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Sequence, Haplotype, and Association Analysis of ADR2 in a Multiethnic Asthma Case-Control Study

Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio

Correspondence and requests for reprints should be addressed to Eugene Bleecker, M.D., Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases Center for Human Genomics, Wake Forest University Health Sciences, Winston-Salem, NC 27157. E-mail: ebleeck{at}wfubmc.edu

Rationale: The comprehensive evaluation of gene variation, haplotype structure, and linkage disequilibrium is important in understanding the function of ₂-adrenergic receptor gene (ADR2) on disease susceptibility, pulmonary function, and therapeutic responses in different ethnic groups with asthma.

Objectives: To identify ADR2 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 ADR2 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 ADR2 may influence lung function, and may be important in delineating variation in -agonist responses, especially in African Americans.

Key Words: asthma • ₂-adrenergic receptor • -agonist therapy • DNA polymorphisms • pharmacogenomics

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Gene variation and haplotypes relating to the effects of the gene ADR2 on disease susceptibility and therapeutic responses had been previously studied in only a limited fashion. What This Study Adds to the Field There are additional ADR2 genetic variants besides +46 (Gly16Arg) and +79 (Gln27Glu) that are important in determining asthma phenotypes.

 

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