Genetic analyses of chr11p15.5 region identify <i>MUC5AC</i>-<i>MUC5B</i> associated with asthma-related phenotypes
dataset
posted on 2023-04-21, 17:40 authored by Xingnan Li, Huashi Li, Stephanie A. Christenson, Mario Castro, Loren C. Denlinger, Serpil C. Erzurum, John V. Fahy, Benjamin M. Gaston, Elliot Israel, Nizar N. Jarjour, Bruce D. Levy, David T Mauger, Wendy C. Moore, Joe Zein, Naftali Kaminski, Sally E. Wenzel, Prescott G. Woodruff, Eugene R. Bleecker, Deborah A. Meyers<p>Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) in chr11p15.5 region associated with asthma and idiopathic interstitial pneumonias (IIPs). We sought to identify functional genes for asthma by combining SNPs and mRNA expression in bronchial epithelial cells (BEC) in the Severe Asthma Research Program (SARP).</p> <p>Correlation analyses of mRNA expression of six candidate genes (<i>AP2A2</i>, <i>MUC6</i>, <i>MUC2</i>, <i>MUC5AC</i>, <i>MUC5B</i>, and <i>TOLLIP</i>) and asthma phenotypes were performed in the longitudinal cohort (<i>n</i> = 156) with RNAseq in BEC, and replicated in the cross-sectional cohort (<i>n</i> = 155). eQTL (<i>n</i> = 114) and genetic association analysis of asthma severity (426 severe vs. 531 non-severe asthma) were performed, and compared with previously published GWASs of IIPs and asthma.</p> <p>Higher expression of <i>AP2A2</i> and <i>MUC5AC</i> and lower expression of <i>MUC5B</i> in BEC were correlated with asthma, asthma exacerbations, and T2 biomarkers (<i>P</i> < 0.01). SNPs associated with asthma and IIPs in previous GWASs were eQTL SNPs for <i>MUC5AC</i>, <i>MUC5B</i>, or <i>TOLLIP</i>, however, they were not in strong linkage disequilibrium. The risk alleles for asthma or protective alleles for IIPs were associated with higher expression of <i>MUC5AC</i> and lower expression of <i>MUC5B</i>. rs11603634, rs12788104, and rs28415845 associated with moderate-to-severe asthma or adult onset asthma in previous GWASs were not associated with asthma severity (<i>P</i> > 0.8).</p> <p>SNPs associated with asthma in chr11p15.5 region are not associated with asthma severity neither with IIPs. Higher expression of <i>MUC5AC</i> and lower expression of <i>MUC5B</i> are risk for asthma but protective for IIPs.</p>
Funding
SARP cross-sectional cohort (stage 1 and 2; SARP1-2) was supported by NIH grants HL69116, HL69130, HL69149, HL69155, HL69167, HL69170, HL69174, HL69349, UL1RR024992, M01RR018390, M01RR07122, M01RR03186, HL087665, and HL091762. SARP longitudinal cohort (stage 3; SARP3) was funded by the NHLBI U10 HL109172, HL109168, HL109152, HL109257, HL109146, HL109250, HL109164, and HL109086 and the Clinical and Translational Science Awards (CTSA) Program UL1 TR001102, UL1 TR000427, UL1 TR001420, and UL1 TR002378. SARP longitudinal cohort (stage 4; SARP4) was funded by NIH HL146002. Genetic studies for SARP cross-sectional cohort were funded by NIH HL87665 and Go Grant RC2HL101487. SARP whole-genome sequencing was supported by National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) X01 grant. This work was also supported by the NIH grants HL142769 and AI149754. The following companies provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up: AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi–Genzyme–Regeneron, and TEVA. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative.
History
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