Genome-wide association study reveals a novel locus for asthma with severe exacerbations in diverse populations.

TitleGenome-wide association study reveals a novel locus for asthma with severe exacerbations in diverse populations.
Publication TypeJournal Article
Year of Publication2020
AuthorsHerrera-Luis, E, Espuela-Ortiz, A, Lorenzo-Diaz, F, Keys, KL, C Y Mak, A, Eng, C, Huntsman, S, Villar, J, Rodriguez-Santana, JR, Burchard, EG, Pino-Yanes, M
JournalPediatr Allergy Immunol
Date Published2020 Aug 25
ISSN1399-3038
Abstract

BACKGROUND: Severe asthma exacerbations are a major cause of asthma morbidity and increased healthcare costs. Several studies have shown racial and ethnic differences in asthma exacerbation rates. We aimed to identify genetic variants associated with severe exacerbations in two high-risk populations for asthma.

METHODS: A genome-wide association study of asthma in children and youth with severe exacerbations was performed in 1283 exacerbators and 2027 controls without asthma of Latino ancestry. Independent suggestive variants (P ≤ 5 × 10 ) were selected for replication in 448 African Americans exacerbators and 595 controls. Case-only analyses were performed comparing the exacerbators with additional 898 Latinos and 524 African Americans asthma patients without exacerbations, while adjusting by treatment category as a proxy of asthma severity. We analyzed the functionality of associated variants with in silico methods and by correlating genotypes with methylation levels in whole blood in a subset of 473 Latinos.

RESULTS: We identified two genome-wide significant associations for susceptibility to asthma with severe exacerbations, including a novel locus located at chromosome 2p21 (rs4952375, odds ratio = 1.39, P = 3.8 × 10 ), which was also associated with asthma exacerbations in a case-only analysis (odds ratio = 1.25, P = 1.95 × 10 ). This polymorphism is an expression quantitative trait locus of the long intergenic non-protein coding RNA 1913 (LINC01913) in lung tissues (P = 1.3 × 10 ) and influences methylation levels of the protein kinase domain-containing cytoplasmic (PKDCC) gene in whole-blood cells (P = 9.8 × 10 ).

CONCLUSION: We identified a novel susceptibility locus for severe asthma exacerbations in Hispanic/Latino and African American youths with functional effects in gene expression and methylation status of neighboring genes.

DOI10.1111/pai.13337
Alternate JournalPediatr Allergy Immunol
PubMed ID32841424
Grant ListP60MD006902 / MD / NIMHD NIH HHS / United States
R01MD010443 / MD / NIMHD NIH HHS / United States
R01HL117004 / HL / NHLBI NIH HHS / United States
/ / Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II /
X01HL134589 / HL / NHLBI NIH HHS / United States
R56MD013312 / MD / NIMHD NIH HHS / United States
24RT-0025 / / Tobacco-Related Disease Research Program /
RL5GM118984 / GM / NIGMS NIH HHS / United States
RL5 GM118984 / GM / NIGMS NIH HHS / United States
PRE2018-083837 SAF2017-83417R / / Ministerio de Ciencia e Innovación /
/ / American Asthma Foundation /
/ / State Research Agency /
GBMF3834 / / Gordon and Betty Moore Foundation /
R01HL128439 / HL / NHLBI NIH HHS / United States
2013-10-27 / / Alfred P. Sloan Foundation /
U01HG009080 / HG / NHGRI NIH HHS / United States
RYC-2015-17205 / / Secretaría de Estado de Investigación, Desarrollo e Innovación /
R01HL135156-S1 / HL / NHLBI NIH HHS / United States
27IR-0030 / / Tobacco-Related Disease Research Program /
/ / ULL Campus America 2019 Initiative /
SAF2017-83417R / / European Union /
R01HL141845 / HL / NHLBI NIH HHS / United States
R01HL135156 / HL / NHLBI NIH HHS / United States
/ / Robert Wood Johnson Foundation /
/ / UCSF Bakar Computational Health Sciences Institute /
R01ES015794 / ES / NIEHS NIH HHS / United States
R01HL141992 / HL / NHLBI NIH HHS / United States
R21ES24844 / ES / NIEHS NIH HHS / United States
/ / Sandler Family Foundation /