MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis

Francesco Bonella, Xiaoping Long, Shinichiro Ohshimo, Yasushi Horimasu, Matthias Griese, Josune Guzman, Nobuoki Kohno, Ulrich Costabel, Francesco Bonella, Xiaoping Long, Shinichiro Ohshimo, Yasushi Horimasu, Matthias Griese, Josune Guzman, Nobuoki Kohno, Ulrich Costabel

Abstract

Background: KL-6, a human MUC1 mucin, is a sensitive biomarker for interstitial lung diseases including pulmonary alveolar proteinosis (PAP). A correlation between MUC1 gene single nucleotide polymorphism (SNP) rs4072037 genotype and serum KL-6 levels has been reported. This study was aimed at investigating the correlation between MUC1 SNP genotype, severity of disease and disease outcome in PAP.

Methods: Twenty four patients with PAP and 30 healthy volunteers were studied. MUC1 rs4072037 was detected by using a real-time polymerase chain reaction (RT-PCR). Genotyping was performed by pyrosequencing. KL-6 levels were measured in serum by Nanopia KL-6 assay (SEKISUI Diagnostics).

Results: The frequency of MUC1 rs4072037 alleles was significantly different between PAP patients and healthy volunteers (PAP, A/A 46%, A/G 54%, G/G 0%; healthy controls, A/A 30%, A/G 40%, G/G 30%; p = 0.013). Serum KL-6 levels were significantly higher in PAP patients than in controls (p < 0.0001), and significantly higher in PAP patients with A/A genotype than in those with A/G genotype (p = 0.007). Patients with A/A genotype had higher alveolar-arterial oxygen difference (A-aDO2) and lower DLco compared to those with A/G genotype (p = 0.027 and p = 0.012, respectively). Multivariate analysis, Kaplan-Meier analysis and C statistics showed that the rs4072037 A/A genotype was associated with higher rate of disease progression (HR: 5.557, p = 0.014).

Conclusions: MUC1 rs4072037 A/A genotype is associated with more severe pulmonary dysfunction and a higher rate of disease progression in PAP patients.

Keywords: Disease outcome; KL-6; MUC1 polymorphisms; Pulmonary alveolar proteinosis.

Figures

Fig. 1
Fig. 1
Comparison of serum levels of KL-6 (a) and LDH (b) in 30 healthy controls and in 24 PAP patients
Fig. 2
Fig. 2
Frequency of MUC1 rs4072037 SNP genotypes in the studied subjects
Fig. 3
Fig. 3
Correlation of MUC1 SNP genotype with serum KL-6 levels (a) and serum LDH levels (b) in 30 healthy controls and in 24 PAP patients
Fig. 4
Fig. 4
Correlation of MUC1 SNP genotype with A-aDO2 (a) and DLco (b) in PAP patients
Fig. 5
Fig. 5
Kaplan-Meier analysis showing disease progression according to MUC1 SNP genotype in 24 PAP patients

