A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease
Vivo, I. De
Rimm, Eric Bruce::0ab2926c8242f35e5a982e3cf59f4987::600
Hotamisligil, G. S.
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CitationTuncman, G., E. Erbay, X. Hom, I. De Vivo, H. Campos, E. B. Rimm, and G. S. Hotamisligil. 2006. “A Genetic Variant at the Fatty Acid-Binding Protein aP2 Locus Reduces the Risk for Hypertriglyceridemia, Type 2 Diabetes, and Cardiovascular Disease.” Proceedings of the National Academy of Sciences 103 (18): 6970–75. https://doi.org/10.1073/pnas.0602178103.
AbstractObesity 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.
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