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No association between variation in the NR4A1 gene locus and metabolic traits in white subjects at increased risk for type 2 diabetes.

ABSTRACT: BACKGROUND:The nuclear receptor NR4A1 is implicated in metabolic regulation in insulin-sensitive tissues, such as liver, adipose tissue, and skeletal muscle. Functional loss of NR4A1 results in insulin resistance and enhanced intramuscular and hepatic lipid content. Therefore, we investigated in a cohort of white European subjects at increased risk for type 2 diabetes whether genetic variation within the NR4A1 gene locus contributes to prediabetic phenotypes, such as insulin resistance, ectopic fat distribution, or beta-cell dysfunction. METHODS:We genotyped 1495 subjects (989 women, 506 men) for five single nucleotide polymorphisms (SNPs) tagging 100% of common variants (MAF = 0.05) within the NR4A1 gene locus with an r2 = 0.8. All subjects underwent an oral glucose tolerance test (OGTT), a subset additionally had a hyperinsulinemic-euglycemic clamp (n = 506). Ectopic hepatic (n = 296) and intramyocellular (n = 264) lipids were determined by magnetic resonance spectroscopy. Peak aerobic capacity, a surrogate parameter for oxidative capacity of skeletal muscle, was measured by an incremental exercise test on a motorized treadmill (n = 270). RESULTS:After appropriate adjustment and Bonferroni correction for multiple comparisons, none of the five SNPs was reliably associated with insulin sensitivity, ectopic fat distribution, peak aerobic capacity, or indices of insulin secretion (all p > or = 0.05). CONCLUSIONS:Our data suggest that common genetic variation within the NR4A1 gene locus may not play a major role in the development of prediabetic phenotypes in our white European population.

SUBMITTER: Mussig K

PROVIDER: S-EPMC2894787 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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No association between variation in the NR4A1 gene locus and metabolic traits in white subjects at increased risk for type 2 diabetes.

Müssig Karsten K Machicao Fausto F Machann Jürgen J Schick Fritz F Claussen Claus D CD Stefan Norbert N Fritsche Andreas A Häring Hans-Ulrich HU Staiger Harald H

BMC medical genetics 20100604

<h4>Background</h4>The nuclear receptor NR4A1 is implicated in metabolic regulation in insulin-sensitive tissues, such as liver, adipose tissue, and skeletal muscle. Functional loss of NR4A1 results in insulin resistance and enhanced intramuscular and hepatic lipid content. Therefore, we investigated in a cohort of white European subjects at increased risk for type 2 diabetes whether genetic variation within the NR4A1 gene locus contributes to prediabetic phenotypes, such as insulin resistance, ...[more]

PMID: 20525362

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Project description:Klotho (KL) gene has been involved in severe alterations of physiological biochemical parameters leading to premature aging-like phenotypes and strikingly shortening lifespan. KL participates to the regulation of a number of intracellular biochemical pathways, including lipid profile and glucose metabolism. Aim of this study was to investigate the possible association between KL locus and biological parameters commonly accepted as indicators of the clinical status in hospitalized older patients. We genotyped the single-nucleotide polymorphisms (SNPs) rs9536314, rs1207568, and rs564481 at the KL locus in 594 hospitalized older patients (65-99 years), consecutively attending a geriatric ward, and tested the association of these KL variants with biological quantitative traits using analyses of covariance and genetic risk score models. Significant associations of rs9536314 with serum levels of hemoglobin, albumin, and high-density lipoprotein cholesterol (HDL-C) as well as significant associations of rs564481 with serum levels of hemoglobin, fasting insulin, and fasting glucose were observed. Gender-segregated analyses confirmed these associations, and suggested that the associations of KL genotypes with HDL-C, fasting glucose and fasting insulin levels may be driven by the female gender, while the association with serum levels of hemoglobin may be driven by the male gender. The association of KL genotypes with creatinine levels was found only in females, while the association with insulin-like growth factor-1 (IGF-1) and lymphocytes count (LC) was found only in males. The genetic risk score (GRS) models further confirmed significant associations among KL SNPs and hemoglobin, total cholesterol, and HDL-C. Gender-segregated analyses with the GRS-tagged approach confirmed the associations with HDL-C, fasting glucose, and fasting insulin levels in females, and with hemoglobin and LC in males. Our findings suggested that KL locus may influence quantitative traits such as serum levels of lipid, fasting glucose, albumin and hemoglobin in hospitalized older patients, with some gender differences suggested for creatinine, IGF-1 levels, and LC, thus being one of the genetic factors possibly contributing to age-related diseases and longevity.

Dataset Information

No association between variation in the NR4A1 gene locus and metabolic traits in white subjects at increased risk for type 2 diabetes.

Publications

No association between variation in the NR4A1 gene locus and metabolic traits in white subjects at increased risk for type 2 diabetes.

Similar Datasets

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