Genetic analyses of chr11p15.5 region identify MUC5AC-MUC5B associated with asthma-related phenotypes

Abstract

Objective

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).

Methods

Correlation analyses of mRNA expression of six candidate genes (AP2A2, MUC6, MUC2, MUC5AC, MUC5B, and TOLLIP) and asthma phenotypes were performed in the longitudinal cohort (n = 156) with RNAseq in BEC, and replicated in the cross-sectional cohort (n = 155). eQTL (n = 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.

Results

Higher expression of AP2A2 and MUC5AC and lower expression of MUC5B in BEC were correlated with asthma, asthma exacerbations, and T2 biomarkers (P < 0.01). SNPs associated with asthma and IIPs in previous GWASs were eQTL SNPs for MUC5AC, MUC5B, or TOLLIP, however, they were not in strong linkage disequilibrium. The risk alleles for asthma or protective alleles for IIPs were associated with higher expression of MUC5AC and lower expression of MUC5B. rs11603634, rs12788104, and rs28415845 associated with moderate-to-severe asthma or adult onset asthma in previous GWASs were not associated with asthma severity (P > 0.8).

Conclusions

SNPs associated with asthma in chr11p15.5 region are not associated with asthma severity neither with IIPs. Higher expression of MUC5AC and lower expression of MUC5B are risk for asthma but protective for IIPs.

Keywords:

• Asthma susceptibility
• asthma severity
• eQTL
• gene expression
• genetic association
• MUC5AC
• MUC5B

Acknowledgements

The authors acknowledge all investigators, staff, and participants in the SARP studies. 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.

Declaration of interest

Dr. Castro receives University Grant Funding from NIH, American Lung Association, PCORI; he receives Pharmaceutical Grant Funding from AstraZeneca, GSK, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi; he is a consultant for Arrowhead, Genentech, Teva, Sanofi-Aventis, Merck, Novartis, OM Pharma; he is a speaker for AstraZeneca, Genentech, Regeneron, Sanofi, Teva; he receives Royalties from Elsevier. Dr. Denlinger receives University Grant Funding from NHLBI; he also receives PrecISE and GRAIL grants from NHLBI and Lung Health Cohort grant from ALA-ACRC which are not related to SARP; he receives drugs for the NHLBI PrecISE trial from GlaxoSmithKline, Laurel, Sun Pharma, Vifor, Vitaeris/CSL Behring, Vitaflo and equipment contracts with the NHLBI PrecISE trial from Vyaire, Caire Diagnostics, MIR, Propeller Health, ZEPHYRx. Dr. Gaston is founder and equity owner in Respiratory Research Incorporated as well as Airbase Breathing Company, LLC; his lab is funded by the NIH, the Eli Lilly Foundation, the Harrington Discovery Institute, and the Riley Children’s Foundation. Dr. Israel reports grants from NHLBI, PCORI, and the ALA-ACRC; Pharmaceutical Grant funding to his institution from AstraZenca, Avillion, Circassia, Gossamer Bio, Novartis; Consulting fees from Allergy and Asthma Network, Amgen, AstraZeneca, Avillion, Genentech, GSK, Merck, NHLBI, Novartis, Regeneron, Sanolfi Genzyme, Teva and Cowen, DSMB fees from Novartis; he has received drugs or equipment for federally sponsored studies from GlaxoSmithKline, Laurel, Sun Pharma, Vifor, Vitaeris/CSL Behring, Vitaflo, Circassia, and Teva. Dr. Jarjour receives University Grant Funding from NHLBI; he is a consultant for AstraZeneca, GSK. Dr. Levy reports grants from NHLBI, personal consulting fees from AstraZeneca, Bayer, Gossamer Bio, NControl, Novartis, Pieris Pharmaceuticals, Sanofi, Teva, participates on NIAID/DAIT COVID-19 DSMB board, and has stock from Entrinsic Biosciences, Nocion Therapeutics. Dr. Mauger reports grants from NHLBI and drugs for NIH-funded clinical trials from Genentech, GSK, OM Pharma, Sanofi-Regeneron. Dr. Kaminski reports grants from NHLBI and Pharmaceutical Grant Funding from Veracyte, BMS, Boehringer Ingelheim, and Three Lakes Foundation administrated through University of Arizona; he has patents of new therapies for IPF and ARDS; he is has stock for Pliant and Thyron; he is a consultant for Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Optikira, Astra Zeneca, RohBar, Veracyte, Augmanity, CSL Behring, Thyron, BMS, MiRagen, Biotech, Gilead, Galapagos, and Chiesi. Dr. Wenzel receives Pharmaceutical Grant Funding from AstraZeneca, Knopp, Regeneron; she is a consultant for AstraZeneca, Knopp, Novartis, Sanofi, GSK; she is on scientific advisory board of Aer Therapeutics. All other authors have nothing to disclose. Dr. Woodruff reports grants from NHLBI, the COPD Foundation, and Foundation of the NIH and Pharmaceutical Grant Funding from Genentech; he is a consultant for Glenmark Pharmaceuticals, University of Wisconsin, NGM Pharma, GSK, Theravance, Sanofi, and Astra Zeneca; he receives payment for CME talks at WSAAI. Dr. Bleecker reports grants from NHLBI and Pharmaceutical Grant Funding from AstraZeneca, Novartis, Regeneron, Sanofi Genzyme, and clinical trials administrated through University of Arizona; he is a consultant for AstraZeneca, Glaxo Smith Kline, Knopp Pharmaceuticals, Novartis, Regeneron, and Sanofi Genzyme; he receives payment for lectures from AstraZeneca and support for travel from AstraZeneca, Glaxo Smith Kline, Novartis, Regeneron, and Sanofi Genzyme. Dr. Meyers reports grants from NHLBI and Pharmaceutical Grant from GSK; she receives consulting fees from AstraZeneca. The rest of the authors declare that they have no relevant conflict of interest.

Additional information

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.