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Respiratory research
Original research
Interaction between Genetic Risk Scores for reduced pulmonary function and smoking, asthma and endotoxin
  1. Sinjini Sikdar1,2,
  2. Annah B Wyss2,
  3. Mi Kyeong Lee2,
  4. Thanh T Hoang2,
  5. Marie Richards3,
  6. Laura E Beane Freeman4,
  7. Christine Parks2,
  8. Peter S Thorne5,
  9. John L Hankinson6,
  10. David M Umbach7,
  11. Alison Motsinger-Reif7,
  12. Stephanie J London2
  1. 1 Department of Mathematics and Statistics, Old Dominion University, Norfolk, Virginia, USA
  2. 2 Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA
  3. 3 Westat, Durham, North Carolina, USA
  4. 4 Occupational and Environmental Epidemiology Branch, National Cancer Institute, Bethesda, Maryland, USA
  5. 5 Department of Occupational and Environmental Health, University of Iowa, Iowa City, Iowa, USA
  6. 6 Hankinson Consulting, Athens, Georgia, USA
  7. 7 Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA
  1. Correspondence to Dr Stephanie J London, Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC 27709, USA; london2{at}niehs.nih.gov

Abstract

Rationale Genome-wide association studies (GWASs) have identified numerous loci associated with lower pulmonary function. Pulmonary function is strongly related to smoking and has also been associated with asthma and dust endotoxin. At the individual SNP level, genome-wide analyses of pulmonary function have not identified appreciable evidence for gene by environment interactions. Genetic Risk Scores (GRSs) may enhance power to identify gene–environment interactions, but studies are few.

Methods We analysed 2844 individuals of European ancestry with 1000 Genomes imputed GWAS data from a case–control study of adult asthma nested within a US agricultural cohort. Pulmonary function traits were FEV1, FVC and FEV1/FVC. Using data from a recent large meta-analysis of GWAS, we constructed a weighted GRS for each trait by combining the top (p value<5×10−9) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r2=0.5). We used linear regression, adjusting for relevant covariates, to estimate associations of each trait with its GRS and to assess interactions.

Results Each trait was highly significantly associated with its GRS (all three p values<8.9×10−8). The inverse association of the GRS with FEV1/FVC was stronger for current smokers (pinteraction=0.017) or former smokers (pinteraction=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (pinteraction=0.053). No significant interactions were observed between any GRS and house dust endotoxin.

Conclusions Evaluation of interactions using GRSs supports a greater impact of increased genetic susceptibility on reduced pulmonary function in the presence of smoking or asthma.

  • asthma
  • respiratory measurement
  • tobacco and the lung

Data availability statement

Data are available upon reasonable request pending all required approvals.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/thoraxjnl-2020-215624

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    Data availability statement

    Data are available upon reasonable request pending all required approvals.

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    Footnotes

    • Contributors SS and SJL designed the study and drafted the manuscript. SS performed data analysis with contributions from ABW, MKL, TTH and MR. JLH was responsible for quality control of the pulmonary function data. PST was responsible for the endotoxin measurements. DMU and AM-R provided statistical guidance. All authors provided critical input on the manuscript.

    • Funding This work was supported by the Intramural Research Programme of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01-ES102385, Z01-ES049030, Z01-ES043012 and, for ABW, contract number HHSN273201600003I) and the National Cancer Institute (Z01-CP010119), and was supported in part by American Recovery and Reinvestment Act funds through National Institute of Environmental Health Sciences (contract number N01-ES-55546). PST was supported by PHR-SUPS2-S-10–00179 and NIH P30 ES005605.

    • Competing interests AM-R and PST report grants from the National Institute of Environmental Health Sciences during the conduct of the study.

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