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Hui-Ju Tsai,
Nishat Shaikh,
Jennifer Y. Kho,
Natalie Battle,
Mariam Naqvi,
Daniel Navarro,
Henry Matallana,
Craig M. Lilly,
Celeste S. Eng, Gunjan Kumar,
Shannon Thyne,
H. George Watson,
Kelley Meade,
Michael LeNoir,
Shweta Choudhry,
Esteban G. Burchard,
from the Study of African Americans, Asthma, Genes Environments (SAGE
[show abstract]
[hide abstract]
ABSTRACT: β2-Adrenergic receptor (β2AR) gene polymorphisms have been reported to be associated with various asthma-related traits in different racial/ethnic populations. However, it is unknown whether β
2
AR genetic variants are associated with asthma in African Americans. In this study, we have examined whether there is association between β
2
AR genetic variants and asthma in African Americans. We have recruited 264 African American asthmatic subjects and 176 matched healthy controls participating in the Study of African Americans, Asthma, Genes and Environments (SAGE). We genotyped seven known and recently identified β
2
AR SNP variants, then tested genotype and haplotype association of asthma-related traits with the β
2
AR SNPs in our African American cohort with adjustment of confounding effect due to admixture background and environmental risk factors. We found a significant association of the SNP −47 (Arg-19Cys) polymorphism with ΔFEF25–75, a measure of bronchodilator drug responsiveness, in African American asthmatics after correction for multiple testing (P=0.001). We did not observe association of the SNP +46 (Arg16Gly) variant with asthma disease diagnosis and asthma-related phenotypes. In contrast to previous results between the Arg16Gly variant and traits related to bronchodilator responsiveness, our results indicate that the Arg-19Cys polymorphism in β upstream peptide may play an important role in bronchodilator drug responsiveness in African American subjects. Our findings highlight the importance of investigating genetic risk factors for asthma in different populations.
Human Genetics 04/2012; 119(5):547-557. · 5.07 Impact Factor
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Shweta Choudhry,
Loretta G. Que,
Zhonghui Yang,
Limin Liu,
Celeste Eng,
Sung O. Kim, Gunjan Kumar,
Shannon Thyne,
Rocio Chapela,
Jose R. Rodriguez-Santana,
William Rodriguez-Cintron,
Pedro C. Avila,
Jonathan S. Stamler,
Esteban G. Burchard
[show abstract]
[hide abstract]
ABSTRACT: Background: Short-acting inhaled β2-agonists such as albuterol are used for bronchodilation and are the mainstay of asthma treatment worldwide. There is significant variation in bronchodilator responsiveness to albuterol not only between individuals but also across racial/ethnic groups. The β2-adrenergic receptor (β2AR) is the target for β2-agonist drugs. The enzyme, S-nitrosoglutathione reductase (GSNOR), which regulates levels of the endogenous bronchodilator S-nitrosoglutathione, has been shown to modulate the response to β2-agonists.
Objective: We hypothesized that there are pharmacogenetic interactions between GSNOR and β2AR gene variants that are associated with variable response to albuterol.
Methods: We performed family-based analyses to test for association between GSNOR gene variants and asthma and related phenotypes in 609 Puerto Rican and Mexican families with asthma. In addition, we tested these individuals for pharmacogenetic interaction between GSNOR and β2AR gene variants and responsiveness to albuterol using linear regression. Cell transfection experiments were performed to test the potential effect of the GSNOR gene variants.
Results: Among Puerto Ricans, several GSNOR SNPs and a haplotype in the 3′UTR were significantly associated with increased risk for asthma and lower bronchodilator responsiveness (P=0.04–0.007). The GSNOR risk haplotype affects expression of GSNOR mRNA and protein, suggesting a gain of function. Furthermore, gene–gene interaction analysis provided evidence of pharmacogenetic interaction between GSNOR and β2AR gene variants and the response to albuterol in Puerto Rican (P=0.03), Mexican (P=0.15) and combined Puerto Rican and Mexican asthmatics (P=0.003). Specifically, GSNOR+17059*β2AR+46 genotype combinations (TG+GG*AG and TG+GG*GG) were associated with lower bronchodilator response.
Conclusion: Genotyping of GSNOR and β2AR genes may be useful in identifying Latino individuals, who might benefit from adjuvant therapy for refractory asthma.
