MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease

Abstract

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.)

Rheumatoid Arthritis Disease Activity Predicting Incident Clinically Apparent Rheumatoid Arthritis–Associated Interstitial Lung Disease: A Prospective Cohort Study

“…We performed alternative analyses with adjustment for additional factors including medication use and RA severity factors, which produced similar results. There may be other unmeasured factors including biomarkers and a recently identified genetic risk factor in the MUC5B gene, the inclusion of which may have affected our results . We encourage continued collaborative studies to identify and validate additional risk factors for RA‐ILD, as well as to develop and test interventions that may reduce RA‐ILD susceptibility and improve outcomes.…”

Mucins and their receptors in chronic lung disease

“…The single greatest risk factor, genetic or otherwise, for the development of IPF and RA‐ILD is a gain of function, single nucleotide polymorphism (SNP) in the promoter region of the MUC5B gene (promoter variant rs35705950) . The wild‐type guanine (G) is switched for the thymidine (T) nucleotide (risk allele).…”

“…The single greatest risk factor, genetic or otherwise, for the development of IPF and RA-ILD is a gain of function, single nucleotide polymorphism (SNP) in the promoter region of the MUC5B gene (promoter variant rs35705950). 52,53 The wild-type guanine (G) is switched for the thymidine (T) nucleotide (risk allele). This variant has a dose-dependent effect, with those individuals heterozygous for the risk allele (GT) 4.5 times more likely to develop the disease, increasing to twenty times more likely if homozygous for the risk allele (TT).…”

Lung inflammation in the pathogenesis of rheumatoid arthritis

“…While several studies have suggested a relationship between the genetic factor the shared epitope and ILD in RA, that relationship may be confounded by other associations between the shared epitope, smoking (another risk factor for lung disease), and autoantibody positivity in RA . More recently, a genetic gain‐of‐function polymorphism in the MUC5B promoter variant, which has been previously associated with idiopathic pulmonary fibrosis (IPF), has also been associated with RA‐ILD, and in particular with UIP which is the form of ILD most similar to the form seen in IPF . Of note, while this polymorphism is associated with an increase in MUC5B expression and mucociliary dysfunction in the distal airway, it has not yet been associated with AD in RA; however, its possible influence on airway inflammation and immunity raises the possibility of a relationship between AD and ILD in RA, as will be discussed further below.…”