Causal effects of COVID-19 on idiopathic pulmonary fibrosis: mendelian randomization and genome-wide cross-trait analysis_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

FENG Jieni ¹ , WANG Yushi ¹ , TAN Zhaoqi ¹ , GAO Ming ^1,2 , LI Zuming ¹ , LU Yue ^1,3 , CHEN Jiankun ^1,3 ,  LI Jiqiang ^1,3 ,  LIU Yuntao ^1,3,4,5 ,  YANG Rongyuan ^1,4,5

1. The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P. R. China;
2. Nanhai District Hospital of Chinese Medicine (Guangdong Provincial Hospital of Integrated Chinese and Western Medicine), Foshan, Guangdong 528000, P. R. China;
3. The Second Affiliated Hospital (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China;
4. Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, Guangdong 510120, P. R. China;
5. State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P. R. China;

Corresponding author：

LI Jiqiang, Email: lijiqiangjizhen@163.com; LIU Yuntao, Email: iamliuyuntao@163.com; YANG Rongyuan, Email: yangrongyuan@163.com

Keywords：

Coronavirus disease 2019; idiopathic pulmonary fibrosis; Mendelian randomization; genome-wide cross-trait analysis; colocalization analysis

DOI：

10.7507/1671-6205.202507055

Video：

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Objective To investigate the causal effect of coronavirus disease 2019 (COVID-19) on idiopathic pulmonary fibrosis (IPF). Methods Genome-wide association studies (GWAS) data were sourced from the COVID-19 Host Genetics Initiative and published research. We employed: ① linkage disequilibrium score regression to estimate heritability of individual traits and genetic correlations between COVID-19 and IPF; ② multi-trait analysis of GWAS to identify genetic loci associated with COVID-19 and IPF; ③ Mendelian randomization (MR) to assess causal effect of COVID-19 on IPF; ④ colocalization analysis to identify shared causal variants. Results ① Three COVID-19 phenotypes showed significant positive genetic correlations with IPF (P<0.05); ② Multi-trait analysis of GWAS identified loci jointly associated with COVID-19 and IPF; ③ MR indicated that COVID-19 hospitalization may increase IPF risk (P=0.006); ④ Two causal variants were identified: rs12585036 (posterior probability>0.8, mapped to ATP11A) and rs12610495 (posterior probability>0.8, mapped to DPP9). Conclusions COVID-19 hospitalization may increase IPF risk through inflammatory pathways, providing new insights for managing COVID-19-related pulmonary diseases.

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4.	Fadista J, Kraven L M, Karjalainen J, et al. Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity. EBioMedicine, 2021, 65: 103277.
5.	Gallay L, Uzunhan Y, Borie R, et al. Risk Factors for Mortality after COVID-19 in Patients with Preexisting Interstitial Lung Disease. Am J Respir Crit Care Med, 2021, 203(2): 245-249.
6.	Drake TM, Docherty AB, Harrison EM, et al. Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study. Am J Respir Crit Care Med, 2020, 202(12): 1656-1665.
7.	Stewart I, Jacob J, George PM, et al. Residual Lung Abnormalities after COVID-19 Hospitalization: Interim Analysis of the UKILD Post-COVID-19 Study. Am J Respir Crit Care Med, 2023, 207(6): 693-703.
8.	Ambardar SR, Hightower SL, Huprikar NA, et al. Post-COVID-19 Pulmonary Fibrosis: Novel Sequelae of the Current Pandemic. J Clin Med, 2021, 10(11): 2452.
9.	Lago VC, Prudente RA, Luzia DA, et al. Persistent interstitial lung abnormalities in post-COVID-19 patients: a case series. J Venom Anim Toxins Incl Trop Dis, 2021, 27: e20200157.
10.	Robertshaw M, Kershaw CD. Post COVID Interstitial Lung Abnormalities-Incidence and Management. Curr Pulmonol Rep, 2023, 12(2): 64-69.
11.	Kousathanas A, Pairo-Castineira E, Rawlik K, et al. Whole-genome sequencing reveals host factors underlying critical COVID-19. Nature, 2022, 607(7917): 93-97.
12.	Wang L, Balmat TJ, Antonia AL, et al. An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility. Genome Med, 2021, 13(1): 83.
13.	Horowitz JE, Kosmicki JA, Damask A, et al. Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease. Nat Genet, 2022, 54(4): 382-392.
14.	Pairo-Castineira E, Clohisey S, Klaric L, et al. Genetic mechanisms of critical illness in COVID-19. Nature, 2021, 591(7848): 92-98.
15.	Allen RJ, Guillen-Guio B, Oldham JM, et al. Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med, 2020, 201(5): 564-574.
16.	Allen RJ, Guillen-Guio B, Croot E, et al. Genetic overlap between idiopathic pulmonary fibrosis and COVID-19. Eur Respir J, 2022, 60(1): 2103132.
17.	Lawlor DA, Harbord RM, Sterne JA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med, 2008, 27(8): 1133-1163.
18.	Weng H, Li H, Zhang Z, et al. Association between uric acid and risk of venous thromboembolism in East Asian populations: a cohort and Mendelian randomization study. Lancet Reg Health West Pac, 2023, 39: 100848.
19.	Zhang Z, Li H, Weng H, et al. Genome-wide association analyses identified novel susceptibility loci for pulmonary embolism among Han Chinese population. BMC Med, 2023, 21(1): 153.
20.	Zhu J, Zhou D, Yu M, et al. Appraising the causal role of smoking in idiopathic pulmonary fibrosis: a Mendelian randomization study. Thorax, 2024, 79(2): 179-181.
21.	Reynolds CJ, Del Greco MF, Allen RJ, et al. The causal relationship between gastro-oesophageal reflux disease and idiopathic pulmonary fibrosis: a bidirectional two-sample Mendelian randomisation study. Eur Respir J, 2023, 61(5): 2201585.
22.	Allen RJ, Stockwell A, Oldham JM, et al. Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis. Thorax, 2022, 77(8): 829-833.
23.	COVID-19 Host Genetics Initiative. Mapping the human genetic architecture of COVID-19. Nature, 2021, 600: 472-477.
24.	Bulik-Sullivan BK, Loh P, Finucane HK, et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet, 2015, 47(3): 291-295.
25.	Yang J, Weedon MN, Purcell S, et al. Genomic inflation factors under polygenic inheritance. Eur J Hum Genet, 2011, 19(7): 807-812.
26.	Huang X, Yao M, Tian P, et al. Genome-wide cross-trait analysis and Mendelian randomization reveal a shared genetic etiology and causality between COVID-19 and venous thromboembolism. Commun Biol, 2023, 6(1): 441.
