Sequence, Haplotype, and Association Analysis ofADRβ2in a Multiethnic Asthma Case-Control Study

Abstract

Rationale: The comprehensive evaluation of gene variation, haplotype structure, and linkage disequilibrium is important in understanding the function of β₂-adrenergic receptor gene (ADRβ2) on disease susceptibility, pulmonary function, and therapeutic responses in different ethnic groups with asthma. Objectives: To identify ADRβ2 polymorphisms and haplotype structure in white and African American subjects and to test for genotype and haplotype association with asthma phenotypes. Methods: A 5.3-kb region of ADRβ2 was resequenced in 669 individuals from 429 whites and 240 African Americans. A total of 12 polymorphisms, representing an optimal haplotype tagging set, were genotyped in whites (338 patients and 326 control subjects) and African Americans (222 patients and 299 control subjects). Results: A total of 49 polymorphisms were identified, 21 of which are novel; 31 polymorphisms (frequency > 0.03) were used to identify 24 haplotypes (frequency > 0.01) and assess linkage disequilibrium. Association with ratio (FEV₁/FVC)² for single-nucleotide polymorphism +79 (p < 0.05) was observed in African Americans. Significant haplotype association for (FEV₁/FVC)² was also observed in African Americans. Conclusions: There are additional genetic variants besides +46 (Gly¹⁶Arg) that are important in determining asthma phenotypes. These data suggest that the length of a poly-C repeat (+1269) in the 3′ untranslated region of ADRβ2 may influence lung function, and may be important in delineating variation in β-agonist responses, especially in African Americans.