Identification of Metabolic Modifiers That Underlie Phenotypic Variations in Energy-Balance Regulation

OBJECTIVE: Although recent studies have shown that human genomes contain hundreds of loci that exhibit signatures of positive selection, variants that are associated with adaptation in energy-balance regulation remain elusive. We reasoned that the difficulty in identifying such variants could be due to heterogeneity in selection pressure and that an integrative approach that incorporated experiment-based evidence and population genetics-based statistical judgments would be needed to reveal important metabolic modifiers in humans. RESEARCH DESIGN AND METHODS: To identify common metabolic modifiers that underlie phenotypic variation in diabetes-associated or obesity-associated traits in humans, or both, we screened 207 candidate loci for regulatory single nucleotide polymorphisms (SNPs) that exhibited evidence of gene–environmental interactions. RESULTS: Three SNPs (rs3895874, rs3848460, and rs937301) at the 5′ gene region of human GIP were identified as prime metabolic-modifier candidates at the enteroinsular axis. Functional studies have shown that GIP promoter reporters carrying derived alleles of these three SNPs (haplotype GIP(−1920A)) have significantly lower transcriptional activities than those with ancestral alleles at corresponding positions (haplotype GIP(−1920G)). Consistently, studies of pregnant women who have undergone a screening test for gestational diabetes have shown that patients with a homozygous GIP(−1920A/A) genotype have significantly lower serum concentrations of glucose-dependent insulinotropic polypeptide (GIP) than those carrying an ancestral GIP(−1920G) haplotype. After controlling for a GIPR variation, we showed that serum glucose concentrations of patients carrying GIP(−1920A/A) homozygotes are significantly higher than that of those carrying an ancestral GIP(−1920G) haplotype (odds ratio 3.53). CONCLUSIONS: Our proof-of-concept study indicates that common regulatory GIP variants impart a difference in GIP and glucose metabolism. The study also provides a rare example that identified the common variant-common phenotypic variation pattern based on evidence of moderate gene–environmental interactions.