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Original research
Novel genetic variants associated with inhaled corticosteroid treatment response in older adults with asthma
  1. Alberta L Wang1,2,
  2. Lies Lahousse3,4,
  3. Amber Dahlin2,
  4. Ahmed Edris4,
  5. Michael McGeachie2,
  6. Sharon M Lutz5,
  7. Joanne E Sordillo5,
  8. Guy Brusselle3,6,7,
  9. Jessica Lasky-Su2,
  10. Scott T Weiss2,
  11. Carlos Iribarren8,
  12. Meng X Lu8,
  13. Kelan G Tantisira9,
  14. Ann C Wu5
  1. 1Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Massachusetts, USA
  2. 2Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  3. 3Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
  4. 4Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
  5. 5PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, Massachusetts, USA
  6. 6Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
  7. 7Department of Respiratory Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
  8. 8Kaiser Permanente Division of Research, Kaiser Permanente, Oakland, California, USA
  9. 9Division of Pediatric Respiratory Medicine, Rady’s Children’s Hospital-San Diego, University of California San Diego School of Medicine, San Diego, California, USA
  1. Correspondence to Dr Alberta L Wang, Brigham and Women's Hospital, Boston, Massachusetts, USA; awang{at}bwh.harvard.edu

Abstract

Introduction Older adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults.

Methods A genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases.

Results In 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six near PTCHD4 validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p<5 × 10−5 were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci for CPED1, CRADD and DST for the OCS burst outcome and GM2A, SNW1, CACNA1C, DPH1, and RPS10 for the asthma-related exacerbation outcome.

Conclusions Multiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, including PTCHD4.

  • asthma
  • asthma genetics

Data availability statement

Data may be obtained from a third party and are not publicly available. Data from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort may be obtained by contacting the the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC), Research Program on Genes, Environment and Health (rpgeh-collab@kp.org). Data from the Mass General Brigham (MGB) Biobank can be obtained by contacting biobank@partners.org. Data from the Rotterdam Study can be obtained by contacting the Department of Epidemiology at Erasmus University Medical Center via telephone 0031 (0)10 704 34 88 or through the contact form on their website.

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Data availability statement

Data may be obtained from a third party and are not publicly available. Data from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort may be obtained by contacting the the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC), Research Program on Genes, Environment and Health (rpgeh-collab@kp.org). Data from the Mass General Brigham (MGB) Biobank can be obtained by contacting biobank@partners.org. Data from the Rotterdam Study can be obtained by contacting the Department of Epidemiology at Erasmus University Medical Center via telephone 0031 (0)10 704 34 88 or through the contact form on their website.

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Footnotes

  • Twitter @Asthma3Ways

  • Contributors ALW, KGT and ACW designed the study. ALW, KGT, ACW, LL, AE, AD, MM, SML, JES analysed the data. LL, GB, JL-S, STW, CI, MXL, KGT and ACW provided access to the data. ALW drafted the manuscript. All authors critically reviewed the manuscript. ACW is responsible for the overall content as guarantor.

  • Funding NIH R01 HL127332, R01 HL129935, R01 HL139634, R01 NR013391, R01 HL152244, U01 HL65899, P01 HL132825, K01 HL125858, K23 HL151819, Thrasher Research Fund Award #15115, European Respiratory Society (LTRF 201801-00302). The Rotterdam Study is supported by the Erasmus MC and Erasmus University Rotterdam; the Netherlands Organisation for Scientific Research (NWO); the Netherlands Organisation for Health Research and Development (ZonMW); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Genomics Initiative; the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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