Adaptive and Innate Immunity Are Key Drivers of Age at Onset of Multiple Sclerosis.

Background and Objectives: Multiple sclerosis (MS) age at onset (AAO) is a clinical predictor of long-term disease outcomes, independent of disease duration. Little is known about the genetic and biological mechanisms underlying age of first symptoms. We conducted a genome-wide association study (GWAS) to investigate associations between individual genetic variation and the MS AAO phenotype. Methods: The study population was comprised participants with MS in 6 clinical trials: ADVANCE (N = 655; relapsing-remitting [RR] MS), ASCEND (N = 555; secondary-progressive [SP] MS), DECIDE (N = 1,017; RRMS), OPERA1 (N = 581; RRMS), OPERA2 (N = 577; RRMS), and ORATORIO (N = 529; primary-progressive [PP] MS). Altogether, 3,905 persons with MS of European ancestry were analyzed. GWAS were conducted for MS AAO in each trial using linear additive models controlling for sex and 10 principal components. Resultant summary statistics across the 6 trials were then meta-analyzed, for a total of 8.3 × 10-6 single nucleotide polymorphisms (SNPs) across all trials after quality control and filtering for heterogeneity. Gene-based tests of associations, pathway enrichment analyses, and Mendelian randomization analyses for select exposures were also performed. Results: Four lead SNPs within 2 loci were identified (p < 5 × 10-8), including a) 3 SNPs in the major histocompatibility complex and their effects were independent of HLA-DRB1*15:01 and b) a LOC105375167 variant on chromosome 7. At the gene level, the top association was HLA-C (p = 1.2 × 10-7), which plays an important role in antiviral immunity. Functional annotation revealed the enrichment of pathways related to T-cell receptor signaling, autoimmunity, and the complement cascade. Mendelian randomization analyses suggested a link between both earlier age at puberty and shorter telomere length and earlier AAO, while there was no evidence for a role for either body mass index or vitamin D levels. Discussion: Two genetic loci associated with MS AAO were identified, and functional annotation demonstrated an enrichment of genes involved in adaptive and complement immunity. There was also evidence supporting a link with age at puberty and telomere length. The findings suggest that AAO in MS is multifactorial, and the factors driving onset of symptoms overlap with those influencing MS risk.

Characterizing causal relationships of visceral fat and body shape on multiple sclerosis risk.

BACKGROUND: Epidemiologic studies have established obesity as a risk factor for multiple sclerosis (MS). These studies relied on body-mass index (BMI) and body size silhouettes as the primary measures of obesity. Unfortunately, the causal mechanisms through which obesity confers MS risk are not yet known. OBJECTIVES: To investigate the causal effects of multiple specific measures of body fat on MS risk in populations of European descent, using Mendelian randomization (MR). METHODS: MR is a genetic instrumental variable analysis utilizing genome-wide association (GWA) summary statistics to infer causality between phenotypes. MR analyses were performed to investigate the relationships between seven measures of body fat (BMI, waist-hip ratio, visceral adipose tissue [VAT], subcutaneous adipose tissue, and arm-, leg-, and trunk-fat to total body fat ratio) and MS risk. RESULTS: Only BMI and VAT were significantly associated with MS risk in separate MR analyses (ßBMI=0.27, pBMI<0.001; ßVAT=0.28, pVAT=0.006). High correlation between BMI and VAT instruments suggest that two-sample MR associations for BMI and VAT likely capture the same causal mechanisms. CONCLUSIONS: BMI and VAT were causally associated with MS risk in European populations, though their effects do not appear independent, suggesting overlap in the role of overall body mass and visceral obesity in MS pathogenesis.

A higher burden of multiple sclerosis genetic risk confers an earlier onset.

