Bruce Taylor

Sun Exposure across the Life Course Significantly Modulates Early Multiple Sclerosis Clinical Course

Background Low vitamin D and/or sun exposure have been associated with increased risk of multiple sclerosis (MS) onset. However, comparatively, few studies have prospectively examined associations between these factors and clinical course. Objectives To evaluate the association of sun exposure parameters and vitamin D levels with conversion to MS and relapse risk in a prospectively monitored cohort of 145 participants followed after a first demyelinating event up to 5-year review (AusLong Study). Methods Sun exposure prior to and after onset measured by annual questionnaire; ultraviolet radiation (UVR) “load” estimated by location of residence over the life course and ambient UVR levels. Serum 25-hydroxyvitamin D [25(OH)D] concentrations measured at baseline, 2/3-year, and 5-year review. MS conversion and relapse assessed by neurologist assessment and medical record review. Results Over two-thirds (69%) of those followed to 5-year review (100/145) converted to MS, with a total of 252 relapses. Higher pre-MS onset sun exposure was associated with reduced risk of MS conversion, with internal consistency between measures and dose–response relationships. Analogous associations were also seen with risk of relapse, albeit less strong. No consistent associations were observed between postonset sun exposure and clinical course, however. Notably, those who increased their sun exposure during follow-up had significantly reduced hazards of MS conversion and relapse. Serum 25(OH)D levels and vitamin D supplementation were not associated with conversion to MS or relapse hazard. Conclusion We found that preonset sun exposure was protective against subsequent conversion to MS and relapses. While consistent associations between postonset sun exposure or serum 25(OH)D level and clinical course were not evident, possibly masked by behavior change, those participants who markedly increased their sun exposure demonstrated a reduced MS conversion and relapse hazard, suggesting beneficial effects of sun exposure on clinical course.

Exome wide association study identifies multiple novel genetic loci associated with multiple sclerosis

Background: Current MS therapies target the systemic circulation. We previously identified that genes encoding transcription factors were over-represented amongst MS risk factors, and that expression of several of these were altered in MS blood, including EOMES, TBX21 and ZMIZ1. Expression was stable over time, so that it defines a molecular phenotype. n nObjectives: Here we tested if this finding could be replicated in independent cohorts, if expression was heritable, longitudinally stable, affected by therapy, and associated with genetic and environmental risk factors. We sought the immune cell subsets expressing these transcription factors, and tested if protein expression was also altered. n nMethods: Whole blood mRNA expression was determined in new cohorts of untreated MS (n = 23, Sydney; n = 47, Perth) and healthy controls (n = 23) and protein expression determined by flow cytometry in PBMCs of untreated MS and healthy controls (n = 28, 30 respectively). Effect of major therapies and correlation of gene expression with risk SNP genotypes, and anti-Epstein Barr Virus EBNA-1 titres was assessed, and heritability tested in a large twin cohort. n nResults: MS Molecular Phenotypes were replicated in new cohorts. Modules of genes, whose expression correlated with EOMES/TBX21 or ZMIZ1, further defined the phenotypes. CD56+ cells, inflammatory monocytes and plasmacytoid dendritic cells expressed lower levels of Molecular Phenotype transcription factors. EOMES and TBX21 risk SNP genotypes, and serum EBNA-1 titres were not correlated with gene expression, but HLA-DRB1*1501 genotype was. Therapies altered expression levels (e.g. TBX21 returned to control levels on natalizumab) with significant variability between individuals. n nConclusions: EOMES/TBX21 and ZMIZ1 tag molecular phenotypes of MS that are affected by therapy. The phenotypes are due to under-representation and altered state of CD56+ and inflammatory monocytes/pDCs respectively. The dysregulated immune cells are a novel target for therapy and, together with gene expression, represent potential biomarkers of therapeutic response.Background: Population based genome wide association studies have identified 110 single nucleotide polymorphisms (SNPs) that are associated with an increase in MS risk. These SNPs are all common, and have odds ratios of between 1.1 and 1.4. Most are found in non-protein coding regions, and their functions are largely unknown. n nObjectives: Importantly, recent work has shown that some non-coding SNPs can function by changing immune gene expression levels as a quantitative trait, termed expression quantitative trait loci (eQTL). We conducted studies to evaluate the effects of MS risk SNPs on gene expression in four main immune cell types. n nMethods: We isolated monocytes, B-cells, CD4- and CD8- T-cells from untreated relapsing MS cases (n=79) and healthy controls (n=101). To test for cis-eQTL associations, we selected all genes within +/-500kb of an MS risk SNP (2500 pairs in total). The Illumina Immunochip was used to genotype for MS risk SNPs, and gene expression was measured for each cell type by microarray. n nResults: We have identified MS risk eQTL associations in each immune cell type, some of which are cell type specific. We also present preliminary data showing that some MS risk SNPs could exert differential effects on gene expression in cases compared to controls. Here we report likely disease state specific eQTLs for all cell types with the top associations being: RNF26/rs9736016, B cells; MACROD1/rs694739, CD8 cells; SLC25A41/rs1077667, CD4 cells; GPR18/rs4772201, monocyte cells. n nConclusions: We have shown that MS risk SNPs contribute to immune heterogeneity. It is hoped that through an understanding of the functions of individual common risk variants, it may be possible to uncover the processes and cell types that are most important for conveying the genetic risk of MS.