References

    1. Rosen SH, Castleman B, Liebow AA. Pulmonary alveolar proteinosis. N Engl J Med. 1958;258(23):1123–42. doi: 10.1056/NEJM195806052582301.
    1. Bonella F, Campo I. Pulmonary alveolar proteinosis. Pneumologia. 2014;63(3):144,147–155.
    1. Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med. 2002;166(2):215–35. doi: 10.1164/rccm.2109105.
    1. Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, et al. Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am J Respir Crit Care Med. 2008;177(7):752–62. doi: 10.1164/rccm.200708-1271OC.
    1. Carey B, Trapnell BC. The molecular basis of pulmonary alveolar proteinosis. Clin Immunol. 2010;135(2):223–35. doi: 10.1016/j.clim.2010.02.017.
    1. Kitamura T, Tanaka N, Watanabe J, Uchida K, Kanegasaki S, Yamada Y, et al. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J Exp Med. 1999;190(6):875–80. doi: 10.1084/jem.190.6.875.
    1. Costabel U, Guzman J. Pulmonary alveolar proteinosis: a new autoimmune disease. Sarcoidosis Vasc Diffuse Lung Dis. 2005;22(Suppl 1):S67–73.
    1. Stahel RA, Gilks WR, Lehmann HP, Schenker T. Third International Workshop on Lung Tumor and Differentiation Antigens: overview of the results of the central data analysis. Int J Cancer Suppl. 1994;8:6–26. doi: 10.1002/ijc.2910570704.
    1. Kohno N, Kyoizumi S, Awaya Y, Fukuhara H, Yamakido M, Akiyama M. New serum indicator of interstitial pneumonitis activity. Sialylated carbohydrate antigen KL-6. Chest. 1989;96(1):68–73. doi: 10.1378/chest.96.1.68.
    1. Ishikawa N, Hattori N, Yokoyama A, Kohno N. Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir Investig. 2012;50(1):3–13. doi: 10.1016/j.resinv.2012.02.001.
    1. Ohtsuki Y, Kobayashi M, Yoshida S, Kishimoto N, Kubo K, Yokoyama A, et al. Immunohistochemical localisation of surfactant proteins A and D, and KL-6 in pulmonary alveolar proteinosis. Pathology. 2008;40(5):536–9. doi: 10.1080/00313020802198077.
    1. Takahashi T, Munakata M, Suzuki I, Kawakami Y. Serum and bronchoalveolar fluid KL-6 levels in patients with pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 1998;158(4):1294–8. doi: 10.1164/ajrccm.158.4.9712003.
    1. Ohshimo S, Bonella F, Sommerwerck U, Teschler H, Kamler M, Jakob HG, et al. Comparison of serum KL-6 versus bronchoalveolar lavage neutrophilia for the diagnosis of bronchiolitis obliterans in lung transplantation. J Heart Lung Transplant. 2011;30(12):1374–80. doi: 10.1016/j.healun.2011.07.010.
    1. Ohnishi H, Yokoyama A, Yasuhara Y, Watanabe A, Naka T, Hamada H, et al. Circulating KL-6 levels in patients with drug induced pneumonitis. Thorax. 2003;58(10):872–5. doi: 10.1136/thorax.58.10.872.
    1. Ohshimo S, Bonella F, Cui A, Beume M, Kohno N, Guzman J, et al. Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179(11):1043–7. doi: 10.1164/rccm.200808-1313OC.
    1. Doishita S, Inokuma S, Asashima H, Nakachi S, Matsuo Y, Rokutanda R, et al. Serum KL-6 level as an indicator of active or inactive interstitial pneumonitis associated with connective tissue diseases. Intern Med. 2011;50(23):2889–92. doi: 10.2169/internalmedicine.50.5866.
    1. Lin FC, Chen YC, Chang SC. Clinical importance of bronchoalveolar lavage fluid and blood cytokines, surfactant protein D, and Krebs von Lungren 6 antigen in idiopathic pulmonary alveolar proteinosis. Mayo Clin Proc. 2008;83(12):1344–9. doi: 10.4065/83.12.1344.
    1. Ligtenberg MJ, Gennissen AM, Vos HL, Hilkens J. A single nucleotide polymorphism in an exon dictates allele dependent differential splicing of episialin mRNA. Nucleic Acids Res. 1991;19(2):297–301. doi: 10.1093/nar/19.2.297.
    1. Janssen R, Kruit A, Grutters JC, Ruven HJ, Gerritsen WB, van den Bosch JM. The mucin-1 568 adenosine to guanine polymorphism influences serum Krebs von den Lungen-6 levels. Am J Respir Cell Mol Biol. 2006;34(4):496–9. doi: 10.1165/rcmb.2005-0151OC.
    1. Horimasu Y, Hattori N, Ishikawa N, Kawase S, Tanaka S, Yoshioka K, et al. Different MUC1 gene polymorphisms in German and Japanese ethnicities affect serum KL-6 levels. Respir Med. 2012;106(12):1756–64. doi: 10.1016/j.rmed.2012.09.001.
