WNT9B-gene variant associated with doubled relapse risk in MS

In a study looking for genetic factors that may account for differences in MS relapse rate, a rare variant –rs11871306 within the WNT9B region– was associated with a more than doubled risk for a relapse. These findings imply that genetic variation within the cross-talking Wnt signalling and vitamin D pathways contributes to differences in relapse occurrence [1].

Over the years, more than 230 gene variations have been identified that contribute to the risk of developing MS, but the role of gene variants in disease heterogeneity remains unclear [2]. Ms Marijne Vandebergh (KU Leuven, Belgium) and colleagues aimed to identify genetic variation associated with relapse risk in MS. To this end, they conducted a large gene study in 991 participants with relapsing MS before they began disease-modifying therapies (DMTs). As Ms Vandebergh explained, a genome-wide association study (GWAS) was performed in a discovery cohort and the genome-wide significant variants were investigated further in a replication cohort. In these cohorts, a total of 2,231 relapses were captured before the start of any immunomodulatory treatment.

In the discovery cohort, age at baseline was 31 years and duration of disease 4.0 years (range 1.35–12.07), while the replication cohort had a baseline age of 33 years and disease duration of 0.50 years (range 0.25–2.57). The low-frequency genetic variant rs11871306 within WNT9B reached genome-wide significance in predicting relapse risk, with an HR of 2.03 (95% CI 1.55–2.67) in the discovery cohort (n=506), 2.53 (95% CI 1.58–4.05) in the replication cohort (n=485), and 2.15 (95% CI 1.70–2.78) in the 2 cohorts combined (P<0.0001). A pathway analysis identified an association of the pathway 'response to vitamin D' with relapse risk (P<0.0001). The MS genetic risk scores were not associated with relapse risk.

Ms Vandebergh concluded: “We have demonstrated the applicability of GWAS to longitudinal data. We have identified an association between genetic variation in WNT9B and relapse risk. This study provides genetic support for a protective role of naturally occurring higher vitamin D levels in MS relapse risk. In contrast, we observed no effect on relapse risk of genetically related increases in body mass index.”

1. Vandebergh M. Genetic variation in WNT9B increases relapse hazard in multiple sclerosis. OP078, ECTRIMS 2021 Virtual Congress, 13–15 October.
2. Cotsapas C, Mitrovic M. Clin Transl Immunol. 2018;7(6):e1018.

 

Copyright ©2021 Medicom Medical Publishers



Posted on 9 December 20219 December 2021