WNT9B Genetic Variant Linked to Increased Relapse Risk

A genetic variant in the WNT9B gene and vitamin D response are both associated with a greater risk of relapses in people with multiple sclerosis (MS), a recent study in Belgium has found.

The study, “Genetic variation in WNT9B increases relapse hazard in multiple sclerosis,” was published in the journal Annals of Neurology.

While certain genetic traits may increase the risk of MS, the genetic factors that increase the risk of relapses remain largely unknown. To date, a single study has addressed this question, in which genetic variants in the LRP2 gene were linked with a greater relapse risk.

To identify additional genetic risk factors, researchers at KU Leuven in Belgium and colleagues conducted a genome-wide association study (GWAS) involving 506 MS patients, who had a median duration of disease of four years.

A GWAS looks for genetic variants that might serve as markers predicting the presence of a certain trait — in this case, a greater rate of relapses.

Relapse was defined according to patient-reported symptoms or signs of acute inflammation due to loss of myelin in the central nervous system — a hallmark of MS — lasting for at least 24 hours, in the absence of fever or infection.

Overall, genetic variants that increase the risk of MS were not associated with a greater risk of relapse in these patients. But the team found 10 single nucleotide polymorphisms (SNPs, a change in a single nucleotide, the building blocks of DNA) that passed the threshold for a potential significant association with relapse risk.

The results were then confirmed in a second group of 485 patients with relapsing-remitting MS, who had not received prior immunosuppressive treatment and had experienced a total of 819 relapses.

Analysis combining both groups found a single SNP within the WNT9B gene, called rs11871306, that was significantly associated with a shorter time to relapse compared with patients not carrying this genetic variant.

More specifically, carriers of this variant remained relapse-free for 0.95 years while that time was 2.22 years for non-carriers. Also, carriers of the variant in the first group received treatment earlier than non-carriers.

The WNT9B gene has the instruction for a protein that is part of the Wnt/beta-catenin signaling pathway, which plays key roles in the development of the nervous system. The researchers noted, however, that this variant has not been linked with MS susceptibility in the most recent GWAS published study of the disease.

This suggests that “the genetic basis for relapse [risk] is distinct from genetic factors driving disease susceptibility. However, larger studies are required to exclude a more modest effect of MS-associated variants on relapse,” they wrote.

Further analysis of biological processes showed that the vitamin D pathway is also associated with relapse risk, while the Wnt cell signaling was not listed in the most important processes in relapses.

Overall, “our findings imply that genetic variation within the Wnt signaling and vitamin D pathways contributes to differences in relapse occurrence,” the researchers wrote.

“The present study highlights these cross-talking pathways as potential modulators of MS disease activity,” they concluded.