Homocysteine and risk of interstitial lung disease: A mendelian randomization approach to causal inference

Shimin  Li; Xiaochen  Hu; Xin  Hu; Hang  Liu; Shanshan Meng

doi:10.36141/svdld.v42i2.16386

Authors

Shimin Li Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University , Harbin, Heilongjiang
Xiaochen Hu Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University , Harbin, Heilongjiang
Xin Hu Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University , Harbin, Heilongjiang
Hang Liu Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University , Harbin, Heilongjiang
Shanshan Meng Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University , Harbin, Heilongjiang

Keywords:

homocysteine, Interstitial lung disease, idiopathic pulmonary fibrosis, mendelian randomization, causal association

Abstract

Background and aim: Homocysteine (Hcy) has been implicated in inflammatory, oxidative stress (OS), and endoplasmic reticulum (ER) stress mechanisms, which are hypothesized to contribute to the pathogenesis of interstitial lung disease (ILD). Given the paucity of evidence regarding Hcy's role in ILD, a two-sample Mendelian randomization study was performed to investigate the causal association between Hcy and ILD.

Methods: We sourced data for total plasma Hcy from genome-wide association studies (GWAS) involving 44,147 European individuals. Data for ILD, idiopathic pulmonary fibrosis (IPF), IPF-related respiratory insufficiency, and systemic autoimmune disease-associated IPF were derived from the FinnGen consortium. To evaluate the causal association of reduced total plasma Hcy with ILD and related conditions, a range of Mendelian randomization (MR) analytical techniques were utilized to analyze the data. The results are reported as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). We conducted sensitivity analyses through leave-one-out procedures and Radial MR plots.

Results: Our IVW estimates suggested that total plasma Hcy had a potential causal association with IPF (OR=0.649, 95%CI: 0.495-0.851), indicating that along with total plasma Hcy depressed 1 µmol/L, odds of IPF decreased 0.351. Although it seemed that decreased total plasma Hcy level is associated with lower odds of IPF-related respiratory insufficiency (OR=0.672, 95%CI: 0.489-0.924), due to the existence of horizontal pleiotropy, this causal association was not robust. In addition, MR leave-one-out and Radial MR sensitivity analyses showed there is no outlier among the selected IVs that could affect the potential causal relationship between Hcy and IPF.

Conclusions: The levels of total plasma Hcy may bear a significant association with the risk of developing IPF, a specific form of ILD. However, to definitively establish a causal relationship between elevated Hcy levels and the pathogenesis of ILD, additional well-controlled, prospective studies are indispensable.

References

1. Samarelli AV, Tonelli R, Marchioni A, et al. Fibrotic idiopathic interstitial lung disease: the molecular and cellular key players. Int J Mol Sci. 2021;22(16):8952. doi: 10.3390/ijms22168952.

2. Perelas A, Silver RM, Arrossi AV, Highland KB. Systemic sclerosis-associated interstitial lung disease. Lancet Respir Med. 2020;8(3):304-20. doi: 10.1016/S2213-2600(19)30480-1.

3. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733-48. doi: 10.1164/rccm.201308-1483ST.

4. Wijsenbeek M, Suzuki A, Maher TM. Interstitial lung diseases. Lancet. 2022;400(10354):769-86. doi: 10.1016/S0140-6736(22)01052-2.

5. Podolanczuk AJ, Wong AW, Saito S, et al. Update in interstitial lung disease 2020. Am J Respir Crit Care Med. 2021;203(11):1343-52. doi: 10.1164/rccm.202103-0559UP.

6. Bast A, Weseler AR, Haenen GR, den Hartog GJ. Oxidative stress and antioxidants in interstitial lung disease. Curr Opin Pulm Med. 2010;16(5):516-20. doi: 10.1097/MCP.0b013e32833c645d.

7. Hu H, Wang C, Jin Y, et al. Alpha-lipoic acid defends homocysteine-induced endoplasmic reticulum and oxidative stress in HAECs. Biomed Pharmacother. 2016;80:63-72. doi: 10.1016/j.biopha.2016.02.022.

8. Zhang S, Lv Y, Luo X, et al. Homocysteine promotes atherosclerosis through macrophage pyroptosis via endoplasmic reticulum stress and calcium disorder. Mol Med. 2023;29(1):73. doi: 10.1186/s10020-023-00656-z.

9. Nakano H, Inoue S, Minegishi Y, et al. Effect of hyperhomocysteinemia on a murine model of smoke-induced pulmonary emphysema. Sci Rep. 2022;12(1):12968. doi: 10.1038/s41598-022-16767-2.

10. Motegi S, Toki S, Yamada K, Uchiyama A, Ishikawa O. Elevated plasma homocysteine level is possibly associated with skin sclerosis in a series of Japanese patients with systemic sclerosis. J Dermatol. 2014;41(11):986-91. doi: 10.1111/1346-8138.12642.

11. Sekiguchi A, Endo Y, Yamazaki S, et al. Plasma homocysteine levels are positively associated with interstitial lung disease in dermatomyositis patients with anti-aminoacyl-tRNA synthetase antibody. J Dermatol. 2021;48(1):34-41. doi: 10.1111/1346-8138.15602.

12. Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014;23(R1):R89-98. doi: 10.1093/hmg/ddu328.

13. Sekula P, Del Greco MF, Pattaro C, Köttgen A. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol. 2016;27(11):3253-65. doi: 10.1681/ASN.2016010098.

14. Luo Q, Zhou P, Chang S, Huang Z, Zhu Y. The gut-lung axis: Mendelian randomization identifies a causal association between inflammatory bowel disease and interstitial lung disease. Heart Lung. 2023;61:120-6. doi: 10.1016/j.hrtlng.2023.05.016.

15. Zhang Y, Ni Y, Li L. The gut-lung axis: Mendelian randomization identifies a causal association between inflammatory bowel disease and interstitial lung disease. Heart Lung. 2024;64:215-6. doi: 10.1016/j.hrtlng.2023.11.015.

16. Zhao T, Lv T. Causal relationship between serum metabolites and interstitial lung disease in humans: a Mendelian randomization study. Technol Health Care. 2024;32(1):45-53. doi: 10.3233/THC-240285.

17. van Meurs JB, Pare G, Schwartz SM, et al. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. Am J Clin Nutr. 2013;98(3):668-76. doi: 10.3945/ajcn.112.044545.

18. Burgess S, Thompson SG. Bias in causal estimates from Mendelian randomization studies with weak instruments. Stat Med. 2011;30(11):1312-23. doi: 10.1002/sim.4197.

19. Wang Y, Gao L, Lang W, et al. Serum calcium levels and Parkinson's disease: a Mendelian randomization study. Front Genet. 2020;11:824. doi: 10.3389/fgene.2020.00824.

20. Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40(3):755-64. doi: 10.1093/ije/dyr036.

21. Bowden J, Del Greco MF, Minelli C, et al. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol. 2019;48(3):728-42. doi: 10.1093/ije/dyy258.

22. Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32(5):377-89. doi: 10.1007/s10654-017-0255-x.

23. Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017;46(6):1985-98. doi: 10.1093/ije/dyx102.

24. Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693-8. doi: 10.1038/s41588-018-0099-7.

25. Xue H, Shen X, Pan W. Constrained maximum likelihood-based Mendelian randomization robust to both correlated and uncorrelated pleiotropic effects. Am J Hum Genet. 2021;108(7):1251-69. doi: 10.1016/j.ajhg.2021.05.014.

26. Khandanpour N, Loke YK, Meyer FJ, Jennings B, Armon MP. Homocysteine and peripheral arterial disease: systematic review and meta-analysis. Eur J Vasc Endovasc Surg. 2009;38(3):316-22. doi: 10.1016/j.ejvs.2009.05.007.

27. Zinellu A, Zinellu E, Pau MC, et al. A systematic review and meta-analysis of homocysteine concentrations in chronic obstructive pulmonary disease. Clin Exp Med. 2023;23(3):751-8. doi: 10.1007/s10238-022-00833-0.

28. Hu Y, Tan P, Wang J, et al. Mendelian randomization study to investigate the causal relationship between plasma homocysteine and chronic obstructive pulmonary disease. World J Emerg Med. 2023;14(5):367-71. doi: 10.5847/wjem.j.1920-8642.2023.078.

29. Moss BJ, Ryter SW, Rosas IO. Pathogenic mechanisms underlying idiopathic pulmonary fibrosis. Annu Rev Pathol. 2022;17:515-46. doi: 10.1146/annurev-pathol-042320-030240.

30. Lu Q, Harrington EO, Rounds S. Apoptosis and lung injury. Keio J Med. 2005;54(4):184-9. doi: 10.2302/kjm.54.184.

31. Bourgonje AR, Abdulle AE, Al-Rawas AM, et al. Systemic oxidative stress is increased in postmenopausal women and independently associates with homocysteine levels. Int J Mol Sci. 2020;21(1):314. doi: 10.3390/ijms21010314.

32. Zinellu A, Mangoni AA. Arginine, transsulfuration, and folic acid pathway metabolomics in chronic obstructive pulmonary disease: a systematic review and meta-analysis. Cells. 2023;12(17):2180. doi: 10.3390/cells12172180.

33. Morellato AE, Umansky C, Pontel LB. The toxic side of one-carbon metabolism and epigenetics. Redox Biol. 2021;40:101850. doi: 10.1016/j.redox.2020.101850.

34. Qu Y, Hao C, Zhai R, Yao W. Folate and macrophage folate receptor-β in idiopathic pulmonary fibrosis disease: the potential therapeutic target? Biomed Pharmacother. 2020;131:110711. doi: 10.1016/j.biopha.2020.110711.

35. Wu C, Duan X, Wang X, Wang L. Advances in the role of epigenetics in homocysteine-related diseases. Epigenomics. 2023;15(15):769-95. doi: 10.2217/epi-2023-0207.

36. Wang Y, Zhang L, Huang T, et al. The methyl-CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation. Eur Respir J. 2022;60(3):2203697. doi: 10.1183/13993003.03697-2020.