BACKGROUND: Age at onset of multiple sclerosis (MS) is an objective, influential predictor of the evolution of MS independent of disease duration. OBJECTIVES: Determine the influence of MS genetic predisposition on age of onset. METHODS: We conducted a comprehensive investigation of MS risk variants and age at onset in 3495 non-Latinx white individuals, including for combinations of HLA-DRB1*15:01 alleles and quintiles of an unweighted genetic risk score (GRS) for 198 of 200 autosomal MS risk variants that reside outside the major histocompatibility complex. RESULTS: The mean age at onset was 32 years, 29% were male, and 46% were HLA-DRB1*15:01 carriers. For those with the greatest genetic risk burden (the highest GRS quintile with two HLA-DRB1*15:01 alleles) were on average 5 years younger at onset (p = 0.002) than those with the lowest genetic risk burden (the lowest GRS quintile with no HLA-DRB1*15:01 alleles). There was a strong inverse relationship between the MS genetic risk burden and age at onset of MS (p < 5 × 10-8). CONCLUSION: We demonstrate a significant gradient between elevated MS genetic risk burden and an earlier onset of MS, suggesting that a higher MS genetic risk burden accelerates onset of the disease.

Predicting onset of secondary-progressive multiple sclerosis using genetic and non-genetic factors.

BACKGROUND: Predicting the transition from relapsing-remitting (RR) to secondary-progressive (SP) multiple sclerosis (MS) from early in the disease course is challenging. OBJECTIVE: To construct prediction models for SPMS using sociodemographic and self-reported clinical measures that would be available at/near MS onset, with specific considerations for MS genetic risk factors. METHODS: We conducted a retrospective cross-sectional study based on 1295 white, non-Hispanic individuals. Cox proportional hazard prediction models were generated for three censored SPMS outcomes (ever transitioning, transitioning within 10 years, and transitioning within 20 years) using sociodemographic, comorbid health information, symptomatology, and other measures of early disease activity. HLADRB1*15:01 and HLA-A*02:01, as well as a genetic risk score, were iteratively considered in each model. We also explored the relationships for all 200 MS risk variants located outside the major histocompatibility complex. Nomograms were generated for the final prediction models. RESULTS: An older age of MS onset and being male predicted a short latency to SPMS, while a longer interval between the first two relapses predicted a much longer latency. Comorbid conditions and onset symptomatology variably predicted the risk for transitioning to SPMS for each censored outcome. The most notable observation was that HLA-A*02:01, which confers decreased risk for MS, also contributed to decreased hazards for SPMS. CONCLUSIONS: These results have the potential to advance prognostication for a person with MS using information available at or near onset, potentially improving care and quality of life for those who live with MS.

Sources of Variability in Structural Bending Response of Pediatric and Adult Human Ribs in Dynamic Frontal Impacts.

Despite safety advances, thoracic injuries in motor vehicle crashes remain a significant source of morbidity and mortality, and rib fractures are the most prevalent of thoracic injuries. The objective of this study was to explore sources of variation in rib structural properties in order to identify sources of differential risk of rib fracture between vehicle occupants. A hierarchical model was employed to quantify the effects of demographic differences and rib geometry on structural properties including stiffness, force, displacement, and energy at failure and yield. Three-hundred forty-seven mid-level ribs from 182 individual anatomical donors were dynamically (~2 m/s) tested to failure in a simplified bending scenario mimicking a frontal thoracic impact. Individuals ranged in age from 4 - 108 years (mean 53 ± 23 years) and included 59 females and 123 males of diverse body sizes. Age, sex, body size, aBMD, whole rib geometry and cross-sectional geometry were explored as predictors of rib structural properties. Measures of cross-sectional rib size (Tt.Ar), bone quantity (Ct.Ar), and bone distribution (Z) generally explained more variation than any other predictors, and were further improved when normalized by rib length (e.g., robustness and WBSI). Cortical thickness (Ct.Th) was not found to be a useful predictor. Rib level predictors performed better than individual level predictors. These findings moderately explain differential risk for rib fracture and with additional exploration of the rib's role in thoracic response, may be able contribute to ATD and HBM development and alterations in addition to improvements to thoracic injury criteria and scaling methods.