AHSG Tag Single Nucleotide Polymorphisms Associate With Type 2 Diabetes and Dyslipidemia

Abstract

OBJECTIVE-The gene encoding the ␣2 Heremans-Schmid glycoprotein (AHSG) is a credible biological and positional candidate gene for type 2 diabetes and the metabolic syndrome, and previous attempts to relate AHSG variation with type 2 diabetes and obesity in Swedish and French Caucasians have been largely successful. We related seven frequent AHSG tag single nucleotide polymorphisms to a range of metabolic traits, including type 2 diabetes, obesity, and dyslipidemia. RESEARCH DESIGN AND METHODS-The polymorphisms were genotyped in 7,683 white Danish subjects using Taqman allelic discrimination or chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, providing a statistical power of Ͼ99% to replicate previous findings. Data were analyzed in case-control and haplotype settings, and quantitative metabolic traits were examined for association. Moreover, epistatic effects between AHSG variants and insulin receptor substrate-1 (IRS1) and ␤-2-adrenergic receptor polymorphisms were investigated.RESULTS-The Ϫ469TϾG (rs2077119) and IVS6ϩ98CϾT (rs2518136) polymorphisms were associated with type 2 diabetes (P ϭ 0.007 and P ϭ 0.006, respectively, or P corr ϭ 0.04 and P corr ϭ 0.03, respectively, following correction for multiple hypothesis testing), and in a combined analysis of the present and a previous study Ϫ469TϾG remained significant (odds ratio 0.90 [95% CI 0.84 -0.97]; P ϭ 0.007). Furthermore, two AHSG haplotypes were associated with dyslipidemia (P ϭ 0.003 and P corr ϭ 0.009). Thr248Met (rs4917) tended to associate with lower fasting and post-oral glucose tolerance test serum insulin release (P ϭ 0.02, P corr ϭ 0.1 for fasting and P ϭ 0.04, P corr ϭ 0.2 for area under the insulin curve) and improved insulin sensitivity estimated by the homeostasis model assessment of insulin resistance (9.0 vs. 8.6 mmol ⅐ l Ϫ1 ⅐ pmol Ϫ1 ⅐ l Ϫ1 ; P ϭ 0.01, P corr ϭ 0.06). Indications of epistatic effects of AHSG variants with the IRS1 Gly971Arg polymorphism were observed for fasting serum triglyceride concentrations.CONCLUSIONS-Based on present and previous findings, common variation in AHSG may contribute to the interindividual variation in metabolic traits. Diabetes 57:1427-1432, 2008 T he ␣ 2 Heremans-Schmid glycoprotein (AHSG) is secreted mainly by the liver and is abundant in plasma. AHSG inhibits insulin-stimulated insulin receptor autophosphorylation, insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 (IRS1), and the association of IRS1 with the p85 subunit of phosphatidylinositol-3 kinase in vitro (1-3). Elevated plasma AHSG was associated with insulin resistance in humans (4), and AHSG levels were higher in subjects with impaired glucose tolerance (5) and women with gestational diabetes (6). Ahsg knockout mice demonstrate increased basal and insulin-stimulated insulin receptor phosphorylation, increased glucose clearance, and insulin sensitivity (7). Moreover, even on a high-fat diet and at old age Ahsg knockout mice were resistant to weight gain and remained insulin sens...

Fetuin-A (AHSG) and its usefulness in clinical practice. Review of the literature

“…Additionally fetuin-null mice have been protected to weight gain when they have been challenging with a high-fat diet 14,21 . Furthermore in those animal model lower serum free fatty acid and triglyceride levels have been observed 15,22 . Mathews et al, based on mice study, suggested that the absence of fetuin-A may contribute to the improvement of insulin sensitivity associated with aging 23 .…”

“…Moreover the role of fetuin-A gene variations in regulation of lipolysis and lipid disturbances have been postulated, for instance two fetuin-A SNPs (-469T>G and IVS6+98C>T) were connected to dyslipidemia and -469T>G SNP which is located in the 5' region of fetuin-A gene was associated with insulin-mediated inhibition of lipolysis and stimulation of lipogenesis. What is more, three fetuin-A gene SNPs (-843A>T, -469T>G and 6670T>C) have been linked to circulating levels of cholesterol 15,30 . Furthermore, fetuin-A knockout mice have a lower triglyceride and free fatty acid level as compared with wild-type controls 7 .…”

“…More than 25 million US adults have type 2 diabetes mellitus, and this figure will likely reach 50 million by 2050 given the current demographic trends and continued progression of obesity 38 . In cross-sectional studies, genetic analyses revealed that SNPs in the fetuin-A gene (located at a susceptibility locus for type 2 diabetes) are linked to type 2 diabetes 15,17 . For instance, Siddq et al based on the cohort of French Caucasians, found that the major allele of fetuin-A SNP rs1071592 is associated with type 2 diabetes.…”

“…In humans, the gene for fetuin-A is localized on chromosome 3q27, which has been mapped as a susceptibility locus for MetS and type 2 diabetes mellitus 6,14,15 . What is more, several single nucleotide polimorphisms (SNPs) of the fetuin-A gene were found to be associated with adipocyte insulin action, dyslipidemia and type 2 diabetes as well [16][17][18] .…”

Principal-component-based multivariate regression for genetic association studies of metabolic syndrome components

“…SNP rs11926347, in an intron of ABCC5 (OMIM 60521), and SNP rs6795506, near the 5' end of AHSG (OMIM 138680), had extremely small p-values (Table 8). Among the other nine genes, ADIPOQ (OMIM 605441, 612556) has been widely reported to be associated with obesity and diabetes [21-24]; FNDC3B (OMIM 611909) is involved in positive regulation of adipogenesis [25]; and DGKG (OMIM 601854) and AHSG (OMIM 138680) have been reported to be associated with obesity-related metabolic traits [26,27]. The remaining genes have no reported relation to obesity-related metabolic traits based on our literature review.…”