MS Susceptibility Gene Variants Linked to Clinical Features

Multiple sclerosis (MS) susceptibility gene variants are associated with relapse severity and recovery and early attack location within the central nervous system, according to 2 genotyping studies by the same group. PLOS ONE published both studies on October 9.

"In the past few years, the number of genes that have been confirmed as important to MS susceptibility has increased substantially," wrote Ellen M. Mowry, M.D., from the Multiple Sclerosis Center, Johns Hopkins University, Baltimore, Maryland, and colleagues. "Whether these genes are associated with the clinical phenotype of the disease is less clear. In this preliminary investigation, we sought to determine if genetic polymorphisms associated with MS susceptibility are associated with the severity of and recovery from early attacks of MS or with the risk of a second attack."

The investigators used published definitions to determine the severity of and recovery from the first 2 attacks of 503 white subjects examined within a year of MS onset. At the University of California, San Francisco, MS Genetics laboratory, the investigators genotyped 17 MS susceptibility genes and assessed each polymorphism in multivariate ordinal models, adjusted for the other polymorphisms. These models allowed evaluation of associations of each polymorphism with attack severity and recovery and with increased risk for a second attack.

The MPHOSPH9 polymorphism was associated with greater attack severity (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.11-1.94; P = .008). In contrast, the TNFRSF1A polymorphism tended to be associated with lesser attack severity (OR, 0.63; 95% CI, 0.40-1.00; P = .05).

Among participants who were HLA-DRB1-negative, the EVI5 polymorphism was associated with attacks of less severity. However, among participants who were HLA-DRB1-positive, those who had the EVI5 polymorphism had attacks of greater severity and worse recovery.

"Some MS susceptibility polymorphisms may be associated with attack severity, recovery, or frequency," the authors wrote. "Further characterization of these genes may lead to a better understanding of MS pathogenesis and to a more individualized treatment approach."

Variants also linked to early attack location

In early MS, the first attack location within the CNS tends to predict the anatomic location of subsequent relapses. Using the same study sample described earlier, the investigators therefore examined whether genetic polymorphisms associated with MS susceptibility were associated with attack location.

Multivariate repeated measures analyses accounted for within-individual correlations, as well as location data from both the first and second attack, in the same model. To determine the independent effect of each gene on the central nervous system location of the first 2 MS attacks, the models included all of the non-HLA susceptibility genes, as well as HLA-DRB1 status. This analysis resulted in generalized estimating equations with robust standard errors.

The analysis revealed increased odds of attacks involving the spinal cord for the IL12A polymorphism (OR, 1.52; 95% CI, 1.11-2.07; P = .009) and for the IRF8 polymorphism (OR, 2.40; 95% CI, 1.04-5.50; P = .040).

Reduced odds of attacks involving the brainstem/cerebellum occurred with the IL7R polymorphism (OR, 0.46; 95% CI, 0.22-0.97; P = .041) and with both the TNFRSF1A and IL12A polymorphisms. The CD6 polymorphism was associated with lower odds of optic neuritis involvement (OR, 0.69; 95% CI, 0.49-0.97; P = .034).

"Some of the MS susceptibility genes may be associated with MS attack location," the authors wrote. "The IL12A polymorphism is of particular interest given that interferon beta therapy appears to influence [interleukin 12] levels."

Clinical implications

Limitations of this study include a lack of generalizability to nonwhite patients, a possible inclusion bias, reliance on the Expanded Disability Status Scale or its components for definitions of severity and recovery, that some information was missing from the data sets, and a lack of correction for multiple comparisons.

On the basis of their findings, the investigators suggested that genetic polymorphisms associated with MS may be useful markers to include in prognostic models.

"The variability in outcomes between patients with MS leads to prognostic uncertainty, which causes significant psychological stress for patients and their caregivers," the study authors concluded. "It also makes the role of the physician more difficult in that for an individual patient, a plan of care must be made using group-level data. With the advent of more potent but more risky [disease-modifying therapies] for MS, developing better models for predicting prognosis is imperative so that those who are unlikely to have bad disease outcomes are not exposed unnecessarily to hazardous therapies."

Key open questions

• Would similar analyses in a larger data set confirm the present findings and reveal additional significant associations of genetic polymorphisms with clinical features and outcomes in MS?
• Will genetic polymorphisms associated with MS prove to be useful predictors of prognosis and/or possible therapeutic targets?

Disclosures

The National Multiple Sclerosis Society supported this study. Some of the study authors reported various financial disclosures involving Teva Pharmaceuticals, Merck Serono, Bayer Schering, Biogen Idec, sanofi-aventis, Novartis, Berlex, Roche, MedImmune, Neutotech Pharma, Digna Biotech, Bionure Farma, Genzyme, Actelion, and/or PLOS ONE.