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Evidence of Interaction Between Peroxisome Proliferator-Activated Receptor-2 (PPARG2) and Hepatocyte Nuclear Factor-4 (HNF4A) Contributing to Variation in Insulin Sensitivity in Mexican Americans

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

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 (S_I) (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 S_I compared to individuals with at least one G allele. S_I did not vary by rs2144908 genotype among PPARG2 Pro/Pro.

The interaction result for S_I 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 S_I 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.

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