The Application Value of Collagen VI Family Proteins in the Diagnosis and Treatment of Bronchiectasis: A Mendelian Randomization Study_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

GUO Qinqin ,  CHENG Mengyu ,  SU Lin

Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi 030032, P.R.China;

Corresponding author：

CHENG Mengyu, Email: cmyy1979@163.com; SU Lin, Email: cmu_sl@126.com

Keywords：

Collagen VI; COL6A3; bronchiectasis; Mendelian randomization; colocalization analysis.

DOI：

10.7507/1671-6205.202408087

Video：

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Objective To explore the causal relationship between the Collagen VI (COL6) family proteins COL6A1, A2, and A3 and bronchiectasis using the Mendelian randomization (MR) method.Methods The primary analysis was conducted using MR combined with summary-data-based Mendelian randomization (SMR) analysis. COL6 family proteins were used as exposure data, and bronchiectasis was used as outcome data. Cis-protein quantitative trait locus (cis-pQTL) data were extracted for analysis, and the results were meta-analyzed. Subsequently, COL6A3-cis-pQTL data from the UK Biobank plasma proteome study were used for further validation. Colocalization analysis was also performed to further explore the association between COL6 proteins and bronchiectasis.Results MR and SMR results revealed a negative causal relationship between COL6A3 and bronchiectasis (p-MRmeta = 0.005, OR = 0.30; p-SMRmeta = 0.004, OR = 0.26). The validation phase also confirmed the negative causal relationship between COL6A3 and bronchiectasis (p-MRmeta = 0.000007, OR = 0.27; p-SMRmeta = 0.0003, OR = 0.29). Colocalization analysis supported the presence of a shared causal variant (rs972974) between COL6A3 and bronchiectasis (PP.H4 = 0.967/0.876).Conclusion There is an inverse causal relationship between COL6A3 and bronchiectasis. Low expression of COL6A3 increases the risk of developing bronchiectasis, making COL6A3 a potential biomarker and therapeutic target for drug development in bronchiectasis.

Citation： GUO Qinqin, CHENG Mengyu, SU Lin. The Application Value of Collagen VI Family Proteins in the Diagnosis and Treatment of Bronchiectasis: A Mendelian Randomization Study. Chinese Journal of Respiratory and Critical Care Medicine, 2025, 24(2): 115-123. doi: 10.7507/1671-6205.202408087 Copy

1.	O'Donnell AE. Bronchiectasis - A Clinical Review. N Engl J Med, 2022, 387(6): 533-545.
2.	Henkle E, Chan B, Curtis JR, et al. Characteristics and Health-care Utilization History of Patients With Bronchiectasis in US Medicare Enrollees With Prescription Drug Plans, 2006 to 2014. Chest, 2018, 154(6): 1311-1320.
3.	Lin JL, Xu JF, Qu JM. Bronchiectasis in China. Ann Am Thorac Soc, 2016, 13(5): 609-616.
4.	Phua HP, Lim WY, Ganesan G, et al. Epidemiology and economic burden of bronchiectasis requiring hospitalisation in Singapore. ERJ Open Res, 2021, 7(4): 00334-02021.
5.	Athanazio RA. Bronchiectasis: moving from an orphan disease to an unpleasant socioeconomic burden. ERJ Open Res, 2021, 7(4): 00507-02021.
6.	Spagnolo P, Kropski JA, Jones MG, et al. Idiopathic pulmonary fibrosis: Disease mechanisms and drug development. Pharmacol Ther, 2021, 222: 107798.
7.	Boulet LP. Airway remodeling in asthma: update on mechanisms and therapeutic approaches. Curr Opin Pulm Med, 2018, 24(1): 56-62.
8.	Bos L, Ware LB. Acute respiratory distress syndrome: causes, pathophysiology, and phenotypes. Lancet, 2022, 400(10358): 1145-1156.
9.	Zanotti S, Magri F, Salani S, et al. Extracellular Matrix Disorganization and Sarcolemmal Alterations in COL6-Related Myopathy Patients with New Variants of COL6 Genes. Int J Mol Sci, 2023, 24(6): 5551.
10.	Mereness JA, Bhattacharya S, Ren Y, et al. Collagen VI Deficiency Results in Structural Abnormalities in the Mouse Lung. Am J Pathol, 2020, 190(2): 426-441.
11.	Kadler KE, Baldock C, Bella J, et al. Collagens at a glance. J Cell Sci, 2007, 120(Pt 12): 1955-1958.
12.	Mereness JA, Mariani TJ. The critical role of collagen VI in lung development and chronic lung disease. Matrix Biol Plus, 2021, 10: 100058.
13.	Leeming DJ, Sand JM, Nielsen MJ, et al. Serological investigation of the collagen degradation profile of patients with chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis. Biomark Insights, 2012, 7: 119-126.
14.	Ferkingstad E, Sulem P, Atlason BA, et al. Large-scale integration of the plasma proteome with genetics and disease. Nat Genet, 2021, 53(12): 1712-1721.
15.	Sun BB, Chiou J, Traylor M, et al. Plasma proteomic associations with genetics and health in the UK Biobank. Nature, 2023, 622(7982): 329-338.
16.	Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081.
17.	Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol, 2015, 30(7): 543-552.
18.	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): 1251-1269.
19.	Bowden J, Davey Smith G, Haycock PC, et al. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol, 2016, 40(4): 304-314.
20.	Wu Y, Zeng J, Zhang F, et al. Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits. Nat Commun, 2018, 9(1): 918.
21.	Foley CN, Staley JR, Breen PG, et al. A fast and efficient colocalization algorithm for identifying shared genetic risk factors across multiple traits. Nat Commun, 2021, 12(1): 764.
22.	Wu Y, Qi T, Wang H, et al. Promoter-anchored chromatin interactions predicted from genetic analysis of epigenomic data. Nat Commun, 2020, 11(1): 2061.
23.	Svoronos C, Tsoulfas G, Souvatzi M, et al. Prognostic value of COL6A3 in pancreatic adenocarcinoma. Ann Hepatobiliary Pancreat Surg, 2020, 24(1): 52-56.
24.	Li Z, Feng J, Zhong J, et al. Screening of the Key Genes and Signalling Pathways for Diabetic Nephropathy Using Bioinformatics Analysis. Front Endocrinol (Lausanne), 2022, 13: 864407.
25.	Lamandé SR, Bateman JF. Collagen VI disorders: Insights on form and function in the extracellular matrix and beyond. Matrix Biol, 2018, 71-72: 348-367.
26.	Sun K, Park J, Gupta OT, et al. Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction. Nat Commun, 2014, 5: 3485.
27.	Marakhonov AV, Tabakov VY, Zernov NV, et al. Two novel COL6A3 mutations disrupt extracellular matrix formation and lead to myopathy from Ullrich congenital muscular dystrophy and Bethlem myopathy spectrum. Gene, 2018, 672: 165-171. [28] Oriano M, Gramegna A, Terranova L, et al. Sputum neutrophil elastase associates with microbiota and Pseudomonas aeruginosa in bronchiectasis. Eur Respir J, 2020, 56(4): 2000769.
28.	Zeng W, Song Y, Wang R, et al. Neutrophil elastase: From mechanisms to therapeutic potential. J Pharm Anal, 2023, 13(4): 355-366.
29.	Raboso B, Pou C, Abril R, et al. Bronchiectasis. Open Respir Arch, 2024, 6(3): 100339.
30.	Williams LM, McCann FE, Cabrita MA, et al. Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300. Proc Natl Acad Sci U S A, 2020, 117(34): 20753-20763.
31.	Zhao Y, Gu X, Zhang N, et al. Divergent functions of endotrophin on different cell populations in adipose tissue. Am J Physiol Endocrinol Metab, 2016, 311(6): E952-E963.
32.	Dankel SN, Grytten E, Bjune JI, et al. COL6A3 expression in adipose tissue cells is associated with levels of the homeobox transcription factor PRRX1. Sci Rep, 2020, 10(1): 20164.

