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Published ahead of print on August 24, 2006, doi:10.1164/rccm.200509-1405OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 10, November 2006, 1101-1109

A more recent version of this article appeared on November 15, 2006
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Submitted on September 8, 2005
Accepted on August 23, 2006

Sequence, Haplotype and Association Analysis of ADR{beta}2 in Multi-Ethnic Asthma Case/Control Subjects

Gregory A Hawkins1, Kelan Tantisira2, Deborah A Meyers1, Elizabeth J Ampleford1, Barbara Klanderman2, Stephen B Liggett3, Stephen P Peters1, Scott T Weiss2, and Eugene R Bleecker1*

1 Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA, 2 Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, 3 Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA

* To whom correspondence should be addressed. 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 ADR{beta}2 on disease susceptibility, pulmonary function, and therapeutic responses in different ethnic groups with asthma. Objectives: To identify ADR{beta}2 polymorphisms and haplotype structure in Caucasians and African Americans and to test for genotype and haplotype association with asthma phenotypes. Methods: A 5.3 kb region of ADR{beta}2 was re-sequenced in 669 individuals from (429 Caucasians and 240 African Americans). Twelve polymorphisms representing an optimal haplotype tagging set were genotyped in Caucasians (338 cases and 326 controls) and African Americans (222 cases and 299 controls). Results: Forty-nine polymorphisms were identified, twenty-one of which are novel. Thirty-one polymorphisms (frequency >0.03) were used to identify twenty-four haplotypes (frequency >0.01) and assess linkage disequilibrium. Association with ratio (FEV1/FVC)2 for SNP +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 ADR{beta}2 may influence lung function, and may be important in delineating variation in beta agonist responses, especially in African Americans.
Key words: Beta-2 adrenergic receptor, beta-agonist, DNA polymorphisms, pharmacogenomics, asthma




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