Clinical study of MUC5B and TOLLIP gene polymorphisms in evaluating the prognosis of patients with idiopathic pulmonary fibrosis_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

 GUO Lu ¹ , ZHONG Zhendong ² , LIU Xiaoshu ¹ , JIANG Caiyu ¹ , YANG Yan ¹ , YANG Yang ¹ , ZHANG Jing ¹ , PU Hong ³ , LI Weimin ⁴

1. Department of Pulmonary and Critical Care Medicine, Sichuan Academy of Medical Sciences•Sichuan Provincial People's Hospital, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, Sichuan 610072, P. R. China;
2. Animal Experimental Center, Sichuan Academy of Medical Sciences•Sichuan Provincial People's Hospital, Chengdu, Sichuan 610212, P. R. China;
3. Department of Radiology, Sichuan Academy of Medical Sciences•Sichuan Province People's Hospital, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, Sichuan 610072, P. R. China;
4. Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

GUO Lu, Email: guolu12345@126.com

Keywords：

Idiopathic pulmonary fibrosis; Gene polymorphism; Radiological feature; Prognosis assessment; Clinical research

DOI：

10.7507/1671-6205.201811081

Video：

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Objective To understand the genetic polymorphisms of MUC5B and TOLLIP in Chinese patients with idiopathic pulmonary fibrosis (IPF), and to explore whether gene polymorphism variation in Chinese IPF patients can be used as a genetic biomarker for accurate treatment and prognosis judgment.Methods A total of one hundred and twenty-six patients with IPF were enrolled in this study. The baseline characteristics, total lung capacity (TLC), forced vital capacity (FVC), carbon monoxide diffusion function (D_LCO), imaging changes of the patients were followed up. The levels of serum sputum glycosylated antigen-6 (Krebs Von den Lungen-6, KL-6) and B lymphocyte chemotactic factor C-X-C motif chemokine 13 (CXCL13) were detected by chemiluminescent enzyme immunoassay and enzyme-linked immunosorbent assay. The gene MUC5B rs35705950 and TOLLIP rs5743890, rs5743894 single nucleotide polymorphism (SNP) were determined by polymerase chain reaction.Results One hundred and twenty-six patients with IPF were found with AA type by TOLLIP rs5743890 and rs5743894 SNP, accounting for 100.0%; MUC5B rs35705950 SNP was expressed as 116 patients (92.1%) with GG type, and 10 patients (7.9%) with GT type, no TT patients were detected. There was no significant difference in clinical characteristics between the two groups in age and non-smokers (P>0.05). Compared with group G, annual decrease of lung function (FVC, D_LCO, and TLC), serum biomarkers (KL-6 and CXCL13), annual increase of reticular and honeycombing lesions, and mortality were significantly lower in group T (P<0.05). The median survival time of IPF patients carrying the MUC5B SNP rs35705950 minor allele (gene phenotype GT) heterozygous was significantly higher than that of homozygous IPF patients with a genetic phenotype of GG.Conclusions There are genetic polymorphisms in Chinese patients with IPF. MUC5B rs35705950 and TOLLIP rs5743890, rs5743894 gene subtypes have low mutation rates in the cohort. Compared with homozygous patients of MUC5B SNP rs35705950, heterozygous patients have smaller changes in lung function and radiological image, lower levels of serum KL-6 and CXCL13, and better prognosis.

Citation： GUO Lu, ZHONG Zhendong, LIU Xiaoshu, JIANG Caiyu, YANG Yan, YANG Yang, ZHANG Jing, PU Hong, LI Weimin. Clinical study of MUC5B and TOLLIP gene polymorphisms in evaluating the prognosis of patients with idiopathic pulmonary fibrosis. Chinese Journal of Respiratory and Critical Care Medicine, 2019, 18(6): 543-548. doi: 10.7507/1671-6205.201811081 Copy

