Author Of 2 Presentations
LB01.05 - Network analysis identifies gut bacteria associated with multiple sclerosis relapse among pediatric-onset patients
Commensal gut microbes are known to affect host immune function and may be modifiable. Recent work suggests gut microbiota composition contributes to onset of MS; however, little is known about its contribution to MS disease activity.
Estimate the association between gut microbiota and subsequent disease activity among individuals with pediatric-onset MS (pedMS) from the U.S. Network of Pediatric MS Centers.
Stool samples were collected from cases (MS symptom onset <18 years) and profiled using 16S rRNA sequencing of the V4 region. Amplicon sequence variants (ASVs) were identified using the Divisive Amplicon Denoising Algorithm-2 (DADA2). ASVs present in <20% of samples were removed. ASV clusters (modules) were identified using weighted genetic correlation network analysis (WGCNA) and sparCC transformation of ASV abundance. Cox proportional hazard recurrent event models were used to examine the relationship between individual ASVs and then ASV clusters, adjusted for age, sex, and disease modifying therapy (DMT) use.
Of 53 pedMS cases, 72% were girls. At stool sample collection, the mean age was 15.5 years (SD: 2.7) and disease duration was 1.1 years (SD: 1.0). Less than half (45%) had one relapse and 30% had >1 relapse over the subsequent mean follow-up of 2.5 years (SD:1.3). Over this time, 91% used a DMT. Among 270 individual ASVs included in the analyses, 20 were nominally significant (p<0.05), e.g. the presence of Blautia stercoris was associated with higher relapse risk (hazard ratio [HR]=2.50; 95% confidence interval [CI]=1.43, 4.37). WGCNA identified 6 ASV modules. Higher values of one module’s eigengene was significantly (false discovery rate q<0.2) associated with higher relapse risk (HR=1.23, 95% CI=1.02, 1.50). Four ASVs nominally associated with higher relapse risk were in this module. These included Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.
We found that a high relative abundance of a gut microbiota species within the Blautia genus, and its interconnected variants, was associated with a higher relapse risk in pedMS cases. While our study represents the largest of its kind in MS, findings need to be replicated. However, Blautia stercoris has been linked to disease activity in other immune-mediated diseases such as systemic lupus erythematosus.
PS08.04 - Polygenic Risk Score Analysis in Multiple Sclerosis
The International Multiple Sclerosis Genetics Consortium (IMSGC) uncovered the contribution of inherited variants to multiple sclerosis (MS) in 115,801 individuals. Polygenic risk profiling intends to summarize and represent the genetic architecture of complex disorders and identify groups of individuals who can benefit from the knowledge of their increased susceptibility. In this context, it is important to explore the relationships between polygenic risk scores (PRS) in MS with disease status and severity in population-level and familial cohorts, in order to leverage potential clinical utilities.
To develop and assess quantifiable measures of MS susceptibility and examine their association with phenotypic variability.
We employed both the Bayesian LDPred algorithm and Pruning and Thresholding to develop multiple MS-PRS from a multi-cohort GWAS comprising 41,505 participants. Models were validated in the UK Biobank phase 1 dataset and tested in both the UK Biobank phase 2 and the Kaiser Permanente Northern California (KPNC) MS datasets. PRS of families was tested in a cohort of 34 families with one affected parent and at least one affected child. Clinical phenotype data was used in the UCSF EPIC cohort including 742 MS patients. Standard quality control of the base (IMSGC) and target datasets was performed prior to final analyses.
We observed a statistically significant difference between PRS distributions of cases and controls in both the UK Biobank and KPNC cohorts (P < 1e-70), and identified individuals at greater risk versus the rest of the population (OR > 3). We confirmed that an increased PRS in siblings of disease discordant parents is associated with a higher risk of MS and showed an enhanced power for disease prediction among siblings in a small cohort of 152 individuals. These results suggest that PRS metric shows promise for prediction of MS within sibships, but needs to be further tested in larger familial cohorts. The predictive prognostic value of PRS for selected MRI metrics and disability scores suggests that PRS modestly explain phenotypic variations.
Polygenic risk scores are currently the best estimate of the complex genetic architecture of MS and, when clinically implemented, could facilitate recognition and management of MS in early stages of the disease. These results provide a direction for translation of MS-GWAS studies into relevant biology and clinically meaningful outcomes.