    1. Bonella F, Ohshimo S, Miaotian C, Griese M, Guzman J, Costabel U. Serum KL-6 is a predictor of outcome in pulmonary alveolar proteinosis. Orphanet J Rare Dis. 2013;8:53. doi: 10.1186/1750-1172-8-53.
    1. Nakajima M, Manabe T, Niki Y, Matsushima T. Serum KL-6 level as a monitoring marker in a patient with pulmonary alveolar proteinosis. Thorax. 1998;53(9):809–11. doi: 10.1136/thx.53.9.809.
    1. Ishikawa N, Kondo K, Oguri T, Kamitsuna M, Sakurai J, Fujitaka K, et al. Usefulness of the modified lavage technique of Bingisser and KL-6 monitoring in a patient with pulmonary alveolar proteinosis. Intern Med. 2002;41(5):381–5. doi: 10.2169/internalmedicine.41.381.
    1. Fujishima T, Honda Y, Shijubo N, Takahashi H, Abe S. Increased carcinoembryonic antigen concentrations in sera and bronchoalveolar lavage fluids of patients with pulmonary alveolar proteinosis. Respiration. 1995;62(6):317–21. doi: 10.1159/000196473.
    1. Bonella F, Bauer PC, Griese M, Ohshimo S, Guzman J, Costabel U. Pulmonary alveolar proteinosis: New insights from a single-center cohort of 70 patients. Respir Med. 2011;105(12):1908–16. doi: 10.1016/j.rmed.2011.08.018.
    1. Ohshimo S, Ishikawa N, Horimasu Y, Fujitaka K, Haruta Y, Murai H, et al. MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis. Eur Respir J. 2013;42(Suppl 57):2351.
    1. Costabel U, Guzman J, Bonella F, Oshimo S. Bronchoalveolar lavage in other interstitial lung diseases. Semin Respir Crit Care Med. 2007;28(5):514–24. doi: 10.1055/s-2007-991525.
    1. Kitamura T, Uchida K, Tanaka N, Tsuchiya T, Watanabe J, Yamada Y, et al. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2000;162(2 Pt 1):658–62. doi: 10.1164/ajrccm.162.2.9910032.
    1. Kruit A, Grutters JC, Ruven HJ, van-Moorsel CC, van-den-Bosch JM. A CHI3L1 gene polymorphism is associated with serum levels of YKL-40, a novel sarcoidosis marker. Respir Med. 2007;101(7):1563–71. doi: 10.1016/j.rmed.2006.12.006.
    1. Standardized lung function testing. Official statement of the European Respiratory Society. Eur Respir J Suppl 1993: 16: 1–100
    1. Available from: . Accessed 20 Apr 2016.
    1. Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004;4(1):45–60. doi: 10.1038/nrc1251.
    1. Imbert Y, Foulks GN, Brennan MD, Jumblatt MM, John G, Shah HA, Newton C, Pouranfar F, WWWWY, Jr. MUC1 and estrogen receptor alpha gene polymorphisms in dry eye patients. Exp Eye Res. 2009;88(3):334–8.
    1. Ng W, Loh AX, Teixeira AS, Pereira SP, Swallow DM. Genetic regulation of MUC1 alternative splicing in human tissues. Br J Cancer. 2008;99(6):978–85. doi: 10.1038/sj.bjc.6604617.
    1. Sun H, Wu X, Wu F, Li Y, Yu Z, Chen X, Chen Y, Yang W. Associations of genetic variants in the PSCA, MUC1 and PLCE1 genes with stomach cancer susceptibility in a Chinese population. PLoS One. 2015;10(2) doi: 10.1371/journal.pone.0117576.
    1. Kupcinskas J, Wex T, Link A, Bartuseviciute R, Dedelaite M, Kevalaite G, Leja M, Skieceviciene J, Kiudelis G, Jonaitis L, Kupcinskas L, Malfertheiner P. PSCA and MUC1 gene polymorphisms are associated with gastric cancer and pre-malignant gastric conditions. Anticancer Res. 2014;34(12):7167–75.
    1. Liu X, Wang Z, Zhang X, Chang J, Tang W, Gan L, Wu Z, Li J. MUC1 gene polymorphism rs4072037 and susceptibility to gastric cancer: a meta-analysis. Springerplus. 2014;3:599. doi: 10.1186/2193-1801-3-599.
    1. Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL. Pulmonary alveolar proteinosis. In: King TE, editor. Non-neoplastic disorders of the lower respiratory tract Atlas of Non-tumor Pathology. Washington, DC: American Registry of Pathology; 2002. pp. 169–176.
    1. Arai T, Inoue Y, Sugimoto C, Inoue Y, Nakao K, Takeuchi N, Matsumuro A, Hirose M, Nakata K, Hayashi S. CYFRA 21–1 as a disease severity marker for autoimmune pulmonary alveolar proteinosis. Respirology. 2014;19(2):246–52. doi: 10.1111/resp.12210.

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