Dataset Information

Genetic ancestry modifies pharmacogenetic gene-gene interaction for asthma.

ABSTRACT: A recent admixture mapping analysis identified interleukin 6 (IL6) and IL6 receptor (IL6R) as candidate genes for inflammatory diseases. In the airways during allergic inflammation, IL6 signaling controls the production of proinflammatory and anti-inflammatory factors. In addition, albuterol, a commonly prescribed asthma therapy, has been shown to influence IL6 gene expression. Therefore, we reasoned that interactions between the IL6 and IL6R genes might be associated with bronchodilator drug responsiveness to albuterol in asthmatic patients.Four functional IL6 single nucleotide polymorphisms (SNPs) and a nonsynonymous IL6R SNP were genotyped in 700 Mexican and Puerto Rican asthma families and in 443 African-American asthma cases and controls. Both family-based association tests and linear regression models were used to assess the association between individual SNPs and haplotypes with bronchodilator response. Gene-gene interactions were tested by using multiple linear regression analyses.No single SNP was consistently associated with drug response in all the three populations. However, on the gene level, we found a consistent IL6 and IL6R pharmacogenetic interaction in the three populations. This pharmacogenetic gene-gene interaction was contextual and dependent upon ancestry (racial background). This interaction resulted in higher drug response to albuterol in Latinos, but lower drug response in African-Americans. Herein, we show that there is an effect modification by ancestry on bronchodilator responsiveness to albuterol.Genetic variants in the IL6 and IL6R genes act synergistically to modify the bronchodilator drug responsiveness in asthma and this pharmacogenetic interaction is modified by the genetic ancestry.

SUBMITTER: Corvol H

PROVIDER: S-EPMC2768127 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic ancestry modifies pharmacogenetic gene-gene interaction for asthma.

Corvol Harriet H De Giacomo Anthony A Eng Celeste C Seibold Max M Ziv Elad E Chapela Rocio R Rodriguez-Santana Jose R JR Rodriguez-Cintron William W Thyne Shannon S Watson H Geoffrey HG Meade Kelley K LeNoir Michael M Avila Pedro C PC Choudhry Shweta S Burchard Esteban González EG

Pharmacogenetics and genomics 20090701 7

<h4>Objective</h4>A recent admixture mapping analysis identified interleukin 6 (IL6) and IL6 receptor (IL6R) as candidate genes for inflammatory diseases. In the airways during allergic inflammation, IL6 signaling controls the production of proinflammatory and anti-inflammatory factors. In addition, albuterol, a commonly prescribed asthma therapy, has been shown to influence IL6 gene expression. Therefore, we reasoned that interactions between the IL6 and IL6R genes might be associated with bron ...[more]

PMID: 19503017

Similar Datasets

Project description:BackgroundInherited cardiomyopathy associates with a range of phenotypes, mediated by genetic and nongenetic factors. Noninherited cardiomyopathy also displays varying progression and outcomes. Expression of cardiomyopathy genes is under the regulatory control of promoters and enhancers, and human genetic variation in promoters and enhancers may contribute to this variability.MethodsWe superimposed epigenomic profiling from hearts and cardiomyocytes, including promoter-capture chromatin conformation information, to identify enhancers for 2 cardiomyopathy genes, MYH7 and LMNA. Enhancer function was validated in human cardiomyocytes derived from induced pluripotent stem cells. We also conducted a genome-wide search to ascertain genomic variation in enhancers positioned to alter cardiac expression and correlated one of these variants to cardiomyopathy progression using biobank data.ResultsMultiple enhancers were identified and validated for LMNA and MYH7, including a key enhancer that regulates the switch from MYH6 expression to MYH7 expression. Deletion of this enhancer resulted in a dose-dependent increase in MYH6 and faster contractile rate in engineered heart tissues. We searched for genomic variation in enhancer sequences across the genome, with a focus on nucleotide changes that create or interrupt transcription factor binding sites. The sequence variant, rs875908, disrupts a T-Box Transcription Factor 5 binding motif and maps to an enhancer region 2 kilobases from the transcriptional start site of MYH7. Gene editing to remove the enhancer that harbors this variant markedly reduced MYH7 expression in human cardiomyocytes. Using biobank-derived data, rs875908 associated with longitudinal echocardiographic features of cardiomyopathy.ConclusionsEnhancers regulate cardiomyopathy gene expression, and genomic variation within these enhancer regions associates with cardiomyopathic progression over time. This integrated approach identified noncoding modifiers of cardiomyopathy and is applicable to other cardiac genes.

Project description:BACKGROUND:Pharmacogenetic testing may change clinical medicine by allowing clinicians to tailor medications based on a patient's genetic makeup, however, these tests must first be validated in large, real-life populations of subjects that include children. A dearth of knowledge exists for whether pediatric populations are as willing as adult populations to provide samples for such studies. OBJECTIVE:(1) To assess whether pediatric and adult patients with persistent asthma are willing to provide specimens for DNA extraction and genetic studies. (2) To assess whether patients' willingness to provide blood as compared to buccal smear specimens differ. METHODS:Of 644 patients ages 4-38 years who had three or more prescription fills for inhaled corticosteroids in one year, 60% (385) were randomized to the blood specimen group and 40% (259) were randomized to the buccal smear group in order to study acceptance of different biospecimen collection methods. Research assistants contacted subjects to obtain consent, perform a phone survey, and request a specimen. RESULTS:There were no baseline differences between subjects randomized to the blood specimen group versus buccal smear group with respect to age, gender, or number of dispensings of inhaled corticosteroids. Of 259 subjects in the buccal smear group, 30% (78) provided samples, and of 385 subjects in the blood specimen group, 16% (60) provided samples. Subjects randomized to the buccal smear group were more likely to provide specimens for genetic study compared to subjects randomized to the blood specimen group (RR 1.21; 95% CI 1.10 - 1.32), even after adjusting for age. Pediatric subjects were more likely to provide specimens for genetic study than adult subjects with 23% (113) of pediatric subjects providing samples and 15% (25) of adult subjects providing samples (p=0.03). CONCLUSION:Children with asthma are as likely to participate in genetic studies as adults. Both children and adult subjects are more likely to provide buccal smear specimens rather than blood specimens for genetic study.

Dataset Information

Genetic ancestry modifies pharmacogenetic gene-gene interaction for asthma.

Publications

Genetic ancestry modifies pharmacogenetic gene-gene interaction for asthma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets