fst values. Our findings are important for clinical medicine. We suggest that melanocortin-4 receptor agonists may be useful drugs for the treatment of obesity and type 2 diabetes, and that further studies should examine the adaptive evolution of obesity, type 2 diabetes, and insulin resistance genes.