Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Multiple sclerosis is a complex neurological disease, with 3c20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFN\u3b3 biology, and NF\u3baB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS. In a large multi-cohort study, unexplained heritability for multiple sclerosis is detected in low-frequency coding variants that are missed by GWAS analyses, further underscoring the role of immune genes in MS pathology

Intravenous Immunoglobulin: Mechanism of Action in Autoimmune and Inflammatory Conditions

International audienceIntravenous immunoglobulin (IVIG) is the mainstay of therapy for humoral immune deficiencies and numerous inflammatory disorders. Although the use of IVIG may be supplanted by several targeted therapies to cytokines, the ability of polyclonal normal IgG to act as an effector molecule as well as a regulatory molecule is a clear example of the polyfunctionality of IVIG. This article will address the mechanism of action of IVIG in a number of important conditions that are otherwise resistant to treatment. In this commentary, we will highlight mechanistic studies that shed light on the action of IVIG. This will be approached by identifying effects that are both common and disease-specific, targeting actions that have been demonstrated on cells and processes that represent both innate and adaptive immune response

Multiple sclerosis patients have a diminished serologic response to vitamin D supplementation compared to healthy controls

BackgroundVitamin D insufficiency is a risk factor for multiple sclerosis (MS), and patients do not always show the expected response to vitamin D supplementation.ObjectiveWe aimed to determine if vitamin D supplementation leads to a similar increase in serum 25-hydroxyvitamin-D (25(OH)D) levels in patients with MS and healthy controls (HCs).MethodsParticipants in this open-label study were female, white, aged 18-60 years, had 25(OH)D levels ⩽ 75 nmol/l at screening, and had relapsing-remitting MS (RRMS) or were HCs. Participants received 5000 IU/day of vitamin D3 for 90 days. Utilizing generalized estimating equations we examined the relationship between the primary outcome (serum 25(OH)D level) and the primary (MS versus HC status) and secondary predictors.ResultsFor this study 27 MS patients and 30 HCs were enrolled. There was no significant difference in baseline 25(OH)D level or demographics except for higher body mass index (BMI) in the MS group (25.3 vs. 23.6 kg/m(2), p=0.035). In total, 24 MS subjects and 29 HCs completed the study. In a multivariate model accounting for BMI, medication adherence, and oral contraceptive use, MS patients had a 16.7 nmol/l (95%CI: 4.2, 29.2, p=0.008) lower increase in 25(OH)D levels compared with HCs.ConclusionsPatients with MS had a lower increase in 25(OH)D levels with supplementation, even after accounting for putative confounders

Multiple sclerosis patients have a diminished serologic response to vitamin D supplementation compared to healthy controls

BACKGROUND: Vitamin D insufficiency is a risk factor for MS, and patients don’t always show the expected response to vitamin D supplementation. OBJECTIVE: To determine if vitamin D supplementation leads to a similar increase in serum 25-hydroxyvitamin-D (25(OH)D) levels in MS patients and healthy controls (HCs). METHODS: Participants in this open-label study were female, white, aged 18–60 years, had 25(OH)D levels ≤ 75 nmol/L at screening, and had RRMS or were HCs. Participants received 5,000 IU/day of vitamin D(3) for 90 days. Utilizing generalized estimating equations we examined the relationship between the primary outcome (serum 25(OH)D level) and the primary (MS versus HC status) and secondary predictors. RESULTS: 27 MS patients and 30 HCs were enrolled. There was no significant difference in baseline 25(OH)D level or demographics except for higher body mass index (BMI) in the MS group (25.3 vs 23.6 kg/m(2), p=0.035). 24 MS subjects and 29 HCs completed the study. In a multivariate model accounting for BMI, medication adherence, and oral contraceptive use, MS patients had a 16.7 nmol/L (95%CI: 4.2, 29.2, p=0.008) lower increase in 25(OH)D levels compared to HCs. CONCLUSIONS: MS patients had a lower increase in 25(OH)D levels with supplementation, even after accounting for putative confounders

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.status: publishe

Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

International audienceGenetic roots of multiple sclerosis The genetics underlying who develops multiple sclerosis (MS) have been difficult to work out. Examining more than 47,000 cases and 68,000 controls with multiple genome-wide association studies, the International Multiple Sclerosis Genetics Consortium identified more than 200 risk loci in MS (see the Perspective by Briggs). Focusing on the best candidate genes, including a model of the major histocompatibility complex region, the authors identified statistically independent effects at the genome level. Gene expression studies detected that every major immune cell type is enriched for MS susceptibility genes and that MS risk variants are enriched in brain-resident immune cells, especially microglia. Up to 48% of the genetic contribution of MS can be explained through this analysis. Science , this issue p. eaav7188 ; see also p. 138