27.	Bone WP, Siewert KM, Jha A, et al. Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits. Alzheimers Res Ther, 2021, 13(1): 34.
28.	Tian Y, Ma G, Li H, et al. Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease. Mov Disord, 2023, 38(10): 1813-1821.
29.	Burgess S, Butterworth A, Thompson SG. Mendelian Randomization Analysis With Multiple Genetic Variants Using Summarized Data. Genet Epidemiol, 2013, 37(7): 658-665.
30.	Giambartolomei C, Vukcevic D, Schadt EE, et al. Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics. PLoS Genet, 2014, 10(5): e1004383.
31.	Han D, Gong H, Wei Y, et al. Hesperidin inhibits lung fibroblast senescence via IL-6/STAT3 signaling pathway to suppress pulmonary fibrosis. Phytomedicine, 2023, 112: 154680.
32.	Gusev E, Sarapultsev A, Solomatina L, et al. SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19. Int J Mol Sci, 2022, 23(3): 1716.
33.	Phan THG, Paliogiannis P, Nasrallah GK, et al. Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis. Cell Mol Life Sci, 2021, 78(5): 2031-2057.
34.	Si S, Li J, Tewara MA, et al. Genetically Determined Chronic Low-Grade Inflammation and Hundreds of Health Outcomes in the UK Biobank and the FinnGen Population: A Phenome-Wide Mendelian Randomization Study. Front Immunol, 2021, 12: 720876.
35.	Kishore A, Žižková V, Kocourková L, et al. Association Study for 26 Candidate Loci in Idiopathic Pulmonary Fibrosis Patients from Four European Populations. Front Immunol, 2016, 7: 274.
36.	Zhang B, Groffen J, Heisterkamp N. Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a. Blood, 2005, 106(4): 1355-1361.
37.	Shulenin S, Nogee L M, Annilo T, et al. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med, 2004, 350(13): 1296-1303.
38.	Bullard JE, Wert SE, Whitsett JA, et al. ABCA3 Mutations Associated with Pediatric Interstitial Lung Disease. Am J Respir Crit Care Med, 2005, 172(8): 1026-1031.
39.	Young L R, Nogee L M, Barnett B, et al. Usual Interstitial Pneumonia in an Adolescent With ABCA3 Mutations. Chest, 2008, 134(1): 192-195.
40.	Sahanic S, Hilbe R, Dünser C, et al. SARS-CoV-2 activates the TLR4/MyD88 pathway in human macrophages: A possible correlation with strong pro-inflammatory responses in severe COVID-19. Heliyon, 2023, 9(11): e21893.
41.	Zhao Y, Kuang M, Li J, et al. SARS-CoV-2 spike protein interacts with and activates TLR41. Cell Res, 2021, 31(7): 818-820.
42.	Dalapati T, Wang L, Jones AG, et al. Context-specific eQTLs provide deeper insight into causal genes underlying shared genetic architecture of COVID-19 and idiopathic pulmonary fibrosis. HGG Adv, 2025, 6(2): 100410.
43.	van der Mark VA, Ghiboub M, Marsman C, et al. Phospholipid flippases attenuate LPS-induced TLR4 signaling by mediating endocytic retrieval of Toll-like receptor 4. Cell Mol Life Sci, 2017, 74(4): 715-730.
44.	Raj VS, Mou H, Smits SL, et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature, 2013, 495(7440): 251-254.
45.	Hollingsworth LR, Sharif H, Griswold AR, et al. DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation. Nature, 2021, 592(7856): 778-783.
46.	Okondo MC, Rao SD, Taabazuing CY, et al. Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome. Cell Chem Biol, 2018, 25(3): 262-267.
47.	Zhong FL, Robinson K, Teo D, et al. Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding. J Biol Chem, 2018, 293(49): 18864-18878.
48.	Acharya PS, Zukas A, Chandan V, et al. Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis. Hum Pathol, 2006, 37(3): 352-360.
49.	Zhang Y, Noth I, Garcia JG, et al. A Variant in the Promoter ofMUC5B and Idiopathic Pulmonary Fibrosis. N Engl J Med, 2011, 364(16): 1576-1577.

