Exploration of the MUC5B promoter variant and ILD risk in patients with autoimmune myositis

Johnson, Clare; Rosen, Paul; Lloyd, Thomas E.; Horton, Maureen R.; Christopher‐Stine, Lisa; Oddis, Chester V.; Mammen, Andrew L.; Danoff, Sonye K.

doi:10.1016/j.rmed.2017.07.010

Cited by 22 publications

(10 citation statements)

References 14 publications

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“…A common variant in the promoter region of this gene (rs35705950) has been associated with an increase in IPF susceptibility and overall mortality. [110][111][112][113] Similar associations have also been observed in patients with RA-ILD, 65 110 as well as in hypersensitivity pneumonitis 109 and IPAF, 114 but not in SSc-ILD, 115 myositis-associated ILD 116 or sarcoidosis, 117 again highlighting not only the similarities but also the differences between ILDs.…”

Section: Genetic Mechanisms Driving Progressive Pulmonary Fibrosismentioning

confidence: 55%

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

et al. 2020

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Interstitial lung diseases (ILDs), which can arise from a broad spectrum of distinct aetiologies, can manifest as a pulmonary complication of an underlying autoimmune and connective tissue disease (CTD-ILD), such as rheumatoid arthritis-ILD and systemic sclerosis (SSc-ILD). Patients with clinically distinct ILDs, whether CTD-related or not, can exhibit a pattern of common clinical disease behaviour (declining lung function, worsening respiratory symptoms and higher mortality), attributable to progressive fibrosis in the lungs. In recent years, the tyrosine kinase inhibitor nintedanib has demonstrated efficacy and safety in idiopathic pulmonary fibrosis (IPF), SSc-ILD and a broad range of other fibrosing ILDs with a progressive phenotype, including those associated with CTDs. Data from phase II studies also suggest that pirfenidone, which has a different—yet largely unknown—mechanism of action, may also have activity in other fibrosing ILDs with a progressive phenotype, in addition to its known efficacy in IPF. Collectively, these studies add weight to the hypothesis that, irrespective of the original clinical diagnosis of ILD, a progressive fibrosing phenotype may arise from common, underlying pathophysiological mechanisms of fibrosis involving pathways associated with the targets of nintedanib and, potentially, pirfenidone. However, despite the early proof of concept provided by these clinical studies, very little is known about the mechanistic commonalities and differences between ILDs with a progressive phenotype. In this review, we explore the biological and genetic mechanisms that drive fibrosis, and identify the missing evidence needed to provide the rationale for further studies that use the progressive phenotype as a target population.

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Section: Genetic Mechanisms Driving Progressive Pulmonary Fibrosismentioning

confidence: 55%

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

et al. 2020

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“…In keeping with our results in ASSD and unlike RA-ILD, no association of MUC5B rs35705950 with ILD in the setting of other connective tissue diseases was found. With respect to this, no influence of this genetic variant on myositis-ILD was disclosed whereas genetic differences regarding MUC5B rs35705950 between myositis-ILD and idiopathic ILD were also reported 29 . Likewise, lack of association between this genetic variant and ILD in the context of sarcoidosis 30 and systemic sclerosis 30,31 was described while differences in MUC5B rs35705950 frequencies were found when patients with sarcoidosis-ILD 30 and those with systemic sclerosis-ILD 30,31 were compared to patients with IPF.…”

Section: Discussionmentioning

confidence: 90%

Influence of MUC5B gene on antisynthetase syndrome

López‐Mejías

Remuzgo‐Martínez

Genre

et al. 2020

Sci Rep

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MUC5B rs35705950 (G/T) is strongly associated with idiopathic pulmonary fibrosis (IPF) and also contributes to the risk of interstitial lung disease (ILD) in rheumatoid arthritis (RA-ILD) and chronic hypersensitivity pneumonitis (CHP). Due to this, we evaluated the implication of MUC5B rs35705950 in antisynthetase syndrome (ASSD), a pathology characterised by a high ILD incidence. 160 patients with ASSD (142 with ILD associated with ASSD [ASSD-ILD+]), 232 with ILD unrelated to ASSD (comprising 161 IPF, 27 RA-ILD and 44 CHP) and 534 healthy controls were genotyped. MUC5B rs35705950 frequency did not significantly differ between ASSD-ILD+ patients and healthy controls nor when ASSD patients were stratified according to the presence/absence of anti Jo-1 antibodies or ILD. No significant differences in MUC5B rs35705950 were also observed in ASSD-ILD+ patients with a usual interstitial pneumonia (UIP) pattern when compared to those with a non-UIP pattern. However, a statistically significant decrease of MUC5B rs35705950 GT, TT and T frequencies in ASSD-ILD+ patients compared to patients with ILD unrelated to ASSD was observed. In summary, our study does not support a role of MUC5B rs35705950 in ASSD. It also indicates that there are genetic differences between ILD associated with and that unrelated to ASSD.

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“…The MUC5B promoter variant has not been found to be associated with a risk of ILDs associated with systemic sclerosis or autoimmune myositis. 21,24,32 Unlike these other types of ILD, RA-ILD shares characteristics with idiopathic pulmonary fibrosis. These include an increased prevalence of the UIP pattern (radiologic and histologic); an increased prevalence of male sex and older age 33 ; rare variants in TERT , RTEL1 , PARN , and SFTPC 15 ; and now the MUC5B promoter variant rs35705950.…”

Section: Discussionmentioning

confidence: 99%

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease

et al. 2018

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BACKGROUND Given the phenotypic similarities between rheumatoid arthritis (RA)–associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P = 9.7×10−17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multi-ethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P = 4.7×10−35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P = 1.3×10−49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P = 7.4×10−5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P = 2.5×10−6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.)

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Exploration of the MUC5B promoter variant and ILD risk in patients with autoimmune myositis

Cited by 22 publications

References 14 publications

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

Influence of MUC5B gene on antisynthetase syndrome

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease

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