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

  1. Sheau Yu Teddy Hsu4
  1. 1Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan, Taiwan
  2. 2Department of Biology, Stanford University, Stanford, California
  3. 3Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas
  4. 4Reproductive Biology and Stem Cell Research Program, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California
  1. Corresponding author: Sheau Yu Teddy Hsu, teddyhsu{at}


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.

  • Received September 22, 2010.
  • Accepted December 12, 2010.

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