1. Martinez FJ, Collard HR, Pardo A, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis Primers, 2017, 3: 17074.
2. Koudstaal T, Funke-Chambour M, Kreuter M, et al. Pulmonary fibrosis: from pathogenesis to clinical decision-making. Trends Mol Med, 2023, 29(12): 1076-1087.
3. George P M, Wells A U, Jenkins R G. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med, 2020, 8(8): 807-815.
4. Fadista J, Kraven L M, Karjalainen J, et al. Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity. EBioMedicine, 2021, 65: 103277.
5. Gallay L, Uzunhan Y, Borie R, et al. Risk Factors for Mortality after COVID-19 in Patients with Preexisting Interstitial Lung Disease. Am J Respir Crit Care Med, 2021, 203(2): 245-249.
6. Drake TM, Docherty AB, Harrison EM, et al. Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study. Am J Respir Crit Care Med, 2020, 202(12): 1656-1665.
7. Stewart I, Jacob J, George PM, et al. Residual Lung Abnormalities after COVID-19 Hospitalization: Interim Analysis of the UKILD Post-COVID-19 Study. Am J Respir Crit Care Med, 2023, 207(6): 693-703.
8. Ambardar SR, Hightower SL, Huprikar NA, et al. Post-COVID-19 Pulmonary Fibrosis: Novel Sequelae of the Current Pandemic. J Clin Med, 2021, 10(11): 2452.
9. Lago VC, Prudente RA, Luzia DA, et al. Persistent interstitial lung abnormalities in post-COVID-19 patients: a case series. J Venom Anim Toxins Incl Trop Dis, 2021, 27: e20200157.
10. Robertshaw M, Kershaw CD. Post COVID Interstitial Lung Abnormalities-Incidence and Management. Curr Pulmonol Rep, 2023, 12(2): 64-69.
11. Kousathanas A, Pairo-Castineira E, Rawlik K, et al. Whole-genome sequencing reveals host factors underlying critical COVID-19. Nature, 2022, 607(7917): 93-97.
12. Wang L, Balmat TJ, Antonia AL, et al. An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility. Genome Med, 2021, 13(1): 83.
13. Horowitz JE, Kosmicki JA, Damask A, et al. Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease. Nat Genet, 2022, 54(4): 382-392.
14. Pairo-Castineira E, Clohisey S, Klaric L, et al. Genetic mechanisms of critical illness in COVID-19. Nature, 2021, 591(7848): 92-98.
15. Allen RJ, Guillen-Guio B, Oldham JM, et al. Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med, 2020, 201(5): 564-574.
16. Allen RJ, Guillen-Guio B, Croot E, et al. Genetic overlap between idiopathic pulmonary fibrosis and COVID-19. Eur Respir J, 2022, 60(1): 2103132.
17. Lawlor DA, Harbord RM, Sterne JA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med, 2008, 27(8): 1133-1163.
18. Weng H, Li H, Zhang Z, et al. Association between uric acid and risk of venous thromboembolism in East Asian populations: a cohort and Mendelian randomization study. Lancet Reg Health West Pac, 2023, 39: 100848.
19. Zhang Z, Li H, Weng H, et al. Genome-wide association analyses identified novel susceptibility loci for pulmonary embolism among Han Chinese population. BMC Med, 2023, 21(1): 153.
20. Zhu J, Zhou D, Yu M, et al. Appraising the causal role of smoking in idiopathic pulmonary fibrosis: a Mendelian randomization study. Thorax, 2024, 79(2): 179-181.
21. Reynolds CJ, Del Greco MF, Allen RJ, et al. The causal relationship between gastro-oesophageal reflux disease and idiopathic pulmonary fibrosis: a bidirectional two-sample Mendelian randomisation study. Eur Respir J, 2023, 61(5): 2201585.
22. Allen RJ, Stockwell A, Oldham JM, et al. Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis. Thorax, 2022, 77(8): 829-833.
23. COVID-19 Host Genetics Initiative. Mapping the human genetic architecture of COVID-19. Nature, 2021, 600: 472-477.
24. Bulik-Sullivan BK, Loh P, Finucane HK, et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet, 2015, 47(3): 291-295.
25. Yang J, Weedon MN, Purcell S, et al. Genomic inflation factors under polygenic inheritance. Eur J Hum Genet, 2011, 19(7): 807-812.
26. Huang X, Yao M, Tian P, et al. Genome-wide cross-trait analysis and Mendelian randomization reveal a shared genetic etiology and causality between COVID-19 and venous thromboembolism. Commun Biol, 2023, 6(1): 441.
