Clinical and genetic study of the rs35705950 polymorphism of the MUC5B gene in patients with interstitial lung diseases

Interstitial lung diseases (ILD) represent a serious medical and social problem due to their progressive course and unfavorable prognosis. Genetic factors, in particular, the MUC5B gene polymorphism, play an important role in their pathogenesis.

The aim of the study was to evaluate the frequency of the T-risk allele of the rs35705950 single nucleotide polymorphism of the MUC5B gene in Russian patients with hypersensitivity pneumonitis (HP) and idiopathic pulmonary fibrosis (IPF) compared with the general population.

Methods. The study included patients (n = 86) with HP (n = 49) and IPF (n = 37). The control group consisted of a sample from the National Genetic Initiative 100,000 + I project (n = 89,261). Genotyping of the rs35705950 polymorphism was performed using polymerase chain reaction followed by restriction fragment length polymorphism analysis (BstHHI restriction enzyme). Statistical analysis included calculation of allele and genotype frequencies, assessment of compliance with Hardy – Weinberg equilibrium, and association analysis based on odds ratios (OR) for allelic and dominant models.

Results. The frequency of the risk allele T was significantly higher in the patient groups compared to the control (p < 0.001): 0.2973 in IPF (OR – 3.82; 95% CI – 2.21–6.41; p =  1.9 × 10^–6) and 0.2551 in GP (OR – 3.10; 95% CI – 1.88–4.94; p = 8.4 × 10^–6). The results of the dominant model analysis (TT+GT genotypes) also revealed a significant increase in the risk of IPF (OR – 5.05; 95% CI – 2.64–9.64) and GP (OR – 3.22; 95% CI – 1.83–5.67) compared with the control group (p < 0.001). When comparing patients with IPF and GP, the differences in T allele frequencies did not reach statistical significance (OR – 1.23; 95% CI – 0.59–2.56; p = 0.61). The distribution of genotypes in all groups corresponded to the Hardy – Weinberg equilibrium.

Conclusion. The rs35705950 polymorphism of the MUC5B gene is a significant genetic risk factor for the development of both IPF and GP in the Russian population. The similar risk profile for these two entities suggests common pathogenetic mechanisms associated with this gene. These findings support the inclusion of MUC5B analysis in the evaluation of patients with suspected ILD.

1. Wijsenbeek M., Suzuki A., Maher T.M. Interstitial lung diseases. Lancet. 2022; 400 (10354): 769–786. DOI: 10.1016/S0140-6736(22)01052-2.

2. Michalski J.E., Schwartz D.A. Genetic risk factors for idiopathic pulmonary fibrosis: insights into immunopathogenesis. J. Inflamm. Res. 2021; 13: 1305–1318. DOI: 10.2147/JIR.S280958.

3. Avdeev S.N., Chikina S.Y., Tiurin I.E. et al. [Chronic fibrosing progressing interstitial lung disease: a decision of Multidisciplinary Expert Board.]. Pul'monologiya. 2021; 31 (4): 505–510. DOI: 10.18093/0869-0189-2021-31-4-505-510 (in Russian).

4. Ilkovich M.M., Novikova L.N., Ilkovich J.M. [Disseminated lung diseases in primary care practice]. Rossiyskiy semeynyy vrach. 2012; 16 (2): 16–22. DOI: 10.17816/RFD2012216-22 (in Russian).

5. Russian Respiratory Society [Clinical guidelines. Idiopathic pulmonary fibrosis]. 2021. Available at: https://spulmo.ru/upload/kr/ILF_2021.pdf [Accessed: September 23, 2025] (in Russian).

6. Russian Respiratory Society. [Clinical guidelines. Hypersensitivity pneumonitis]. 2022. Available at: https://spulmo.ru/upload/kr_GP_040422_2.pdf [Accessed: September 23, 2025] (in Russian).

7. Fernández Pérez E.R., Travis W.D., Lynch D.A. et al. Diagnosis and evaluation of hypersensitivity pneumonitis: CHEST guideline and expert panel report. Chest. 2021; 160 (2): e97–156. DOI: 10.1016/j.chest.2021.03.066.

