The Variant rs7665090 Is Associated With Interferon-Beta Response in Multiple Sclerosis Patients

Abstract

Background: GG homozygosity for the risk gene variant rs7665090 has been reported to enhance nuclear factor kappa B (NFκB) activity in T cells from multiple sclerosis (MS) patients. Here, we investigated the association between this polymorphism and the response to different disease-modifying therapies in MS.

Methods: The rs7665090 polymorphism was genotyped in 558 MS patients treated with injectable therapies [IFNβ (n = 213) and glatiramer acetate (n = 55)], oral therapies [dimethylfumarate (n = 97), teriflunomide (n = 41), and fingolimod (n = 37)], and natalizumab (n = 115). Treatment response was assessed after 1 year for injectable therapies using the Rio Score, which considers relapses, EDSS progression, and radiological activity on MRI. For oral therapies and natalizumab, response was evaluated after 2 years based on clinical and radiological disease activity. Univariable and multivariable logistic regression analyses were performed to assess treatment response for each therapy independently.

Results: GG homozygosity was associated with a favorable response outcome in patients treated with IFNβ in the multivariable analysis after adjusting for age and EDSS at treatment onset [OR 0.42 (0.18-0.94); p = 0.037]. This finding was restricted to MS patients carrying the GG risk genotype and seemed specific for IFNβ treatment, since the rs7665090 polymorphism did not influence the response to the other MS therapies.

Conclusion: The polymorphism rs7665090 is associated with a favorable response to IFNβ. This study illustrates how genotyping this polymorphism could serve as a useful biomarker in clinical practice to help identify MS patients who are likely to respond favorably to treatment, and encourages further replication in larger cohorts.

Keywords: biomarkers; genetics; interferon; multiple sclerosis; nuclear factor kappa B; treatment response.

FIGURE 1

Proxies for rs7665090 in European (EUR) populations (NIH LD proxy tool). In orange noncoding and in red coding variants, numbers and circle sizes represent the regulatory potential (FORGEdb) and the minor allele frequency of the polymorphisms, respectively. R ² on the Y‐axis refers to the correlation coefficient, which measures the linkage disequilibrium between the rs7665090 variant and other proxies. Arrows indicate the transcriptional direction of the genes. LOC depicts ncRNAs.

FIGURE 2

Association between rs7665090 genotypes and response to different treatments. Data are represented as odds ratios with 95% confidence intervals. Note that confidence intervals are capped at 6 (for upper values of S1P and TF, please refer to Table 2). DMF, dimethyl fumarate; GA, glatiramer acetate; IFN, interferon‐beta; NTZ, natalizumab; S1P, Fingolimod; TF, teriflunomide.