title: Identification of metabolic modifiers that underlie phenotypic variations in energy-balance regulation.
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.
  
  
  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.
authors.affiliation: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Kweishan, Taoyuan, Taiwan.
authors.forename: Chia Lin
authors.initials: CL
authors.lastname: Chang
authors.forename: James J
authors.initials: JJ
authors.lastname: Cai
authors.forename: Po Jen
authors.initials: PJ
authors.lastname: Cheng
authors.forename: Ho Yen
authors.initials: HY
authors.lastname: Chueh
authors.forename: Sheau Yu Teddy
authors.initials: SY
authors.lastname: Hsu
mesh_terms: D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D016640:Diabetes, Gestational / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D005951:Glucose Tolerance Test; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy
chemical_list: D005749:Gastric Inhibitory Polypeptide