A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease.
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.
Tuncman
G
G
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Erbay
E
E
Hom
X
X
De Vivo
I
I
Campos
H
H
Rimm
E B
EB
Hotamisligil
G S
GS
D000273:Adipose Tissue / Q000502:physiology; D000328:Adult; D000818:Animals; D001483:Base Sequence; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000235:genetics*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D050556:Fatty Acid-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009765:Obesity / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014280:Triglycerides / Q000097:blood
D022763:CCAAT-Enhancer-Binding Protein-alpha; D050556:Fatty Acid-Binding Proteins; D020033:Protein Isoforms; D014280:Triglycerides