Carole Ober1, Chris G McKennan2, Kevin M Magnaye3, Matthew C Altman4, Charles Washington3, Catherine Stanhope3, Katherine A Naughton3, Mario G Rosasco5, Leonard B Bacharier6, Dean Billheimer7, Diane R Gold8, Lisa Gress9, Tina Hartert10, Suzanne Havstad11, Gurjit K Khurana Hershey12, Brian Hallmark7, D Kyle Hogarth13, Daniel J Jackson9, Christine C Johnson11, Meyer Kattan14, Robert F Lemanske9, Susan V Lynch15, Eneida A Mendonca16, Rachel L Miller17, Edward T Naureckas13, George T O'Connor18, Christine M Seroogy9, Ganesa Wegienka11, Steven R White13, Robert A Wood19, Anne L Wright20, Edward M Zoratti21, Fernando D Martinez22, Dennis Ownby23, Dan L Nicolae3, Albert M Levin11, James E Gern9. 1. Department of Human Genetics, University of Chicago, Chicago, IL, USA. Electronic address: c-ober@genetics.uchicago.edu. 2. Department of Statistics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 3. Department of Human Genetics, University of Chicago, Chicago, IL, USA. 4. Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA. 5. Systems Immunology Program, Benaroya Research Institute, Seattle, WA, USA. 6. Division of Pediatric Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Washington University and St Louis Children's Hospital, St Louis, MO, USA. 7. College of Public Health, University of Arizona, Tucson, AZ, USA; BIO5 Institute, University of Arizona, Tucson, AZ, USA. 8. The Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Environmental Health, Harvard T H Chan School of Public Health, Boston, MA, USA. 9. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. 10. Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. 11. Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA. 12. Division of Asthma Research, Cincinnati Children's Hospital and Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA. 13. Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA. 14. Department of Pediatrics, Columbia University Medical Center, New York, NY, USA. 15. Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. 16. Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA; Department of Pediatrics and Biostatistics, Indiana University, Indianapolis, IN, USA; Regenstrief Institute, Indianapolis, IN, USA. 17. Department of Medicine, Division of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 18. Department of Pediatrics, Boston University, Boston, MA, USA. 19. Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA. 20. Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA. 21. Division of Allergy and Clinical Immunology, Henry Ford Health System, Detroit, MI, USA. 22. Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA; BIO5 Institute, University of Arizona, Tucson, AZ, USA. 23. Department of Pediatrics, Medical College of Georgia, Augusta, GA, USA.
Abstract
BACKGROUND: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12-21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12-21 locus. METHODS: We first did a genetic association study and meta-analysis using 17q12-21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12-21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12-21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). FINDINGS: 17q12-21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p<0·0055 (for rs2305480_G, odds ratio [OR] 1·36 [95% CI 1·12-1·65], p=0·0014; and for rs8076131_A, OR 1·37 [1·13-1·67], p=0·0010). In upper airway epithelial cells from African American children, genotype at rs2305480 was the most significant eQTL for GSDMB (eQTL effect size [β] 1·35 [95% CI 1·25-1·46], p<0·0001), and to a lesser extent showed an eQTL effect for post-GPI attachment to proteins phospholipase 3 (β 1·15 [1·08-1·22], p<0·0001). No SNPs were eQTLs for ORMDL3. By contrast, in PBMCs, the five core SNPs were associated only with expression of GSDMB and ORMDL3. Genotype at rs12936231 (in zona pellucida binding protein 2) showed the strongest associations across both genes (for GSDMB, eQTLβ 1·24 [1·15-1·32], p<0·0001; and for ORMDL3 (β 1·19 [1·12-1·24], p<0·0001). The eQTL effects of rs2305480 on GSDMB expression were replicated in lower airway cells from African American adults (β 1·29 [1·15-1·44], p<0·0001). INTERPRETATION: Our study suggests that SNPs regulating GSDMB expression in airway epithelial cells have a major role in childhood-onset asthma, whereas SNPs regulating the expression levels of 17q12-21 genes in resting blood cells are not central to asthma risk. Our genetic and gene expression data in African Americans and European Americans indicated GSDMB to be the leading candidate gene at this important asthma locus. FUNDING: National Institutes of Health, Office of the Director.
BACKGROUND: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12-21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12-21 locus. METHODS: We first did a genetic association study and meta-analysis using 17q12-21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12-21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12-21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). FINDINGS: 17q12-21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p<0·0055 (for rs2305480_G, odds ratio [OR] 1·36 [95% CI 1·12-1·65], p=0·0014; and for rs8076131_A, OR 1·37 [1·13-1·67], p=0·0010). In upper airway epithelial cells from African American children, genotype at rs2305480 was the most significant eQTL for GSDMB (eQTL effect size [β] 1·35 [95% CI 1·25-1·46], p<0·0001), and to a lesser extent showed an eQTL effect for post-GPI attachment to proteins phospholipase 3 (β 1·15 [1·08-1·22], p<0·0001). No SNPs were eQTLs for ORMDL3. By contrast, in PBMCs, the five core SNPs were associated only with expression of GSDMB and ORMDL3. Genotype at rs12936231 (in zona pellucida binding protein 2) showed the strongest associations across both genes (for GSDMB, eQTLβ 1·24 [1·15-1·32], p<0·0001; and for ORMDL3 (β 1·19 [1·12-1·24], p<0·0001). The eQTL effects of rs2305480 on GSDMB expression were replicated in lower airway cells from African American adults (β 1·29 [1·15-1·44], p<0·0001). INTERPRETATION: Our study suggests that SNPs regulating GSDMB expression in airway epithelial cells have a major role in childhood-onset asthma, whereas SNPs regulating the expression levels of 17q12-21 genes in resting blood cells are not central to asthma risk. Our genetic and gene expression data in African Americans and European Americans indicated GSDMB to be the leading candidate gene at this important asthma locus. FUNDING: National Institutes of Health, Office of the Director.
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