Pharmacogenetics and Genomics 05/2010; 20(6):351-358. · 3.48 Impact Factor
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Shweta Choudhry,
Loretta G Que,
Zhonghui Yang,
Limin Liu,
Celeste Eng,
Sung O Kim, Gunjan Kumar,
Shannon Thyne,
Rocio Chapela,
Jose R Rodriguez-Santana,
William Rodriguez-Cintron,
Pedro C Avila,
Jonathan S Stamler,
Esteban G Burchard
[show abstract]
[hide abstract]
ABSTRACT: Short-acting inhaled beta2-agonists such as albuterol are used for bronchodilation and are the mainstay of asthma treatment worldwide. There is significant variation in bronchodilator responsiveness to albuterol not only between individuals but also across racial/ethnic groups. The beta2-adrenergic receptor (beta2AR) is the target for beta2-agonist drugs. The enzyme, S-nitrosoglutathione reductase (GSNOR), which regulates levels of the endogenous bronchodilator S-nitrosoglutathione, has been shown to modulate the response to beta2-agonists.
We hypothesized that there are pharmacogenetic interactions between GSNOR and beta2AR gene variants that are associated with variable response to albuterol.
We performed family-based analyses to test for association between GSNOR gene variants and asthma and related phenotypes in 609 Puerto Rican and Mexican families with asthma. In addition, we tested these individuals for pharmacogenetic interaction between GSNOR and beta2AR gene variants and responsiveness to albuterol using linear regression. Cell transfection experiments were performed to test the potential effect of the GSNOR gene variants.
Among Puerto Ricans, several GSNOR SNPs and a haplotype in the 3'UTR were significantly associated with increased risk for asthma and lower bronchodilator responsiveness (P=0.04-0.007). The GSNOR risk haplotype affects expression of GSNOR mRNA and protein, suggesting a gain of function. Furthermore, gene-gene interaction analysis provided evidence of pharmacogenetic interaction between GSNOR and beta2AR gene variants and the response to albuterol in Puerto Rican (P=0.03), Mexican (P=0.15) and combined Puerto Rican and Mexican asthmatics (P=0.003). Specifically, GSNOR+17059*beta2AR+46 genotype combinations (TG+GG*AG and TG+GG*GG) were associated with lower bronchodilator response.
Genotyping of GSNOR and beta2AR genes may be useful in identifying Latino individuals, who might benefit from adjuvant therapy for refractory asthma.
Pharmacogenetics and Genomics 03/2010; 20(6):351-8. · 3.48 Impact Factor
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Max A Seibold,
Bin Wang,
Celeste Eng, Gunjan Kumar,
Kenneth B Beckman,
Saunak Sen,
Shweta Choudhry,
Kelley Meade,
Michael Lenoir,
H Geoffrey Watson,
Shannon Thyne,
L Keoki Williams,
Rajesh Kumar,
Kevin B Weiss,
Leslie C Grammer,
Pedro C Avila,
Robert P Schleimer,
Esteban González Burchard,
Robert Brenner
[show abstract]
[hide abstract]
ABSTRACT: A highly heritable and reproducible measure of asthma severity is baseline pulmonary function. Pulmonary function is largely determined by airway smooth muscle (ASM) tone and contractility. The large conductance, voltage and calcium-activated potassium (BK) channel negatively regulates smooth muscle tone and contraction in ASM. The modulatory subunit of BK channels, the beta1-subunit, is critical for proper activation of BK channels in smooth muscle and has shown sex hormone specific regulation. We hypothesized that KCNMB1 genetic variants in African Americans may underlie differences in bronchial smooth muscle tone and thus pulmonary function, possibly in a sex-specific manner. Through resequencing of the KCNMB1 gene we identified several common variants including a novel African-specific coding polymorphism (C818T, R140W). The C818T SNP and four other KCNMB1 variants were genotyped in two independent groups of African American asthmatics (n = 509) and tested for association with the pulmonary function measure--forced expiratory volume (FEV(1)) % of predicted value. The 818T allele is associated with a clinically significant decline (-13%) in FEV(1) in both cohorts of asthmatics among males but not females (P(combined) = 0.0003). Patch clamp electrophysiology studies of the BK channel expressed with the 140Trp variant of the beta1-subunit demonstrated significantly reduced channel openings, predicted by the loss of pulmonary function observed. African American male asthmatics carrying the 818T allele (10% of population) are potentially at risk for greater airway obstruction and increased asthma morbidity. Female asthmatics may be insulated from the deleterious effects of the 818T allele by estrogen-mediated upregulation in BK channel activity.
