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- Title
Identification of Metabolic Modifiers That Underlie Phenotypic Variations in Energy-Balance Regulation.
- Authors
Chia Lin Chang; Cai, James J.; Po Jen Cheng; Ho Yen Chueh; Sheau Yu Teddy Hsu
- Abstract
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.
- Publication
Diabetes, 2011, Vol 60, Issue 3, p726
- ISSN
0012-1797
- Publication type
Academic Journal
- DOI
10.2337/db10-1331