A novel missense mutation in ADRB3 increases risk for type 2 diabetes in a Mexican American family

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Abstract
Background The human β3-adrenergic receptor gene (ADRB3) has been investigated as a candidate gene for diabetes-related traits in many studies. However, the results have been inconsistent so it is unclear whether variation in ADRB3 is a risk factor for type 2 diabetes. We have identified a novel missense mutation of ADRB3 in a single large pedigree of the San Antonio Family Diabetes/Gallbladder Study (SAFDGS) that is located in the first transmembrane domain at amino acid 62 (Ile62Met). The aim of this study was to investigate the association of this mutation in the SAFDGS with risk for diabetes. Methods Variance components-based statistical methods were used to determine association of this mutation with diabetes traits in the SAFDGS. The ADRB3 gene was also resequenced to identify all variants present in this pedigree. Results Significant association was observed for the Ile62Met mutation and type 2 diabetes (p = 0.01, relative risk 2.3), an earlier age of onset (p = 0.01) and 2-h glucose measures (p = 0.006) in the single pedigree. Average age and body mass index do not differ between the two genotypic groups. In a recent genome-wide linkage analysis of SAFDGS, we observed suggestive linkage of diabetes to this region at marker D8S1477 (2pt LOD of 2.55). The variance attributed to Ile62Met accounted for nearly all of the family-specific LOD score. Conclusions These results suggest that this variant in ADRB3 is influencing diabetes risk in this Mexican American family and supports a role for alterations of the β3-adrenergic receptor in the pathogenesis of type 2 diabetes. Copyright © 2006 John Wiley & Sons, Ltd.