New Genetic Risk Factors for MS Identified: More Targets for Immune Therapy
By Brian R. Apatoff, MD, PhD, Director, Multiple Sclerosis Clinical Care and Research Center, Department of Neurology and Neuroscience, NewYork-Presbyterian Hospital, Cornell Campus; Dr. Apatoff reports no financial relationship relevant to this field of study.
Synopsis: Whole genome scans identified two new genetic variations associated with multiple sclerosis (MS) that may provide sites of immune intervention.
Sources: International Multiple Sclerosis Genetics Consortium. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007;357:851-862; Gregory SG, et al. Interleukin 7 receptor alpha-chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 2007;39:1083-1091; Lundmark F, et al. Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet 2007;39:1108-1113; Peltonen L. Editorial. Old suspects found guilty the first genome profile of multiple sclerosis. N Engl J Med 2007;357:927-929; Rose JW, et al. Daclizumab phase II in relapsing and remitting multiple sclerosis: MRI and clinical results. Neurology 2007;69:785-789.
Using new DNA chip technologies, the above investigators were able to screen the whole genome of many thousands of subjects, testing more than 300,000 genetic locations for single-nucleotide polymorphisms (SNPs), variations more commonly seen in MS compared to those without the disease. These data reconfirmed the strong association of the HLA-DR locus in MS. Additional alleles were identified in the interleukin-2 receptor (IL2RA) gene and the interleukin-7 receptor (IL7R) gene. The IL2RA gene also has been associated with diabetes and Graves disease.
In an accompanying editorial, however, Peltonen provides perspective on the relative significance of these novel genetic markers and their association with MS. For example, the SNP genetic variants associated with MS for IL2RA and IL7RA also are quite common in the general population (up to 70%), and contribute only a very minor increased risk for disease. Thus, the relative risk of MS from the IL2RA and IL7RA SNPs is quite small, compared to the previously identified HLA region that confers the major genetic risk of MS.
The IL7R is critical for the regulation of the regulatory T-cell pool. Similarly, the IL2R is important in the regulation of T-cell responses, and a humanized monoclonal antibody against the IL2R, daclizumab (anti-CD25), is already FDA-approved for treatment of renal allograft rejection.
In a recent phase II clinical trial, Rose and colleagues studied nine patients with relapsing-remitting MS on beta-interferon (beta-IFN) therapy with break-through relapses and continued enhancing lesions on brain MRI. Patients were treated with daclizumab (1 mg/kg IV) every two weeks for the first two doses, and then monthly for 27.5 months. At 5.5 months, beta-IFN was discontinued. Patients were monitored with monthly MRI scans and clinical rating scales. In three of the nine patients in whom continued brain MRI activity was noted, the daclizumab dosing was increased (1.5 mg/kg IV) and beta-IFN was restarted. Overall, there were significant reductions in contrast enhancing lesions and clinical relapses in the daclizumab treated patients compared to their baseline disease activity. The effectiveness of this anti-IL-2 receptor monoclonal antibody supports its role in MS disease pathogenesis. The relative safety and benefits of this selective immune intervention, especially compared to other monoclonal therapies such as natalizumab and rituximab, remains to be defined in a larger phase III trial.