title: Variation in PPARG is associated with longitudinal change in insulin resistance in Mexican Americans at risk for type 2 diabetes.
abstract: BACKGROUND
  Peroxisome proliferator-activated receptor gamma (PPARG) is a susceptibility locus for type 2 diabetes mellitus (T2DM). Although cross-sectional associations have been reported, primarily for Pro12Ala, few longitudinal studies in nondiabetic populations have been conducted.
  
  
  OBJECTIVE
  This study aimed to examine whether and to what extent variation in PPARG is associated with longitudinal changes in anthropometric and metabolic traits in Mexican Americans at risk for T2DM.
  
  
  METHODS
  Subjects were participants of BetaGene, a family-based study of obesity, insulin resistance, and β-cell function, who completed a baseline and follow-up study visit (n = 378; mean followup, 4.6 ± 1.5 y). Phenotypes included body fat assessed by dual-energy x-ray absorptiometry; insulin sensitivity (SI), acute insulin response, and β-cell function (disposition index; DI) were estimated from iv glucose tolerance tests with Minimal Model analysis. Eighteen tag single nucleotide polymorphisms (SNPs) capturing variation in a 156-kb region surrounding PPARG were tested for association with changes in longitudinal traits. P-values were Bonferroni-corrected for multiple testing.
  
  
  RESULTS
  Six SNPs (rs2972164, rs11128598, rs17793951, rs1151996, rs1175541, rs3856806) were significantly associated with rate of change in SI after adjustment for age, sex, and body fat percentage, but not with changes in adiposity. rs17793951 also had a significant effect on change in DI over time. Association between rs1175541 and change in SI varied by changes in adiposity such that only carriers of the minor allele who reduced body fat over followup improved SI. rs1306470 (captured Pro12Ala, r(2) = 0.9) was not associated with rates of change in any traits and its effects were not modified by changes in adiposity.
  
  
  CONCLUSIONS
  Variation in PPARG, but not Pro12Ala, contributes to declining SI and concomitant deterioration in β-cell function in Mexican Americans at risk for T2DM.
authors.affiliation: Department of Research & Evaluation (M.H.B., J.W., M.T., J.M.L., A.H.X.), Kaiser Permanente Southern California, Pasadena, California; Department of Preventive Medicine (N.W., R.M.W., T.A.B.), Keck School of Medicine of University of Southern California (USC), Los Angeles, California; Medical Genetics Institute (K.D.T., T.H.), Cedars-Sinai Medical Center, Los Angeles, California; Department of Medicine (E.T.), Keck School of Medicine of USC, Los Angeles, California; USC Diabetes and Obesity Research Institute (R.M.W., T.A.B.), Los Angeles, California; Department of Physiology & Biophysics (R.M.W., T.A.B.), Keck School of Medicine of USC, Los Angeles, California.
authors.forename: Mary Helen
authors.initials: MH
authors.lastname: Black
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Miwa
authors.initials: M
authors.lastname: Takayanagi
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Talin
authors.initials: T
authors.lastname: Haritunians
authors.forename: Enrique
authors.initials: E
authors.lastname: Trigo
authors.forename: Jean M
authors.initials: JM
authors.lastname: Lawrence
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watanabe
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Buchanan
authors.forename: Anny H
authors.initials: AH
authors.lastname: Xiang
mesh_terms: D000328:Adult; D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D017058:Mexican Americans / Q000235:genetics*; D047495:PPAR gamma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000235:genetics; D055815:Young Adult
chemical_list: D047495:PPAR gamma; D011392:Proline; D000409:Alanine