Association of the β3-adrenergic receptor Trp64Arg polymorphism with common metabolic traits: Studies of 7605 middle-aged white people

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Abstract

Aim/hypothesis

The functional variant Trp64Arg in the β3-adrenergic receptor has previously been examined for association with obesity and insulin resistance with ambiguous results. For further evaluation the present study examined the impact of the Trp64Arg variant on the pathogenesis of type 2 diabetes and obesity in a relatively large, homogenous study population.

Methods

The Trp64Arg polymorphism was genotyped in 7605 Danish subjects using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Association was examined in case-control studies of obesity (1529 cases and 6049 controls) and type 2 diabetes (1373 cases and 4742 controls) and quantitative trait analyses among 5822 individuals. Furthermore, the association of Trp64Arg with type 2 diabetes was examined in a meta-analysis.

Results

The Trp64Arg polymorphism was not associated with obesity. However, the Arg-allele was associated with a slightly increased risk of type 2 diabetes (OR1.15 (CI: 1.01–1.31); p = 0.04), increased insulin resistance estimated by homeostasis model assessment (p = 0.01), higher fasting serum insulin levels (p = 0.01), and higher levels of plasma glucose 2-h after glucose ingestion (p = 0.02). After sex stratification these associations were only present among women. Furthermore, the Arg-allele was borderline associated with type 2 diabetes in a meta-analysis of the present and 26 previous studies (p = 0.06, OR1.27 (CI: 0.99–1.63)) (n = 18891).

Conclusion/interpretation

Trp64Arg does not confer an increased risk of obesity among Danes. Yet, in the present study of 7605 Danes the variant is associated with type 2 diabetes and quantitative traits related to type 2 diabetes.

Section snippets

Study population

Genotyping of the ADRB3 Trp64Arg (rs4994) variant was performed in a total of 7605 Danish white subjects. Three study populations were included in the analyses:

(1) 6215 middle-aged Danes from the greater Copenhagen area sampled at Research Centre for Prevention and Health (the population-based Inter99 cohort) [24]. These individuals included 3045 men and 3170 women aged 46 ± 8 years (mean ± SD) and having a BMI of 26.3 ± 4.6 kg/m2. The prevalence of fasting normoglycaemia and normal glucose tolerance

Results

Heterogeneity between the three study populations with respect to the Arg-allele or genotype frequencies was examined and no heterogeneity was identified. Therefore, combined analyses were conducted. The ADRB3 Trp64Arg allele frequency in 7605 Danes was 7.1% (95% CI: 6.7–7.5%). The Trp64Arg variant was examined for differences in genotype distribution and allele frequency between obese and non-obese individuals (data not shown); but no significant differences were detected. The same analysis

Discussion

The minor allele frequency of the ADRB3 Trp64Arg polymorphism observed in this study population was 0.07 (95% CI: 0.067–0.075) which is consistent with the allele frequency in comparable populations composed of mixed whites, white Americans, and Germans [3], [8], [22]. No consistent and convincing association of the Trp64Arg variant was detected in relation to the pathogenesis of obesity. The power of the present study to detect the effect previously seen [10] was more than 99%. The lack of

Acknowledgments

The study was supported by the Danish Medical Research Council, the Danish Diabetes Association, the Danish Heart Foundation, the Velux Foundation, the European Economic Community (Exgenesis LSHM-CT-2004-005272) and the FOOD Study Group/the Danish Ministry of Food, Agriculture and Fisheries and Ministry of Family and Consumer Affairs (2101-05-0044). The authors wish to thank Annemette Forman, Inge-Lise Wantzin, Tina Lorentzen, and Marianne Stendal for technical assistance and Grete Lademann for

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