?2-Heremans?Schmid glycoprotein gene polymorphisms are associated with adipocyte insulin action

Dahlman, Ingrid; Eriksson, Per; Kaaman, Maria; Jiao, Hong; Lindgren, Cecilia M.; Kere, Juha; Arner, Peter

doi:10.1007/s00125-004-1556-7

Cited by 62 publications

(63 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The biological function of AHSG and the Ahsg knockout mouse, as well as the chromosomal localization of AHSG, suggest a potential involvement of AHSG variation in the pathogenesis of metabolic diseases (2,7,10,11), and previous genetic epidemiological studies have shown association of AHSG variants with obesity (14), type 2 diabetes (15), and plasma cholesterol levels (12). In the present study we aimed at replicating these findings by genotyping the previously investigated variants, as well as AHSG tagSNPs.…”

Section: Discussionmentioning

confidence: 61%

“…Thus, attempts have been made to associate AHSG variation with metabolic phenotypes. Three polymorphisms (Ϫ843AϾT/rs2248690, Ϫ469TϾG/rs2077119, and Thr248Met/rs4917) were associated with plasma cholesterol among 291 Swedish women for whom a relationship of Ϫ469TϾG with insulin-mediated inhibition of lipolysis was also shown (12). Thr248Met and Thr256Ser (rs4918), which are in almost perfect linkage disequilibrium (LD), were examined among 176 Japanese subjects in relation to serum concentrations of AHSG, which proved to be largely dependent on AHSG Thr248Met and Thr256Ser genotypes (13).…”

Section: Research Design and Methods-mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2008

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 61%

Section: Research Design and Methods-mentioning

confidence: 99%

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

et al. 2008

View full text Add to dashboard Cite

show abstract

“…24 Abdominal subcutaneous fat biopsies were obtained and basal and hormone (chatecholamines and insulin)-stimulated lipolysis and lipogenesis investigated as described previously. 25 mRNA quantification Total RNA was prepared using the RNeasy Mini Kit (Qiagen GmbH, Hilden, Germany). RNA samples were treated with RNase-free DNase (Qiagen GmbH).…”

Section: Phenotypic Evaluationmentioning

confidence: 99%

“…Cohort 2 was genotyped using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (Sequenom Inc., San Diego, CA, USA) as described. 25 Primers are provided on request. Evaluation of genotyping accuracy is described in the 'Results' section.…”

Section: Phenotypic Evaluationmentioning

confidence: 99%

Association analysis of positional obesity candidate genes based on integrated data from transcriptomics and linkage analysis

et al. 2008

View full text Add to dashboard Cite

Context: Obesity is a typical complex disorder resulting from behaviors promoted in westernized societies in the presence of a genetic predisposition. We hypothesized that new genes predisposing to obesity can be detected at the mRNA level. Objective: To identify susceptibility genes for obesity. Design: Linkage and expression profile data from different cohorts were combined to select novel candidate genes that were analyzed for association with obesity. Setting and participants: University Hospital in Stockholm. Adipose tissue mRNA levels were quantified in 96 women. Two large cohorts with a wide distribution in body mass index (BMI, n ¼ 1013 and 1423) were genotyped. Main outcome measure: mRNA levels and allelic association with obesity. Results: We confirmed association between candidate gene mRNA levels in adipose tissue and obesity. A total of 118 polymorphisms in 16 genes were analyzed for association with obesity. Single nucleotide polymorphism rs1064891, located in the 3 0 UTR of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) gene, was nominally associated with obesity in combined analysis of cohorts 1 and 2 (P ¼ 0.007) and, in men that were lean or had severe obesity, with BMI (P ¼ o0.005). Conclusion: To combine linkage and expression profile data is valuable in finding new obesity genes. PFKFB3, a potential regulator of glycolysis, displays decreased mRNA levels in adipose tissue of obese women, is associated with obesity and is a new promising candidate gene for obesity warranting further studies.

show abstract

“…140 SNPs in the human AHSG gene have been reported to be associated with adipocyte insulin action, obesity and T2DM. [141][142][143] Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an inhibitor of insulin-receptor tyrosine kinase. One ENPP1 haplotype is associated with childhood and morbid obesity, T2DM, as well as circulating levels of ENPP1.…”

Section: Pathways Controlling Lipid Storage In Adipocytesmentioning

confidence: 99%

Obesity and polymorphisms in genes regulating human adipose tissue

Dahlman

Arner

2007

Int J Obes

View full text Add to dashboard Cite

Obesity is the result of an imbalance between food intake and energy expenditure resulting in the storing of energy as fat. Adipose tissue contains the largest store of energy in the body and plays important roles in regulating energy partitioning. Developments in genomics, in particular microarray-based expression profiling, have provided scientists with a number of new candidate genes whose expression in adipose tissue is regulated by obesity. Integrating expression profiles with genome-wide linkage and/or association analyses is a promising strategy to identify new genes underlying susceptibility to obesity. This article provides a comprehensive review of adipose-tissue-expressed genes implicated in predisposition to human obesity. The authors consider the following genes of particular interest: peroxisome proliferator-activated receptor gamma and, potentially, INSIG2 acting in adipogenesis; the adrenoreceptors beta 2 and 3, as well as hormone-sensitive lipase acting on lipolysis; uncoupling protein 2 acting in mitochondria energy expenditure; and among secreted molecules the cytokine tumor necrosis factor alpha and the hormone leptin. With the rapid development in genome research, we predict that additional alleles in genes regulating adipose tissue function will be established as risk factors for common obesity in the coming years. This has important implications for the prevention of obesity and may also offer new therapeutic targets.

show abstract

?2-Heremans?Schmid glycoprotein gene polymorphisms are associated with adipocyte insulin action

Cited by 62 publications

References 22 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 analysis of positional obesity candidate genes based on integrated data from transcriptomics and linkage analysis

Obesity and polymorphisms in genes regulating human adipose tissue

Contact Info

Product

Resources

About