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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 482-492 |
| Number of pages | 11 |
| Journal | The Lancet Respiratory Medicine |
| Volume | 8 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2020 |
Bibliographical note
Funding Information:This work was supported by the US National Institutes of Health (NIH), Office of the Director ( UG3 OD023282 , UL1 TR002373 , UM1 AI114271 , and U19 AI095230 ). Members of the Children's Respiratory Research Workgroup have also received NIH grant support: for the Childhood Asthma Study, R01 AI024156, R03 HL067427, and R01 AI051598; for the Cincinnati Childhood Allergy and Air Pollution Study, R01 ES11170 and R01 ES019890; for the Columbia Center for Children's Environmental Health study, P01 ES09600, R01 ES008977, P30ES09089, R01 ES013163, and EPA R827027; for the Childhood Origins of Asthma study, P01 HL070831, U10 HL064305, and R01 HL061879; for the Epidemiology of Home Allergens and Asthma Study, R01 AI035786; for the Infant Immune Study, HL56177; for the Tucson Children's Respiratory Study, R01 HL132523; for the Urban Environment and Childhood Asthma study, NO1 AI25496, NO1 AI25482, HHS N272200900052C, HHS N272201000052I, NCRR/NIH RR00052, M01 RR00533, UL1 RR025771, M01 RR00071, UL1 RR024156, UL1 TR001079, UL1 RR024992, and NCATS/NIH UL1TR000040; and for the Wayne County Health, Environment, Allergy, and Asthma Longitudinal Study, R01 AI050681, R56 AI050681, R01 AI061774, R21 AI059415, K01 AI070606, R21 AI069271, R01 HL113010, R21 ES022321, P01 AI089473, R21 AI080066, R01 AI110450, and R01 HD082147. Members of the Children's Respiratory Research Workgroup have also been supported by the Fund for Henry Ford Health System.
Funding Information:
This work was supported by the US National Institutes of Health (NIH), Office of the Director (UG3 OD023282, UL1 TR002373, UM1 AI114271, and U19 AI095230). Members of the Children's Respiratory Research Workgroup have also received NIH grant support: for the Childhood Asthma Study, R01 AI024156, R03 HL067427, and R01 AI051598; for the Cincinnati Childhood Allergy and Air Pollution Study, R01 ES11170 and R01 ES019890; for the Columbia Center for Children's Environmental Health study, P01 ES09600, R01 ES008977, P30ES09089, R01 ES013163, and EPA R827027; for the Childhood Origins of Asthma study, P01 HL070831, U10 HL064305, and R01 HL061879; for the Epidemiology of Home Allergens and Asthma Study, R01 AI035786; for the Infant Immune Study, HL56177; for the Tucson Children's Respiratory Study, R01 HL132523; for the Urban Environment and Childhood Asthma study, NO1 AI25496, NO1 AI25482, HHS N272200900052C, HHS N272201000052I, NCRR/NIH RR00052, M01 RR00533, UL1 RR025771, M01 RR00071, UL1 RR024156, UL1 TR001079, UL1 RR024992, and NCATS/NIH UL1TR000040; and for the Wayne County Health, Environment, Allergy, and Asthma Longitudinal Study, R01 AI050681, R56 AI050681, R01 AI061774, R21 AI059415, K01 AI070606, R21 AI069271, R01 HL113010, R21 ES022321, P01 AI089473, R21 AI080066, R01 AI110450, and R01 HD082147. Members of the Children's Respiratory Research Workgroup have also been supported by the Fund for Henry Ford Health System.
Funding Information:
LBB reports grants from the US National Institutes of Health (NIH; the National Institute of Allergy and Infectious Diseases [NIAID]), during the conduct of the study; personal fees from Aerocrine, GlaxoSmithKline, Genentech, and Novartis, and personal fees and non-financial support from Merck, Teva, and Boehringer Ingelheim, outside of the submitted work. JEG reports grants from NIH, during the conduct of the study; personal fees from Regeneron, AstraZeneca (MedImmune), and Ena Therapeutics, and personal fees and stock options from Meissa Vaccines, outside of the submitted work. DRG reports grants from NIH, during the conduct of the study. TH reports grants from NIH, during the conduct of the study; and personal fees from Pfizer, outside of the submitted work. DKH reports personal fees from Ambu, Boston Scientific, Johnson and Johnson, OncoCyte, Veracyte, Heritage Biologics, IDbyDNA, Level Ex, Medtronic, Neurotronics, Olympus, PulmonX, Astra-Zeneca, Biodesix, Genetech, Grifols, Takeda, CSL, and InhibRX, personal fees and other from Auris, Eolo, Noah Medical, LX-Medical, Preora, and Broncus, personal fees, non-financial support, and other from Body Vision, grants and personal fees from Gala, and other from Eon, Gravitas, Med-Opsys, Monogram Orthopedics, Vida Health, and Viomics, outside of the submitted work. DJJ reports grants from NIH, during the conduct of the study; personal fees from Sanofi, Regeneron, AstraZeneca, Novartis, Vifor, Pfizer, Merck, Boehringer Ingelheim, and Commense, and grants and personal fees from GlaxoSmithKline, outside of the submitted work. MK reports grants from NIH (NIAID), during the conduct of the study; and personal fees from Sanofi and Regeneron, outside of the submitted work. RFL reports grants from NIH (National Heart, Lung, and Blood Institute [NHLBI]), during the conduct of the study; non-financial support from the American Academy of Allergy, Asthma, and Immunology, personal fees from Louisiana State University and UpToDate, and editor fees from Elsevier, outside of the submitted work. SVL reports grants from NIH (NIAID and the Eunice Kennedy Shriver National Institute of Child Health and Human), during the conduct of the study; and personal fees from Siolta Therapeutics, outside of the submitted work. FDM reports grants from NIH (NHLBI), during the conduct of the study; grants from NIH (NHLBI, the National Institute of Environmental Health Sciences, NIAID, and NIH Office of the Director) and Johnson and Johnson, and personal fees from Copeval, outside of the submitted work. GTO'C reports grants from NIH, during the conduct of the study; and personal fees from AstraZeneca and grant support from Janssen Pharmaceuticals, outside of the submitted work. CO reports grants from NIH, during the conduct of the study; grants and personal fees from NIH, and personal fees from the American Academy of Asthma, Allergy and Immunology, outside of the submitted work. SRW reports personal fees from Genentech and grants from NIH (NHLBI) outside of the submitted work. RAW reports grants from NIH, during the conduct of the study; grants from NIH, Astellas, DBV Technologies, Regeneron, Aimmune, and personal fees from UptoDate, outside of the submitted work. EMZ reports grants from NIH, during the conduct of the study. All other authors declare no competing interests.
Publisher Copyright:
© 2020 Elsevier Ltd
Keywords
- African Americans/genetics
- Asthma/genetics
- Child
- Chromosomes, Human, Pair 17
- Epithelial Cells/metabolism
- European Continental Ancestry Group/genetics
- Female
- Gene Expression Profiling
- Genetic Association Studies
- Genetic Predisposition to Disease
- Genotype
- Humans
- Leukocytes, Mononuclear/metabolism
- Linkage Disequilibrium
- Male
- Membrane Proteins/genetics
- Neoplasm Proteins/genetics
- Polymorphism, Single Nucleotide
- Quantitative Trait Loci
- United States
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
