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dc.contributor.authorOber, Carole
dc.contributor.authorMcKennan, Chris G
dc.contributor.authorMagnaye, Kevin M
dc.contributor.authorAltman, Matthew C
dc.contributor.authorWashington, Charles
dc.contributor.authorStanhope, Catherine
dc.contributor.authorNaughton, Katherine A
dc.contributor.authorRosasco, Mario G
dc.contributor.authorBacharier, Leonard B
dc.contributor.authorBillheimer, Dean
dc.contributor.authorGold, Diane R
dc.contributor.authorGress, Lisa
dc.contributor.authorHartert, Tina
dc.contributor.authorHavstad, Suzanne
dc.contributor.authorKhurana Hershey, Gurjit K
dc.contributor.authorHallmark, Brian
dc.contributor.authorHogarth, D Kyle
dc.contributor.authorJackson, Daniel J
dc.contributor.authorJohnson, Christine C
dc.contributor.authorKattan, Meyer
dc.contributor.authorLemanske, Robert F
dc.contributor.authorLynch, Susan V
dc.contributor.authorMendonca, Eneida A
dc.contributor.authorMiller, Rachel L
dc.contributor.authorNaureckas, Edward T
dc.contributor.authorO'Connor, George T
dc.contributor.authorSeroogy, Christine M
dc.contributor.authorWegienka, Ganesa
dc.contributor.authorWhite, Steven R
dc.contributor.authorWood, Robert A
dc.contributor.authorWright, Anne L
dc.contributor.authorZoratti, Edward M
dc.contributor.authorMartinez, Fernando D
dc.contributor.authorOwnby, Dennis
dc.contributor.authorNicolae, Dan L
dc.contributor.authorLevin, Albert M
dc.contributor.authorGern, James E
dc.contributor.authorHoepner, Lori
dc.date.accessioned2022-10-11T15:46:54Z
dc.date.available2022-10-11T15:46:54Z
dc.identifier.citationOber C, McKennan CG, Magnaye KM, Altman MC, Washington C 3rd, Stanhope C, Naughton KA, Rosasco MG, Bacharier LB, Billheimer D, Gold DR, Gress L, Hartert T, Havstad S, Khurana Hershey GK, Hallmark B, Hogarth DK, Jackson DJ, Johnson CC, Kattan M, Lemanske RF, Lynch SV, Mendonca EA, Miller RL, Naureckas ET, O'Connor GT, Seroogy CM, Wegienka G, White SR, Wood RA, Wright AL, Zoratti EM, Martinez FD, Ownby D, Nicolae DL, Levin AM, Gern JE; Environmental Influences on Child Health Outcomes-Children's Respiratory Research Workgroup. Expression quantitative trait locus fine mapping of the 17q12-21 asthma locus in African American children: a genetic association and gene expression study. Lancet Respir Med. 2020 May;8(5):482-492. doi: 10.1016/S2213-2600(20)30011-4. PMID: 32380068; PMCID: PMC7335429.en_US
dc.identifier.eissn2213-2619
dc.identifier.doi10.1016/S2213-2600(20)30011-4
dc.identifier.pmid32380068
dc.identifier.urihttp://hdl.handle.net/20.500.12648/7689
dc.description.abstractBackground: 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.en_US
dc.language.isoenen_US
dc.relation.urlhttps://www.clinicalkey.com/#!/content/playContent/1-s2.0-S2213260020300114en_US
dc.rightsCopyright © 2020 Elsevier Ltd. All rights reserved.
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.titleExpression quantitative trait locus fine mapping of the 17q12-21 asthma locus in African American children: a genetic association and gene expression study.en_US
dc.typeArticle/Reviewen_US
dc.source.journaltitleThe Lancet. Respiratory medicineen_US
dc.source.volume8
dc.source.issue5
dc.source.beginpage482
dc.source.endpage492
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited Kingdom
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dc.source.countryUnited Kingdom
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dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryEngland
dc.description.versionVoRen_US
refterms.dateFOA2022-10-11T15:46:55Z
dc.description.institutionSUNY Downstateen_US
dc.description.departmentEnvironmental and Occupational Health Sciencesen_US
dc.description.degreelevelN/Aen_US
dc.identifier.journalThe Lancet. Respiratory medicine


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Except where otherwise noted, this item's license is described as Copyright © 2020 Elsevier Ltd. All rights reserved.