Human Molecular Genetics 07/2008; 17(17):2681-90. · 7.64 Impact Factor
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Natalie C Battle,
Shweta Choudhry,
Hui-Ju Tsai,
Celeste Eng, Gunjan Kumar,
Kenneth B Beckman,
Mariam Naqvi,
Kelley Meade,
H George Watson,
Michael Lenoir,
Esteban González Burchard
[show abstract]
[hide abstract]
ABSTRACT: Genes in the interleukin (IL)-4/IL-13/IL-4Ralpha pathway have been shown to be associated with asthma and related phenotypes in some populations, but not in others. Furthermore, interaction between these genes has been shown to affect asthma in white and Chinese populations.
To determine whether there are IL-4/IL-13 and IL-4Ralpha gene-gene interactions that are associated with asthma in African Americans.
Eighteen single-nucleotide polymorphisms (SNPs) in IL-4, IL-13, and IL-4Ralpha genes were genotyped in 264 African Americans with asthma and 176 healthy control subjects. We tested the SNPs for genetic associations and gene-gene interactions with asthma, baseline lung function, bronchodilator drug response, and total serum IgE levels.
We identified 94 SNPs in IL-4, IL-13, and IL-4Ralpha genes by directly sequencing these genes in 24 African-American subjects with asthma. Seventeen SNPs were analyzed for association with asthma and related phenotypes. We found no evidence of association in the IL-4 gene. One SNP in the IL-13 gene (A-646G, rs2069743) and two SNPs in the IL-4Ralpha gene (A+4679G, rs1805010, and C+22656T, rs1805015) showed association with lung function (both baseline and post-bronchodilator). Although the association between individual SNPs and asthma-related phenotypes differed from previous studies performed in white and Chinese populations, significant gene-gene interaction was found between the IL-13 (A-646G) and IL-4Ralpha (A+4679G) SNPs for baseline lung function among African-American subjects with asthma.
Gene-gene interaction between the IL-13 and IL-4Ralpha genes may play an important role in asthma among African Americans.
American Journal of Respiratory and Critical Care Medicine 06/2007; 175(9):881-7. · 11.08 Impact Factor
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Natalie C Battle,
Shweta Choudhry,
Hui-Ju Tsai,
Celeste Eng, Gunjan Kumar,
Kenneth Beckman,
Mariam Naqvi,
Kelley Meade,
H George Watson,
Michael Lenoir,
Esteban González Burchard
AJRCCM Articles in Press. Published on February. 01/2007; 15.
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Hui-Ju Tsai,
Nishat Shaikh,
Jennifer Y Kho,
Natalie Battle,
Mariam Naqvi,
Daniel Navarro,
Henry Matallana,
Craig M Lilly,
Celeste S Eng, Gunjan Kumar,
Shannon Thyne,
H George Watson,
Kelley Meade,
Michael LeNoir,
Shweta Choudhry,
Esteban G Burchard
[show abstract]
[hide abstract]
ABSTRACT: Beta2-adrenergic receptor (beta2AR) gene polymorphisms have been reported to be associated with various asthma-related traits in different racial/ethnic populations. However, it is unknown whether beta2AR genetic variants are associated with asthma in African Americans. In this study, we have examined whether there is association between beta2AR genetic variants and asthma in African Americans. We have recruited 264 African American asthmatic subjects and 176 matched healthy controls participating in the Study of African Americans, Asthma, Genes and Environments (SAGE). We genotyped seven known and recently identified beta2AR SNP variants, then tested genotype and haplotype association of asthma-related traits with the beta2AR SNPs in our African American cohort with adjustment of confounding effect due to admixture background and environmental risk factors. We found a significant association of the SNP -47 (Arg-19Cys) polymorphism with DeltaFEF(25-75), a measure of bronchodilator drug responsiveness, in African American asthmatics after correction for multiple testing (P = 0.001). We did not observe association of the SNP +46 (Arg16Gly) variant with asthma disease diagnosis and asthma-related phenotypes. In contrast to previous results between the Arg16Gly variant and traits related to bronchodilator responsiveness, our results indicate that the Arg-19Cys polymorphism in beta upstream peptide may play an important role in bronchodilator drug responsiveness in African American subjects. Our findings highlight the importance of investigating genetic risk factors for asthma in different populations.
Human Genetics 07/2006; 119(5):547-57. · 5.07 Impact Factor
