Genetically increased circulating FUT3 level leads to reduced risk of idiopathic pulmonary fibrosis: a Mendelian randomisation study

Tomoko Nakanishi; Agustin Cerani; Vincenzo Forgetta; Sirui Zhou; Richard J Allen; Olivia C Leavy; Masaru Koido; Deborah Assayag; R Gisli Jenkins; Louise V Wain; Ivana V Yang; G Mark Lathrop; Paul J Wolters; David A Schwartz; J Brent Richards

doi:10.1183/13993003.03979-2020

Genetically increased circulating FUT3 level leads to reduced risk of idiopathic pulmonary fibrosis: a Mendelian randomisation study

Eur Respir J. 2022 Feb 10;59(2):2003979. doi: 10.1183/13993003.03979-2020. Print 2022 Feb.

Authors

Tomoko Nakanishi^{1

2

3

4}, Agustin Cerani^{2

5}, Vincenzo Forgetta², Sirui Zhou^{2

5}, Richard J Allen⁶, Olivia C Leavy⁶, Masaru Koido⁷, Deborah Assayag^{8

9}, R Gisli Jenkins^{10

11}, Louise V Wain^{6

12}, Ivana V Yang^{13

14}, G Mark Lathrop¹⁵, Paul J Wolters¹⁶, David A Schwartz^{14

17}, J Brent Richards^{18

2

5

19

20}

Affiliations

¹ Dept of Human Genetics, McGill University, Montréal, QC, Canada.
² Centre for Clinical Epidemiology, Dept of Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
³ Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁴ Japan Society for the Promotion of Science, Tokyo, Japan.
⁵ Dept of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, QC, Canada.
⁶ Dept of Health Sciences, University of Leicester, Leicester, UK.
⁷ Dept of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁸ Dept of Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.
⁹ Translational Research in Respiratory Diseases, Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada.
¹⁰ National Heart and Lung Institute, Imperial College London, London, UK.
¹¹ Dept of Interstitial Lung Disease, Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London, UK.
¹² National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
¹³ Center for Genes, Environment and Health and Dept of Medicine, National Jewish Health, Denver, CO, USA.
¹⁴ Dept of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
¹⁵ McGill Genome Centre and Dept of Human Genetics, McGill University, Montréal, QC, Canada.
¹⁶ Dept of Medicine, School of Medicine, University of California, San Francisco, CA, USA.
¹⁷ Dept of Immunology, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
¹⁸ Dept of Human Genetics, McGill University, Montréal, QC, Canada brent.richards@mcgill.ca.
¹⁹ Division of Endocrinology, Dept of Medicine, Jewish General Hospital, McGill University, Montréal, QC, Canada.
²⁰ Dept of Twin Research, King's College London, London, UK.

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF.

Methods: To identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data. For instruments, we used genetic determinants of circulating proteins which reside cis to the encoded gene (cis-single nucleotide polymorphisms (SNPs)), identified by two genome-wide association studies (GWASs) in European individuals (3301 and 3200 subjects). We then applied MR methods to test if the levels of these circulating proteins influenced IPF susceptibility in the largest IPF GWAS (2668 cases and 8591 controls). We validated the MR results using colocalisation analyses to ensure that both the circulating proteins and IPF shared a common genetic signal.

Results: MR analyses of 834 proteins found that a 1 sd increase in circulating galactoside 3(4)-l-fucosyltransferase (FUT3) and α-(1,3)-fucosyltransferase 5 (FUT5) was associated with a reduced risk of IPF (OR 0.81, 95% CI 0.74-0.88; p=6.3×10^-7 and OR 0.76, 95% CI 0.68-0.86; p=1.1×10^-5, respectively). Sensitivity analyses including multiple cis-SNPs provided similar estimates both for FUT3 (inverse variance weighted (IVW) OR 0.84, 95% CI 0.78-0.91; p=9.8×10^-6 and MR-Egger OR 0.69, 95% CI 0.50-0.97; p=0.03) and FUT5 (IVW OR 0.84, 95% CI 0.77-0.92; p=1.4×10^-4 and MR-Egger OR 0.59, 95% CI 0.38-0.90; p=0.01). FUT3 and FUT5 signals colocalised with IPF signals, with posterior probabilities of a shared genetic signal of 99.9% and 97.7%, respectively. Further transcriptomic investigations supported the protective effects of FUT3 for IPF.

Conclusions: An efficient MR scan of 834 circulating proteins provided evidence that genetically increased circulating FUT3 level is associated with reduced risk of IPF.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Fucosyltransferases* / genetics
Genome-Wide Association Study
Humans
Idiopathic Pulmonary Fibrosis* / genetics
Mendelian Randomization Analysis / methods
Polymorphism, Single Nucleotide

Substances

Fucosyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding