alpha2-Heremans-Schmid glycoprotein gene polymorphisms are associated with adipocyte insulin action.

AIMS/HYPOTHESIS: The aim of this study was to investigate the effect of single-nucleotide polymorphisms (SNPs) in the gene encoding the human alpha(2)-Heremans-Schmid glycoprotein (AHSG) on obesity and insulin action in adipocytes. METHODS: We screened 24 individuals for SNPs in AHSG. Six haplotype-tagging SNPs were genotyped in 188 lean and 176 obese otherwise healthy women for whom common blood chemistry phenotypes were also available. Adipocyte lipolysis and lipogenesis phenotypes were quantified in a subset of 117 lean and 174 obese women. RESULTS: The -469T>G SNP, which is located in the 5' region of AHSG, was associated with insulin-mediated inhibition of lipolysis and stimulation of lipogenesis, as well as basal and 8-bromocyclic AMP-stimulated lipolysis. Three AHSG SNPs were associated with circulating levels of cholesterol. None of the six genotyped SNPs or inferred haplotypes were associated with BMI, calculated percent body fat, waist circumference, circulating levels of glucose or insulin, or homeostasis model assessment of insulin resistance, which was used as an estimate of in vivo insulin sensitivity. CONCLUSIONS/INTERPRETATION: Our results are in agreement with a threshold model of susceptibility for insulin resistance and type 2 diabetes, in which specific genetic loci regulate intermediate molecular phenotypes. When an individual's set of susceptibility alleles at such loci exceeds a threshold, clinical disease occurs. Lipolysis in adipocytes appears to be a phenotype that is particularly sensitive to variation in AHSG.