Evidence of Interaction Between Peroxisome Proliferator-Activated Receptor-γ2 (PPARG2) and Hepatocyte Nuclear Factor-4α (HNF4A) Contributing to Variation in Insulin Sensitivity in Mexican Americans

  1. Mary Helen Black1,
  2. Tasha E. Fingerlin2,
  3. Hooman Allayee1,,3,
  4. Weiming Zhang2,
  5. Anny H. Xiang1,
  6. Enrique Trigo4,
  7. Jaana Hartiala1,,3,
  8. Allison B. Lehtinen5,
  9. Steven M. Haffner6,
  10. Richard N. Bergman7,
  11. Richard C. McEachin8,
  12. Siri L. Kjos9,
  13. Jean M. Lawrence,
  14. Thomas A. Buchanan4,,7 and
  15. Richard M. Watanabe (rwatanab{at}usc.edu)1,,7
  1. 1 Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine of USC, Los Angeles, CA
  2. 2 Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, CO
  3. 3 Institute for Genetic Medicine, Keck School of Medicine of USC, Los Angeles, CA
  4. 4 Department of Medicine, Division of Diabetes and Endocrinology, Keck School of Medicine of USC, Los Angeles, CA
  5. 5 Department of Biochemistry and Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC
  6. 6 Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio, San Antonio, TX
  7. 7 Department of Physiology and Biophysics, Keck School of Medicine of USC, Los Angeles, CA
  8. 8 Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI
  9. 9 Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Los Angeles, CA
  10. 10 Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA

    Abstract

    Objective: We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are be associated with type 2 diabetes (T2D)-related quantitative traits (QT) in Mexican-American families of a proband with previous gestational diabetes mellitus (GDM).

    Research Design and Methods: The BetaGene project genotyped PPARG2 Pro12Ala and 9 HNF4A single nucleotide polymorphisms (SNPs) in 473 individuals in 89 families. Members of the proband generation had fasting glucose <126 mg/dl and were phenotyped by oral (OGTT) and intravenous (IVGTT) glucose tolerance tests.

    Results: Neither PPARG2 Pro12Ala nor any of the 9 HNF4A SNPs were independently associated with T2D-related QTs. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity (SI) (Bonferroni p=0.0006) and 2-hr insulin (Bonferroni p=0.039). Subjects with at least one PPARG2 Ala allele and homozygous for HNF4A rs2144908 A allele had 40% higher SI compared to individuals with at least one G allele. SI did not vary by rs2144908 genotype among PPARG2 Pro/Pro.

    Results: The interaction result for SI was replicated by the IRAS Family Study (p=0.018) in their San Antonio sample (n=484) where subjects with at least one PPARG2 Ala allele and homozygous for HNF4A rs2144908 A allele had a 29% higher SI compared to individuals with at least one G allele. However, the interaction was not replicated in their San Luis Valley sample (n=496; p=0.401).

    Conclusions: Together, these results suggest that variation in PPARG2 and HNF4A may interact to regulate insulin sensitivity in Mexican-Americans at risk for T2D.

    Footnotes

      • Received June 22, 2007.
      • Accepted December 19, 2007.

    This Article

    1. Published online before print December 27, 2007, doi: 10.2337/db07-0848
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