Differences in Candidate Gene Association between European Ancestry and African American Asthmatic Children

et al. (2011) Differences in Candidate Gene Association between European Ancestry and African American Asthmatic Children. PLoS ONE 6(2): e16522. doi:10.1371/journal.pone.0016522 Differences in Candidate Gene Association between European Ancestry and African American Asthmatic Children Tesfaye M. Baye 0 Melinda Butsch Kovacic 0 Jocelyn M. Biagini Myers 0 Lisa J. Martin 0 Mark Lindsey 0 Tia L. Patterson 0 Hua He 0 Mark B. Ericksen 0 Jayanta Gupta 0 Anna M. Tsoras 0 Andrew Lindsley 0 Marc E. Rothenberg 0 Marsha Wills-Karp 0 N. Tony Eissa 0 Larry Borish 0 Gurjit K. Khurana Hershey 0 Anna Goldberg, Albert Einstein Institute for Research and Education, Brazil 0 1 Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, United States of America, 2 Department of Medicine, Baylor College of Medicine , Houston , Texas, United States of America, 3 Department of Medicine, University of Virginia , Charlottesville, Virginia , United States of America Background: Candidate gene case-control studies have identified several single nucleotide polymorphisms (SNPs) that are associated with asthma susceptibility. Most of these studies have been restricted to evaluations of specific SNPs within a single gene and within populations from European ancestry. Recently, there is increasing interest in understanding racial differences in genetic risk associated with childhood asthma. Our aim was to compare association patterns of asthma candidate genes between children of European and African ancestry. Methodology/Principal Findings: Using a custom-designed Illumina SNP array, we genotyped 1,485 children within the Greater Cincinnati Pediatric Clinic Repository and Cincinnati Genomic Control Cohort for 259 SNPs in 28 genes and evaluated their associations with asthma. We identified 14 SNPs located in 6 genes that were significantly associated (pvalues ,0.05) with childhood asthma in African Americans. Among Caucasians, 13 SNPs in 5 genes were associated with childhood asthma. Two SNPs in IL4 were associated with asthma in both races (p-values ,0.05). Gene-gene interaction studies identified race specific sets of genes that best discriminate between asthmatic children and non-allergic controls. Conclusions/Significance: We identified IL4 as having a role in asthma susceptibility in both African American and Caucasian children. However, while IL4 SNPs were associated with asthma in asthmatic children with European and African ancestry, the relative contributions of the most replicated asthma-associated SNPs varied by ancestry. These data provides valuable insights into the pathways that may predispose to asthma in individuals with European vs. African ancestry. - Funding: This work was supported by National Institutes of Health grant U19A170235-01 (G.K.H.) and 1K01HL103165 (T.M.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Asthma (MIM 600807) is a disease of chronic airway inflammation characterized by recurrent episodes of wheezing, dyspnea, chest tightness, and cough. It affects nearly 300 million individuals worldwide including 20 million adults and children in the United States [1,2]. Approximately 5,000 asthma deaths occur in the US every year [3]. Previous studies have revealed strong familial aggregation with heritability estimates between 36 and 79%, supporting the existence of asthma susceptibility genes. Indeed, more than 120 genes have been found to be associated with asthma- or atopy-related phenotypes as reported in greater than 600 studies [4]. While many studies have evaluated the importance of genetics on asthma susceptibility, most studies employ samples from populations of European descent. Few have focused on asthma risk in African Americans, despite the fact that asthma morbidity and mortality are more prevalent in this subgroup. In the PubMed database, European populations are mentioned 5 times more often in various asthma related literature than African Americans (http://www.ncbi.nlm.nih.gov). Studies in other ethnicities, particularly African-derived populations, are valuable, because they may help localize the signals of association and because additional variants present at high frequency in African-derived populations may be absent or rare in Caucasian samples [5]. Furthermore, it is not clear whether associations with asthma found in the Caucasian samples can be consistently replicated in samples from predominantly recent African ancestry. Genetic, environmental or phenotypic heterogeneity, gene-gene and gene by environment interactions or different recombination histories between populations could all contribute to a lack of replication in African-derived populations. Genetic variants may also have different effects in different populations because of unmeasured (and perhaps unknown) environmental risk factors. Hence, the prognostic utility value of specific variants for asthma risk assessment differs across populations [6]. Given the greater genetic diversity and different linkage disequilibrium (LD) structure exhibited by Africanancestry populations, understanding genetic variation in asthma related genes in African American population could provide novel insights into the etiology of asthma. Therefore, the objective of this study was to identify the similarities and differences in association patterns of asthma and known candidate genes between European ancestry and African American children. To accomplish this objective, we used a carefully collected cohort of children from the greater Cincinnati area as the discovery cohort and an independent replication cohort of Caucasians and publicly available dataset of African Americans. Materials and Methods Study population The analysis included Caucasian and African American asthmatic, allergic and non-allergic children enrolled in the Greater Cincinnati Pediatric Clinic Repository (GCPCR) and Cincinnati Genomic Control Cohort (GCC) and who met the case and control definitions (outlined below). Recruitment for GCPCR began in November, 2003 and is ongoing. Children with asthma and other allergic conditions visiting the allergy/immunology, pulmonary, and dermatology outpatient specialty clinics and from the Emergency Department at CCHMC were invited to participate in the GCPCR. Non-allergic control children were recruited into GCPCR from headache, dental and orthopedic clinics as well as from the community at large using paper and online advertising media. Following written informed consent, participants were asked to provide a buccal (using a cytobrush) or saliva sample (Oragene DNA Self-Collection Kit, DNA Genotek Inc., Ottawa, ON Canada) for DNA isolation and to complete repository specific questionnaires. The GCC is an ongoing community-based cohort of over 1,020 healthy children ages 3 (...truncated)