Evidence of interaction between PPARG2 and HNF4A contributing to variation in insulin sensitivity in Mexican Americans.
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.


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 (S(I)) (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 S(I) compared with 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 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 S(I) 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.
Black
Mary Helen
MH
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 1540 Alcazar St., CHP-220, Los Angeles, CA 90089-9011, USA.
Fingerlin
Tasha E
TE
Allayee
Hooman
H
Zhang
Weiming
W
Xiang
Anny H
AH
Trigo
Enrique
E
Hartiala
Jaana
J
Lehtinen
Allison B
AB
Haffner
Steven M
SM
Bergman
Richard N
RN
McEachin
Richard C
RC
Kjos
Siri L
SL
Lawrence
Jean M
JM
Buchanan
Thomas A
TA
Watanabe
Richard M
RM
D019943:Amino Acid Substitution; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D016640:Diabetes, Gestational / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000502:physiology*; D008297:Male; D047495:PPAR gamma / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D012495:San Francisco; D035781:Siblings; D013781:Texas
C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; D047495:PPAR gamma