8. Furusawa H., Peljto A.L., Walts A.D. et al. Common idiopathic pulmonary fibrosis risk variants are associated with hypersensitivity pneumonitis. Thorax. 2022; 77 (5): 508–510. DOI: 10.1136/thoraxjnl-2021-217693.

9. Ley B., Torgerson D.G., Oldham J.M. et al. Rare protein-altering telomere-related gene variants in patients with chronic hypersensitivity pneumonitis. Am. J. Respir. Crit. Care Med. 2019; 200 (9): 1154–1163. DOI: 10.1164/rccm.201902-0360OC.

10. Hutchinson J.P., McKeever T.M., Fogarty A.V. et al. Rising global mortality from idiopathic pulmonary fibrosis in the twenty-first century. An. Am. Thorac. Soc. 2014; 11 (8): 1176–1185. DOI: 10.1513/AnnalsATS.201404-145OC.

11. Evans C.M., Fingerlin T.E., Schwarz M.I. et al. Idiopathic pulmonary fibrosis: a genetic disease that involves mucociliary dysfunction of the peripheral airways. Physiol. Rev. 2016; 96 (4): 1567–1591. DOI: 10.1152/physrev.00004.2016.

12. Noth I., Zhang Y., Ma S.F. et al. Genetic variants associated with susceptibility and mortality to idiopathic pulmonary fibrosis: a genome-wide association study. Lancet Respir. Med. 2013; 1 (4): 309–317. DOI: 10.1016/S2213-2600(13)70045-6.

13. Zhang Y., Noth I., Garcia J.G., Kaminsky N. A Variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N. Engl. J. Med. 2011; 364 (16): 1576–1577. DOI: 10.1056/NEJMc1013504.

14. Seibold M.A., Wise A.L., Speer M.C. et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N. Engl. J. Med. 2011; 364 (16): 1503–1512. DOI: 10.1056/NEJMoa1013660.

15. Kasper M., Haroske G. Alterations in the alveolar epithelium after injury leading to pulmonary fibrosis. Histol. Histopathol. 1996; 11 (2): 463–483.

16. Moss B.J., Ryter S.W., Rosas I.O. Pathogenic mechanisms underlying idiopathic pulmonary fibrosis. Annu. Rev. Pathol. 2022; 17: 515–546. DOI: 10.1146/annurev-pathol-042320-030240.

17. Ryerson C.J., Adegunsoye A., Piciucchi S. et al. Update of the international multidisciplinary classification of the interstitial pneumonias: an ERS/ATS statement. Eur. Respir. J. 2025; 66 (6): 2500158. DOI: 10.1183/13993003.00158-2025.

18. Borie R., Cardwell J., Konigsberg I.R. et al. Colocalization of gene expression and DNA methylation with genetic risk variants supports functional roles of MUC5B and DSP in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2022; 206 (10): 1259–1270. DOI: 10.1164/rccm.202110-2308OC.

19. Stock C.J., Conti C., Montero-Fernandez Á. et al. Interaction between the promoter MUC5B polymorphism and mucin expression: is there a difference according to ILD subtype? Thorax. 2020; 75 (10): 901–903. DOI: 10.1136/thoraxjnl-2020-214579.

20. Mota P.C., Soares M.L., Ferreira A.C. et al. Polymorphisms and haplotypes of TOLLIP and MUC5B are associated with susceptibility and survival in patients with fibrotic hypersensitivity pneumonitis. Pulmonology. 2025; 31 (1): 2416788. DOI: 10.1016/j.pulmoe.2024.01.002.

21. Ley B., Newton C.A., Arnould I. et al. The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study. Lancet Respir. Med. 2017; 5 (8): 639–647. DOI: 10.1016/S2213-2600(17)30216-3.

22. Lou H.Q., Huang C.X., Li G.Y. et al. The association between MUC5B Rs35705950 and risks of idiopathic interstitial pneumonia, systemic sclerosis interstitial lung disease, and familial interstitial pneumonia: a meta-analysis. Iran. J. Public Health. 2020; 49 (12): 2240–2250. DOI: 10.18502/ijph.v49i12.4801.

23. Furusawa H., Peljto A.L., Walts A.D. et al. Common idiopathic pulmonary fibrosis risk variants are associated with hypersensitivity pneumonitis. Thorax. 2022; 77 (5): 508–510. DOI: 10.1136/thoraxjnl-2021-217693.