title: A novel missense mutation in ADRB3 increases risk for type 2 diabetes in a Mexican American family.
abstract: BACKGROUND
  The human beta3-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 beta3-adrenergic receptor in the pathogenesis of type 2 diabetes.
authors.affiliation: Department of Medicine/Clinical Epidemiology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. lehman@uthscsa.edu
authors.forename: Donna M
authors.initials: DM
authors.lastname: Lehman
authors.forename: Jeanette
authors.initials: J
authors.lastname: Hamlington
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Hunt
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Leach
authors.forename: Rector
authors.initials: R
authors.lastname: Arya
authors.forename: Hanna
authors.initials: H
authors.lastname: Abboud
authors.forename: Ravindranath
authors.initials: R
authors.lastname: Duggirala
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: Harald H H
authors.initials: HH
authors.lastname: Göring
authors.forename: Michael P
authors.initials: MP
authors.lastname: Stern
mesh_terms: D020413:3' Untranslated Regions; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D017058:Mexican Americans; D020125:Mutation, Missense; D010375:Pedigree; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics*; D013781:Texas
chemical_list: D020413:3' Untranslated Regions; D017931:DNA Primers; D022702:Receptors, Adrenergic, beta-3