A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease

doi:10.1073/pnas.0602178103

A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease

Departments of *Genetics and Complex Diseases,
^¶Nutrition, and
^†Epidemiology and
^‡Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA 02115; and
^§Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115

Communicated by Barry R. Bloom, Harvard School of Public Health, Boston, MA, March 16, 2006 (received for review December 15, 2005)

Abstract

Obesity and the associated pathologies including dyslipidemia, insulin resistance, type 2 diabetes, and cardiovascular disease constitute a major threat to global human health. Yet, the genetic factors that differentially predispose individuals to this cluster of pathologies are unclear. The fatty acid-binding protein aP2 is a cytoplasmic lipid chaperon expressed in adipocytes and macrophages. Mice with aP2 deficiency are partially resistant to obesity-induced insulin resistance and type 2 diabetes, have lower circulating triglycerides, and exhibit marked protection against atherosclerosis. Here, we demonstrate a functionally significant genetic variation at the aP2 locus in humans that results in decreased adipose tissue aP2 expression due to alteration of the CAAT box/enhancer-binding protein binding and reduced transcriptional activity of the aP2 promoter. In population genetic studies with 7,899 participants, individuals that carry this T-87C polymorphism had lower serum triglyceride levels and significantly reduced risk for coronary heart disease and type 2 diabetes compared with subjects homozygous for the WT allele. Taken together, our results indicate that reduction in aP2 activity in humans generate a metabolically favorable phenotype that is similar to aP2 deficiency in experimental models.

Footnotes

^‖To whom correspondence may be addressed. E-mail: erimm{at}hsph.harvard.edu or ghotamis{at}hsph.harvard.edu
Author contributions: E.B.R. and G.S.H. designed research; G.T., E.E., and X.H. performed research; H.C. contributed new reagents/analytic tools; I.D.V., H.C., E.B.R., and G.S.H. analyzed data; and G.T., E.B.R., and G.S.H. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

C/EBP,

CAAT box/enhancer-binding protein;

CHD,

coronary heart disease;

FABP,

fatty acid-binding protein.
Freely available online through the PNAS open access option.