MUC5B promoter variant tied to RA-ILD risk
medwireNews: Individuals who carry the MUC5B promoter variant rs35705950 have an elevated risk for rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), researchers report.
These findings, which were presented at the 2018 ACR/ARHP Annual Meeting in Chicago, Illinois, USA, and are published in The New England Journal of Medicine, suggest that “the MUC5B promoter variant could be used to detect preclinical ILD in patients with RA,” say Philippe Dieudé (Hôpital Bichat, Paris, France) and study co-authors.
Moreover, given that the gain-of-function variant is known to be “the strongest genetic risk factor for idiopathic pulmonary fibrosis,” they propose that “drugs that are known to be effective in treating patients with idiopathic pulmonary fibrosis [should] be evaluated in the treatment of RA-ILD.”
The study involved a total of 620 patients with RA-ILD, 614 RA patients without ILD, and 5448 unaffected controls, and included a French discovery cohort, as well as a replication cohort comprising case series of patients from China, Greece, Japan, Mexico, the Netherlands, and the USA.
In the discovery cohort, Dieudé and colleagues demonstrated that the MUC5B promoter variant was significantly more common among the 118 patients with RA-ILD compared with the 1229 unaffected controls, with a minor allele frequency of 32.6% versus 10.9%, translating into a significant odds ratio (OR) of 3.8 after adjustment for sex.
Similarly, the variant was “significantly overrepresented” in patients with ILD versus controls in each of the replication case series, with the exception of patients from Japan and China. The researchers explain that this was due to the MUC5B promoter variant being “underrepresented in Asian patients,” and therefore the association tests were underpowered.
Nonetheless, when the validation case series were analyzed together, the MUC5B promoter variant was significantly associated with RA-ILD (adjusted OR=5.5), and there was a similar significant association when the discovery and validation data were combined (adjusted OR=4.7).
Dieudé and team also found that RA-ILD patients were significantly more likely to carry the promoter variant than RA patients without ILD, with adjusted ORs of 3.1, 2.9, and 3.1 in the discovery, replication, and combined cohorts, respectively. They note that this association was particularly strong when the analysis was restricted to RA-ILD patients with evidence of usual interstitial pneumonia (UIP) on high-resolution computed tomography, suggesting that the relationship between the promoter variant and RA-ILD is “specific to the UIP pattern and not generalizable to other autoimmune conditions of the lung.”
The authors of an accompanying editorial, Peter Gregersen and Ellen Gravallese (both from the University of Massachusetts, Worcester, USA), say that these results “support the concept that genetics really can add to our understanding of disease heterogeneity.”
They add that the findings raise “the question of whether all patients with RA should be evaluated for MUC5B carrier status,” and suggest that “once clinical disease is present, MUC5B genotyping might provide information on prognosis and […] guide management” of RA-ILD.
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