Abstract Details

Title Discovering Context-dependent Whole Blood Gene Expression Quantitative Trait Loci (eQTL) In Relapsing Remitting Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) P2 - Poster Session 2 (5:30 PM-6:30 PM)

Poster/Presentation
Number 15-051

Objective Identification and context-dependent characterization of whole blood gene expression quantitative trait loci (eQTL) from MS patients in clinical cohorts.

Background Development of transformative MS therapies requires investigation of disease heterogeneity and pathology at a molecular level. Integrative molecular analysis of well-phenotyped clinical trial samples offers an unique opportunity to generate therapeutic hypotheses and biomarkers for patient stratification.

Design/Methods DNA and total RNA from whole blood baseline samples from 1,130 patients from the phase 3 pivotal trials DEFINE (NCT00420212) and CONFIRM (NCT00451451) for efficacy of dimethyl fumarate (DMF) were used to genotype SNPs and measure mRNA levels with microarray. A genome-wide eQTL analysis of 10,826 genes and ~1 million SNPs was performed to identify eQTLs significantly associated with gene expression in cis, adjusting for demographic and genomic covariates. Modifiers of eQTL-target gene associations were analyzed, including cell counts and clinical disease severity measures.

Results In all, 9,867 unique genes were associated with baseline gene expression in cis. A comparison of MS eQTL and healthy blood eQTL associations from Genotype-Tissue Expression (GTEx) project revealed significant concordance between the direction/strength of associations (r_s=0.80, p<2x10^-16). Associations were replicated in a subset of placebo treated patients using RNA samples at 48 weeks of study (r_s=0.97, p<2x10^-16). MS eQTL-target gene association strength (beta) was enriched for genes involved in innate immune pathways. Forty-five percent of 200 GWAS risk regions (IMSGC 2017, preprint) were correlated (r²>=0.8) with at least 1 eQTL-gene association. There were significant association-modifier interactions observed for each of cell counts, disease severity and disease duration (FDR < 0.05).

Conclusions We report the largest blood eQTL analysis conducted in RRMS patients. We identified MS disease, cell type and disease severity context dependent enrichment in eQTL associations that provided new insights into MS disease biology and with further validation, can lead to novel target hypothesis.

Authors/Disclosures
PRESENTER	No disclosure on file
Paola G. Bronson, PhD, MPH (Biogen, Inc.)	Dr. Bronson has received personal compensation for serving as an employee of Biogen.
Dipen P. Sangurdekar, PhD	No disclosure on file

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