BOSTON—More than 45 new multiple sclerosis (MS) susceptibility variants were reported by researchers.
“We now present a comprehensive view of MS genetic susceptibility and provide a detailed map of proximal biologic effects that identify new molecular pathways involved in the transition from health to MS,” said Philip Laurence De Jager, MD, PhD, Assistant Professor, Harvard Medical School in Boston, on behalf of the International MS Genetics Consortium.
To identify MS susceptibility associations outside the validated MS susceptibility loci and uncover new biologic processes that drive the onset of MS, the researchers conducted a genomewide discovery study of approximately eight million single-nucleotide polymorphisms (SNPs) in each of 14,802 MS cases and 26,703 controls. This step was followed by a deep replication study of more than 80,000 SNPs in more than 19,217 MS cases and 17,842 controls. The 4,716 SNPs with a P value of less than 0.05 in the discovery study were included in the present study. Functional evaluations of the results were conducted using DEPICT for pathway analysis, as well as analyses of immune cell RNA expression data from ImmVar and reference epigenomic maps from the Epigenome Roadmap and ENCODE projects.
At the end of the replication study, more than 45 new susceptibility variants were identified, with 10 major histocompatibility complex (MHC) and more than 150 non-MHC SNPs meeting a threshold of genomewide significance. The depth of the replication effort identified multiple independent effects in many regions that were previously unresolvable. For example, the EVI5 region has as many as four independent susceptibility variants.
“Uncovering this multiplicity of associations in certain regions is critical to our efforts to model the biologic consequences of MS susceptibility variants and to develop predictive algorithms,” Dr. De Jager said. “With more than 150 independent susceptibility effects and a high resolution analysis of each locus in hand, we have created a reference map of MS susceptibility and now turn to the task of understanding the biology of MS susceptibility.
“With the new MS map and multiple approaches to epigenomic annotation and functional evaluations, it is clear that non-TH1/Th17/Treg processes are important in the onset of MS,” he continued. “Myeloid, NK, and CD8 cells are now implicated, and B and dendritic cell functions are suggested to be altered by MS variants.”
Leveraging RNA data from 405 subjects with purified CD4 T and monocytes, 29% of MS variants with RNA effects are unique to monocytes, which is now the same proportion as for T cells (29%). Pathway analyses highlighted an enrichment of NK and B cell activation molecular networks in addition to T cell effects.
—Glenn S. Williams
Investigational Oral Drug Reduces Disease Activity in Relapsing-Remitting MS
An oral, selective sphingosine 1-phosphate 1 receptor modulator appears to reduce MRI measures of disease activity in patients with relapsing-remitting multiple sclerosis (MS), according to data presented. The drug, RPC1063, may be safe and tolerable for these patients.
Data are from the international, combined phase II/III RADIANCE trial. Jeffrey Cohen, MD, Director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research in Cleveland, and colleagues randomized 258 patients with relapsing-remitting MS. A total of 87 participants received a low dose (0.5 mg) of RPC1063, 83 participants received a high dose (1.0 mg) of RPC1063, and 88 participants received placebo for 24 weeks.
The trial’s primary end point was the cumulative number of total gadolinium-enhancing lesions on MRI at weeks 12, 16, 20, and 24. Key secondary end points included the number of gadolinium-enhancing lesions at week 24, the cumulative number of new or enlarging T2 lesions from weeks 12 to 24, and annualized relapse rate.
The researchers assessed safety using vital signs, laboratory tests, ECG, Holter monitoring, pulmonary function test, optical coherence tomography, and adverse events. Patients were titrated to their assigned doses during one week to mitigate the first doses’ effects on heart rate.
Approximately 98% of patients completed the trial. The cumulative number of gadolinium-enhancing lesions from weeks 12 to 24 was reduced by 86% in both treatment arms, compared with placebo. The numbers of gadolinium-enhancing lesions at week 24 were significantly reduced by 91% in the low-dose group and by 94% in the high-dose group, compared with placebo. The cumulative number of new or enlarging T2 lesions from weeks 12 to 24 was reduced by 84% in the low-dose group and by 91% in the high-dose group. The researchers observed a favorable trend toward a reduction in annualized relapse rate among treated patients, compared with controls.
The adverse event profiles were similar between groups. The most common adverse events in the treated groups, compared with placebo, were nasopharyngitis (9.4% vs 13.6%), headache (4.7% vs 9.1%), and urinary tract infection (4.7% vs 2.3%). During the first six hours after the first dose of RPC1063, maximum reductions in mean hourly heart rate were < 2 bpm from baseline, and no patient had a minimum hourly heart rate < 45 bpm. The investigators did not observe any notable cardiac, pulmonary, ophthalmologic, or malignancy adverse events.