27. Bone WP, Siewert KM, Jha A, et al. Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits. Alzheimers Res Ther, 2021, 13(1): 34.
28. Tian Y, Ma G, Li H, et al. Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease. Mov Disord, 2023, 38(10): 1813-1821.
29. Burgess S, Butterworth A, Thompson SG. Mendelian Randomization Analysis With Multiple Genetic Variants Using Summarized Data. Genet Epidemiol, 2013, 37(7): 658-665.
30. Giambartolomei C, Vukcevic D, Schadt EE, et al. Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics. PLoS Genet, 2014, 10(5): e1004383.
31. Han D, Gong H, Wei Y, et al. Hesperidin inhibits lung fibroblast senescence via IL-6/STAT3 signaling pathway to suppress pulmonary fibrosis. Phytomedicine, 2023, 112: 154680.
32. Gusev E, Sarapultsev A, Solomatina L, et al. SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19. Int J Mol Sci, 2022, 23(3): 1716.
33. Phan THG, Paliogiannis P, Nasrallah GK, et al. Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis. Cell Mol Life Sci, 2021, 78(5): 2031-2057.
34. Si S, Li J, Tewara MA, et al. Genetically Determined Chronic Low-Grade Inflammation and Hundreds of Health Outcomes in the UK Biobank and the FinnGen Population: A Phenome-Wide Mendelian Randomization Study. Front Immunol, 2021, 12: 720876.
35. Kishore A, Žižková V, Kocourková L, et al. Association Study for 26 Candidate Loci in Idiopathic Pulmonary Fibrosis Patients from Four European Populations. Front Immunol, 2016, 7: 274.
36. Zhang B, Groffen J, Heisterkamp N. Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a. Blood, 2005, 106(4): 1355-1361.
37. Shulenin S, Nogee L M, Annilo T, et al. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med, 2004, 350(13): 1296-1303.
38. Bullard JE, Wert SE, Whitsett JA, et al. ABCA3 Mutations Associated with Pediatric Interstitial Lung Disease. Am J Respir Crit Care Med, 2005, 172(8): 1026-1031.
39. Young L R, Nogee L M, Barnett B, et al. Usual Interstitial Pneumonia in an Adolescent With ABCA3 Mutations. Chest, 2008, 134(1): 192-195.
40. Sahanic S, Hilbe R, Dünser C, et al. SARS-CoV-2 activates the TLR4/MyD88 pathway in human macrophages: A possible correlation with strong pro-inflammatory responses in severe COVID-19. Heliyon, 2023, 9(11): e21893.
41. Zhao Y, Kuang M, Li J, et al. SARS-CoV-2 spike protein interacts with and activates TLR41. Cell Res, 2021, 31(7): 818-820.
42. Dalapati T, Wang L, Jones AG, et al. Context-specific eQTLs provide deeper insight into causal genes underlying shared genetic architecture of COVID-19 and idiopathic pulmonary fibrosis. HGG Adv, 2025, 6(2): 100410.
43. van der Mark VA, Ghiboub M, Marsman C, et al. Phospholipid flippases attenuate LPS-induced TLR4 signaling by mediating endocytic retrieval of Toll-like receptor 4. Cell Mol Life Sci, 2017, 74(4): 715-730.
44. Raj VS, Mou H, Smits SL, et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature, 2013, 495(7440): 251-254.
45. Hollingsworth LR, Sharif H, Griswold AR, et al. DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation. Nature, 2021, 592(7856): 778-783.
46. Okondo MC, Rao SD, Taabazuing CY, et al. Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome. Cell Chem Biol, 2018, 25(3): 262-267.
47. Zhong FL, Robinson K, Teo D, et al. Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding. J Biol Chem, 2018, 293(49): 18864-18878.
48. Acharya PS, Zukas A, Chandan V, et al. Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis. Hum Pathol, 2006, 37(3): 352-360.
49. Zhang Y, Noth I, Garcia JG, et al. A Variant in the Promoter ofMUC5B and Idiopathic Pulmonary Fibrosis. N Engl J Med, 2011, 364(16): 1576-1577.

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Latest ArticlesCausal effects of COVID-19 on idiopathic pulmonary fibrosis: mendelian randomization and genome-wide cross-trait analysis

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