1. O'Donnell AE. Bronchiectasis - A Clinical Review. N Engl J Med, 2022, 387(6): 533-545.
2. Henkle E, Chan B, Curtis JR, et al. Characteristics and Health-care Utilization History of Patients With Bronchiectasis in US Medicare Enrollees With Prescription Drug Plans, 2006 to 2014. Chest, 2018, 154(6): 1311-1320.
3. Lin JL, Xu JF, Qu JM. Bronchiectasis in China. Ann Am Thorac Soc, 2016, 13(5): 609-616.
4. Phua HP, Lim WY, Ganesan G, et al. Epidemiology and economic burden of bronchiectasis requiring hospitalisation in Singapore. ERJ Open Res, 2021, 7(4): 00334-02021.
5. Athanazio RA. Bronchiectasis: moving from an orphan disease to an unpleasant socioeconomic burden. ERJ Open Res, 2021, 7(4): 00507-02021.
6. Spagnolo P, Kropski JA, Jones MG, et al. Idiopathic pulmonary fibrosis: Disease mechanisms and drug development. Pharmacol Ther, 2021, 222: 107798.
7. Boulet LP. Airway remodeling in asthma: update on mechanisms and therapeutic approaches. Curr Opin Pulm Med, 2018, 24(1): 56-62.
8. Bos L, Ware LB. Acute respiratory distress syndrome: causes, pathophysiology, and phenotypes. Lancet, 2022, 400(10358): 1145-1156.
9. Zanotti S, Magri F, Salani S, et al. Extracellular Matrix Disorganization and Sarcolemmal Alterations in COL6-Related Myopathy Patients with New Variants of COL6 Genes. Int J Mol Sci, 2023, 24(6): 5551.
10. Mereness JA, Bhattacharya S, Ren Y, et al. Collagen VI Deficiency Results in Structural Abnormalities in the Mouse Lung. Am J Pathol, 2020, 190(2): 426-441.
11. Kadler KE, Baldock C, Bella J, et al. Collagens at a glance. J Cell Sci, 2007, 120(Pt 12): 1955-1958.
12. Mereness JA, Mariani TJ. The critical role of collagen VI in lung development and chronic lung disease. Matrix Biol Plus, 2021, 10: 100058.
13. Leeming DJ, Sand JM, Nielsen MJ, et al. Serological investigation of the collagen degradation profile of patients with chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis. Biomark Insights, 2012, 7: 119-126.
14. Ferkingstad E, Sulem P, Atlason BA, et al. Large-scale integration of the plasma proteome with genetics and disease. Nat Genet, 2021, 53(12): 1712-1721.
15. Sun BB, Chiou J, Traylor M, et al. Plasma proteomic associations with genetics and health in the UK Biobank. Nature, 2023, 622(7982): 329-338.
16. Hemani G, Tilling K, Davey Smith G. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. PLoS Genet, 2017, 13(11): e1007081.
17. Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol, 2015, 30(7): 543-552.
18. 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): 1251-1269.
19. Bowden J, Davey Smith G, Haycock PC, et al. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol, 2016, 40(4): 304-314.
20. Wu Y, Zeng J, Zhang F, et al. Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits. Nat Commun, 2018, 9(1): 918.
21. Foley CN, Staley JR, Breen PG, et al. A fast and efficient colocalization algorithm for identifying shared genetic risk factors across multiple traits. Nat Commun, 2021, 12(1): 764.
22. Wu Y, Qi T, Wang H, et al. Promoter-anchored chromatin interactions predicted from genetic analysis of epigenomic data. Nat Commun, 2020, 11(1): 2061.
23. Svoronos C, Tsoulfas G, Souvatzi M, et al. Prognostic value of COL6A3 in pancreatic adenocarcinoma. Ann Hepatobiliary Pancreat Surg, 2020, 24(1): 52-56.
24. Li Z, Feng J, Zhong J, et al. Screening of the Key Genes and Signalling Pathways for Diabetic Nephropathy Using Bioinformatics Analysis. Front Endocrinol (Lausanne), 2022, 13: 864407.
25. Lamandé SR, Bateman JF. Collagen VI disorders: Insights on form and function in the extracellular matrix and beyond. Matrix Biol, 2018, 71-72: 348-367.
26. Sun K, Park J, Gupta OT, et al. Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction. Nat Commun, 2014, 5: 3485.
27. Marakhonov AV, Tabakov VY, Zernov NV, et al. Two novel COL6A3 mutations disrupt extracellular matrix formation and lead to myopathy from Ullrich congenital muscular dystrophy and Bethlem myopathy spectrum. Gene, 2018, 672: 165-171. [28] Oriano M, Gramegna A, Terranova L, et al. Sputum neutrophil elastase associates with microbiota and Pseudomonas aeruginosa in bronchiectasis. Eur Respir J, 2020, 56(4): 2000769.
28. Zeng W, Song Y, Wang R, et al. Neutrophil elastase: From mechanisms to therapeutic potential. J Pharm Anal, 2023, 13(4): 355-366.
29. Raboso B, Pou C, Abril R, et al. Bronchiectasis. Open Respir Arch, 2024, 6(3): 100339.
30. Williams LM, McCann FE, Cabrita MA, et al. Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300. Proc Natl Acad Sci U S A, 2020, 117(34): 20753-20763.
31. Zhao Y, Gu X, Zhang N, et al. Divergent functions of endotrophin on different cell populations in adipose tissue. Am J Physiol Endocrinol Metab, 2016, 311(6): E952-E963.
32. Dankel SN, Grytten E, Bjune JI, et al. COL6A3 expression in adipose tissue cells is associated with levels of the homeobox transcription factor PRRX1. Sci Rep, 2020, 10(1): 20164.

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The Application Value of Collagen VI Family Proteins in the Diagnosis and Treatment of Bronchiectasis: A Mendelian Randomization Study

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