1.	Hobbs BD, Putman RK, Araki T, et al. Overlap of genetic risk between interstitial lung abnormalities and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2019 Jul 24.[Epub ahead of print] doi: 10.1164/rccm.201903-0511OC.
2.	Allen RJ, Porte J, Braybrooke R, et al. Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study. Lancet Respir Med, 2017, 5(11): 869-880.
3.	Fingerlin TE, Zhang W, Yang IV, et al. Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet, 2016, 17(1): 74.
4.	李炯, 苏立. 特发性肺纤维化病情评估和预后生物标志物的研究进展. 重庆医学, 2017, 46(25): 3591-3594.
5.	Conti C, Montero-Fernandez A, Borg E, et al. Mucins MUC5B and MUC5AC in distal airways and honeycomb spaces: comparison among idiopathic pulmonary fibrosis/usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonitis, and control lungs. Am J Respir Crit Care Med, 2016, 193(4): 462-464.
6.	Byun EB, Kim WS, Sung NY, et al. Epigallocatechin-3-gallate regulates anti-inflammatory action through 67-kDa laminin receptor-mediated Tollip signaling induction in lipopolysaccharide-stimulated human intestinal epithelial cells. Cell Physiol Biochem, 2018, 46(5): 2072-2081.
7.	Lorenzo-Salazar JM, Ma SF, Jou J, et al. Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing. ERJ Open Res, 2019, 5(2): 00071-2019.
8.	Chen G, Ribeiro CMP, Sun L, et al. XBP1S regulates MUC5B in a promoter variant-dependent pathway in IPF airway epithelia. Am J Respir Crit Care Med, 2019, 200(2): 220-234.
9.	Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med, 2018, 198(5): e44-e68.
10.	Maldonado F, Moua T, Rajagopalan S, et al. Automated quantification of radiological patterns predicts survival in idiopathic pulmonary fibrosis. Eur Respir J, 2014, 43(1): 204-212.
11.	Olson AL, Swigris JJ, Belkin A, et al. Physical functional capacity in idiopathic pulmonary fibrosis: performance characteristics of the continuous-scale physical function performance test. Expert Rev Respir Med, 2015, 9(3): 361-367.
12.	Wakamatsu K, Nagata N, Kumazoe H, et al. Prognostic value of serial serum KL-6 measurements in patients with idiopathic pulmonary fibrosis. Respir Investig, 2017, 55(1): 16-23.
13.	Neighbors M, Cabanski CR, Ramalingam TR, et al. Prognostic and predictive biomarkers for patients with idiopathic pulmonary fibrosis treated with pirfenidone: post-hoc assessment of the CAPACITY and ASCEND trials. Lancet Respir Med, 2018, 6(8): 615-626.
14.	Hata A, Nakajima T, Matsusaka K, et al. A low DNA methylation epigenotype in lung squamous cell carcinoma and its association with idiopathic pulmonary fibrosis and poorer prognosis. Int J Cancer, 2019 Jun 26. [Epub ahead of print] doi: 10.1002/ijc.32532.
15.	Kumar A, Dougherty M, Findlay GM, et al. Genome sequencing of idiopathic pulmonary fibrosis in conjunction with a medical school human anatomy course. PLoS One, 2014, 9(9): e106744.
16.	Scholand MB, Wolff R, Crossno PF, et al. Severity of cough in idiopathic pulmonary fibrosis is associated with MUC5 B genotype. Cough, 2014, 10(1): 3.
17.	Plantier L, Crestani B, Wert SE, et al. Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosis. Thorax, 2011, 66(8): 651-657.
18.	Zhang Q, Wang Y, Qu D, et al. The possible pathogenesis of idiopathic pulmonary fibrosis considering MUC5B. BioMed Res Int, 2019, 2019: 9712464.
19.	Peljto AL, Selman M, Kim DS, et al. The MUC5B promoter polymorphism is associated with idiopathic pulmonary fibrosis in a Mexican cohort but is rare among Asian ancestries. Chest, 2015, 147(2): 460-464.
20.	Latsi PI, du Bois RM, Nicholson AG, et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med, 2003, 168(5): 531-537.
21.	Collard HR, King TE Jr, Bartelson BB, et al. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2003, 168(5): 538-542.
22.	Chung JH, Peljto AL, Chawla A, et al. CT imaging phenotypes of pulmonary fibrosis in the MUC5B promoter site polymorphism. Chest, 2016, 149(5): 1215-1222.
23.	Best AC, Meng J, Lynch AM, et al. Idiopathic pulmonary fibrosis: physiologic tests, quantitative CT indexes, and CT visual scores as predictors of mortality. Radiology, 2008, 246(3): 935-940.
24.	Ishii H, Kushima H, Kinoshita Y, et al. The serum KL-6 levels in untreated idiopathic pulmonary fibrosis can naturally decline in association with disease progression. Clin Respir J, 2018, 12(9): 2411-2418.
25.	Mertens JS, de Jong E, van den Hoogen LL, et al. The identification of CCL18 as biomarker of disease activity in localized scleroderma. J Autoimmun, 2019, 101: 86-93.
26.	Vuga LJ, Tedrow JR, Pandit KV, et al. CXC motif chemokine 13(CXCL13) is a prognostic biomarker of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2014, 189(8): 966-974.
27.	Jiang H, Hu Y, Shang L, et al. Association between MUC5B polymorphism and susceptibility and severity of idiopathic pulmonary fibrosis. Int J Clin Exp Pathol, 2015, 8(11): 14953-14958.

