Genetic Risk Factors for MS Identified

Alleles of two genes have been identified as heritable risk factors for multiple sclerosis (MS), according to a study in the August 30 New England Journal of Medicine. The findings are part of the International Multiple Sclerosis Genetics Consortium’s effort to define the genetic profile underlying a predisposition to MS.

David A. Hafler, MD, and colleagues used DNA microarray technology to identify common DNA sequence variants in 931 family trios consisting of an affected child and both parents, which yielded 334,923 single nucleotide polymorphisms for the screening phase. The investigators monitored the overtransmission of any single nucleotide polymorphisms to the affected child with the use of transmission disequilibrium testing. For the replication phase, the research team genotyped a second set of 609 family trios, 2,322 patients with MS, and 789 controls, and used genotyping data from an additional 2,198 controls. For the subsequent combined analysis, a total of 12,360 subjects were included to confirm associations—and to estimate the effect size of these associations—between alleles and MS risk.

Two single nucleotide polymorphisms within the interleukin-2 receptor a gene (IL2RA), one nonsynonymous single nucleotide polymorphism in the interleukin-7 receptor a gene (IL7RA), and multiple single nucleotide polymorphisms in the major histocompatibility complex, class II, DR a (HLA-DRA) locus were strongly associated with MS. That the IL2RA and IL7RA genes were found to be linked to MS supports the theory that polymorphisms within genes related to the regulation of immune responses are important in MS, the researchers pointed out. Although the alleles are polymorphic variants that occur in healthy populations, each allele was more common in MS patients than in controls and has a small effect on MS risk.

“In considering the complex genetic architecture of MS, we recognize that our approach has little if any statistical power to detect rare variants that could contribute to susceptibility—even those conferring a relatively large genetic risk,” Dr. Hafler, Professor of Neurology at Harvard Medical School in Boston, and colleagues stated. “We anticipate that MS will show some degree of genetic heterogeneity and that with increasing sample sizes and better statistical power, alternative genetic mechanisms will be revealed for certain subgroups of patients with the disease. However, for most patients, we expect that the variants identified in our study and those that may emerge in follow-up studies could account for a substantial part of the heritability of MS in the general population.”

In an accompanying editorial, Leena Peltonen, MD, PhD, Professor of Medical Genetics at the University of Helsinki in Finland, stated that the study’s findings “strongly support the dominance of the HLA locus in the genetic background of patients with MS but also indicate the involvement of two interesting genes.” The relevance of both the IL2RA and IL7RA genes in the pathogenesis of MS is supported by previous data, Dr. Peltonen stated; in addition, the IL7RA gene has been linked to type 1 diabetes and Graves’ disease, which suggests a potentially broader role in autoimmunity. However, because the increased risk contributed by these alleles is low and the alleles account for a minimal proportion (0.2%) of the variance in MS risk, Dr. Peltonen affirmed that the “HLA region retains its unique position as the only known major risk gene for MS.”            

NR