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Published online December 27, 2007
Diabetes 57:1048-1056, 2008
DOI: 10.2337/db07-0848
© 2008 by the American Diabetes Association
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Evidence of Interaction Between PPARG2 and HNF4A Contributing to Variation in Insulin Sensitivity in Mexican Americans

Mary Helen Black1, Tasha E. Fingerlin2, Hooman Allayee1,3, Weiming Zhang2, Anny H. Xiang1, Enrique Trigo4, Jaana Hartiala1,3, Allison B. Lehtinen5, Steven M. Haffner6, Richard N. Bergman7, Richard C. McEachin8, Siri L. Kjos9, Jean M. Lawrence10, Thomas A. Buchanan4,7, and Richard M. Watanabe1,7

1 Department of Preventive Medicine, Division of Biostatistics, Keck School of Medicine, University of Southern California, Los Angeles, California
2 Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
3 Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
4 Department of Medicine, Division of Diabetes and Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California
5 Department of Biochemistry and Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
6 Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas
7 Department of Physiology and Biophysics, Keck School of Medicine of University of Southern California, Los Angeles, California
8 Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan
9 Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Los Angeles, California
10 Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California

Address correspondence and reprint requests to Richard M. Watanabe, PhD, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1540 Alcazar St., CHP-220, Los Angeles, CA 90089-9011. E-mail: rwatanab{at}usc.edu

Abbreviations: AIR, acute insulin response; GDM, gestational diabetes mellitus; IRASFS, Insulin Resistance Atherosclerosis Family Study; IVGTT, intravenous glucose tolerance test; MTTP, microsomal triglyceride transfer protein; OGTT, oral glucose tolerance test; SNP, single nucleotide polymorphism

OBJECTIVE—We hypothesized that interaction between PPARG2 Pro12Ala and variants in the promoter region of HNF4A are associated with type 2 diabetes–related quantitative traits in Mexican-American families of a proband with previous gestational diabetes.

RESEARCH DESIGN AND METHODS—The BetaGene project genotyped PPARG2 Pro12Ala and nine 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 and intravenous glucose tolerance tests.

RESULTS—Neither PPARG2 Pro12Ala nor any of the nine HNF4A SNPs were independently associated with type 2 diabetes–related quantitative traits. However, the interaction between PPARG2 Pro12Ala and HNF4A rs2144908 was significantly associated with both insulin sensitivity (SI) (Bonferroni P = 0.0006) and 2-h insulin (Bonferroni P = 0.039). Subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had 40% higher SI compared with individuals with at least one G allele. SI did not vary by rs2144908 genotype among PPARG2 Pro/Pro. The interaction result for SI was replicated by the Insulin Resistance Atherosclerosis Family Study (P = 0.018) in their San Antonio sample (n = 484) where subjects with at least one PPARG2 Ala allele and homozygous for the HNF4A rs2144908 A allele had a 29% higher SI compared with 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 type 2 diabetes.


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