1. Hobbs BD, Putman RK, Araki T, et al. Overlap of genetic risk between interstitial lung abnormalities and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2019 Jul 24.[Epub ahead of print] doi: 10.1164/rccm.201903-0511OC.
2. Allen RJ, Porte J, Braybrooke R, et al. Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study. Lancet Respir Med, 2017, 5(11): 869-880.
3. Fingerlin TE, Zhang W, Yang IV, et al. Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet, 2016, 17(1): 74.
4. 李炯, 苏立. 特发性肺纤维化病情评估和预后生物标志物的研究进展. 重庆医学, 2017, 46(25): 3591-3594.
5. Conti C, Montero-Fernandez A, Borg E, et al. Mucins MUC5B and MUC5AC in distal airways and honeycomb spaces: comparison among idiopathic pulmonary fibrosis/usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonitis, and control lungs. Am J Respir Crit Care Med, 2016, 193(4): 462-464.
6. Byun EB, Kim WS, Sung NY, et al. Epigallocatechin-3-gallate regulates anti-inflammatory action through 67-kDa laminin receptor-mediated Tollip signaling induction in lipopolysaccharide-stimulated human intestinal epithelial cells. Cell Physiol Biochem, 2018, 46(5): 2072-2081.
7. Lorenzo-Salazar JM, Ma SF, Jou J, et al. Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing. ERJ Open Res, 2019, 5(2): 00071-2019.
8. Chen G, Ribeiro CMP, Sun L, et al. XBP1S regulates MUC5B in a promoter variant-dependent pathway in IPF airway epithelia. Am J Respir Crit Care Med, 2019, 200(2): 220-234.
9. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med, 2018, 198(5): e44-e68.
10. Maldonado F, Moua T, Rajagopalan S, et al. Automated quantification of radiological patterns predicts survival in idiopathic pulmonary fibrosis. Eur Respir J, 2014, 43(1): 204-212.
11. Olson AL, Swigris JJ, Belkin A, et al. Physical functional capacity in idiopathic pulmonary fibrosis: performance characteristics of the continuous-scale physical function performance test. Expert Rev Respir Med, 2015, 9(3): 361-367.
12. Wakamatsu K, Nagata N, Kumazoe H, et al. Prognostic value of serial serum KL-6 measurements in patients with idiopathic pulmonary fibrosis. Respir Investig, 2017, 55(1): 16-23.
13. Neighbors M, Cabanski CR, Ramalingam TR, et al. Prognostic and predictive biomarkers for patients with idiopathic pulmonary fibrosis treated with pirfenidone: post-hoc assessment of the CAPACITY and ASCEND trials. Lancet Respir Med, 2018, 6(8): 615-626.
14. Hata A, Nakajima T, Matsusaka K, et al. A low DNA methylation epigenotype in lung squamous cell carcinoma and its association with idiopathic pulmonary fibrosis and poorer prognosis. Int J Cancer, 2019 Jun 26. [Epub ahead of print] doi: 10.1002/ijc.32532.
15. Kumar A, Dougherty M, Findlay GM, et al. Genome sequencing of idiopathic pulmonary fibrosis in conjunction with a medical school human anatomy course. PLoS One, 2014, 9(9): e106744.
16. Scholand MB, Wolff R, Crossno PF, et al. Severity of cough in idiopathic pulmonary fibrosis is associated with MUC5 B genotype. Cough, 2014, 10(1): 3.
17. Plantier L, Crestani B, Wert SE, et al. Ectopic respiratory epithelial cell differentiation in bronchiolised distal airspaces in idiopathic pulmonary fibrosis. Thorax, 2011, 66(8): 651-657.
18. Zhang Q, Wang Y, Qu D, et al. The possible pathogenesis of idiopathic pulmonary fibrosis considering MUC5B. BioMed Res Int, 2019, 2019: 9712464.
19. Peljto AL, Selman M, Kim DS, et al. The MUC5B promoter polymorphism is associated with idiopathic pulmonary fibrosis in a Mexican cohort but is rare among Asian ancestries. Chest, 2015, 147(2): 460-464.
20. Latsi PI, du Bois RM, Nicholson AG, et al. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med, 2003, 168(5): 531-537.
21. Collard HR, King TE Jr, Bartelson BB, et al. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2003, 168(5): 538-542.
22. Chung JH, Peljto AL, Chawla A, et al. CT imaging phenotypes of pulmonary fibrosis in the MUC5B promoter site polymorphism. Chest, 2016, 149(5): 1215-1222.
23. Best AC, Meng J, Lynch AM, et al. Idiopathic pulmonary fibrosis: physiologic tests, quantitative CT indexes, and CT visual scores as predictors of mortality. Radiology, 2008, 246(3): 935-940.
24. Ishii H, Kushima H, Kinoshita Y, et al. The serum KL-6 levels in untreated idiopathic pulmonary fibrosis can naturally decline in association with disease progression. Clin Respir J, 2018, 12(9): 2411-2418.
25. Mertens JS, de Jong E, van den Hoogen LL, et al. The identification of CCL18 as biomarker of disease activity in localized scleroderma. J Autoimmun, 2019, 101: 86-93.
26. Vuga LJ, Tedrow JR, Pandit KV, et al. CXC motif chemokine 13(CXCL13) is a prognostic biomarker of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2014, 189(8): 966-974.
27. Jiang H, Hu Y, Shang L, et al. Association between MUC5B polymorphism and susceptibility and severity of idiopathic pulmonary fibrosis. Int J Clin Exp Pathol, 2015, 8(11): 14953-14958.

Chinese Journal of Respiratory and Critical Care Medicine

Clinical study of MUC5B and TOLLIP gene polymorphisms in evaluating the prognosis of patients with idiopathic pulmonary fibrosis

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