A promoter polymorphism of the α2-HS glycoprotein gene is associated with its transcriptional activity

Inoue, Mari; Takata, Hiroshi; Ikeda, Yukio; Suehiro, Tadashi; Inada, Shojiro; Osaki, Fumiaki; Arii, Kaoru; Kumon, Yoshitaka; Hashimoto, Kozo

doi:10.1016/j.diabres.2007.08.005

Cited by 20 publications

(22 citation statements)

References 27 publications

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“…This interpretation is supported by a previous study among Swedes, in which lower plasma cholesterol was observed in subjects homozygous for the minor allele (12). Moreover, there are strong indications that this variant is biologically functional; in a Japanese study, serum AHSG levels were associated with Ϫ469TϾG, in which the G allele conferred the higher expression (26). Additionally, the results of the haplotype analysis, together with the finding of higher fasting serum cholesterol, suggest that the Ϫ726T allele may act in the opposite direction to increase the risk of dyslipidemia, although this was not supported by the case-control study.…”

Section: Discussionsupporting

confidence: 74%

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

et al. 2008

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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...

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Section: Discussionsupporting

confidence: 74%

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

et al. 2008

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“…Thus, a greater transcriptional repression of the gene might occur in hepatocytes of minor T-allele carriers, which would lead to lower circulating fetuin-A in T-allele carriers compared with A-allele carriers. The minor T-allele was associated with significantly lower fetuin-A levels in previous studies 42,43 and in this report, giving support to a biological function of this mutation. The pivotal question, why we found concordant associations for all gene tagging polymorphisms, is difficult to answer.…”

Section: Discussionsupporting

confidence: 63%

“…40 -43 The AHSG rs2248690 (g.-799 A/T) polymorphism has been shown to change a transcription factor binding site in the 5Ј-flanking gene region and to alter fetuin-A expression levels in HepG2 cells. 42 Transcription factor AP-1, a corepressor, showed higher affinity to the rs2248690 T-coding sequence. Thus, a greater transcriptional repression of the gene might occur in hepatocytes of minor T-allele carriers, which would lead to lower circulating fetuin-A in T-allele carriers compared with A-allele carriers.…”

Section: Discussionmentioning

confidence: 99%

Association of AHSG Gene Polymorphisms With Fetuin-A Plasma Levels and Cardiovascular Diseases in the EPIC-Potsdam Study

Fisher

Stefan

Saar

et al. 2009

Circ Cardiovasc Genet

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Background-Elevated circulating levels of fetuin-A in blood have been associated with increased risk of cardiovascular disease. The goal of our study was to prospectively investigate the potential causal nature of the association between fetuin-A levels and myocardial infarction (MI) and ischemic stroke by applying a Mendelian randomization approach. Methods and Results-Five tagging single-nucleotide polymorphisms (rs2248690, rs2070633, rs2070635, rs4917, and rs6787344) capturing the common genetic variation of the fetuin-A coding gene ␣ 2 -Heremans-Schmid glycoprotein (AHSG) were genotyped in a case-cohort comprising 214 MI cases, 154 ischemic stroke cases, and 2152 persons who remained free of cardiovascular disease events in the European Prospective Investigation into Cancer and NutritionPotsdam study. One single-nucleotide polymorphism (rs6787344) was discarded because of Hardy-Weinberg disequilibrium. All AHSG tagging single-nucleotide polymorphisms were associated with fetuin-A plasma levels (PϽ0.0001). AHSG rs4917 CϾT showed the strongest association, explaining 21.2% of the phenotypic variance independent of potential confounding factors (ϩ35.5 g/mL increase per C-allele, Pϭ2ϫ10

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“…Thus, serum fetuin-A levels in subjects with DM may vary among clinical settings. Furthermore, some genetic polymorphisms can influence circulating fetuin-A levels 29,30) ; therefore, these factors should be taken into consideration to confirm the relationship between fetuin-A and DM.…”

Section: Discussionmentioning

confidence: 99%

Serum Fetuin-A is an Independent Marker of Insulin Resistance in Japanese Men

Ishibashi

Ikeda

Ohguro

et al. 2010

JAT

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A promoter polymorphism of the α2-HS glycoprotein gene is associated with its transcriptional activity

Cited by 20 publications

References 27 publications

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

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

Association of AHSG Gene Polymorphisms With Fetuin-A Plasma Levels and Cardiovascular Diseases in the EPIC-Potsdam Study

Serum Fetuin-A is an Independent Marker of Insulin Resistance in Japanese Men

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