A functional variant that affects exon-skipping and protein expression ofSP140as genetic mechanism predisposing to multiple sclerosis

Abstract

Several variants in strong linkage disequilibrium (LD) at the SP140 locus have been associated with multiple sclerosis (MS), Crohn's disease (CD) and chronic lymphocytic leukemia (CLL). To determine the causal polymorphism, we have integrated high-density data sets of expression quantitative trait loci (eQTL), using GEUVADIS RNA sequences and 1000 Genomes genotypes, with MS-risk variants of the high-density Immunochip array performed by the International Multiple Sclerosis Genetic Consortium (IMSGC). The variants most associated with MS were also correlated with a decreased expression of the full-length RNA isoform of SP140 and an increase of an isoform lacking exon 7. By exon splicing assay, we have demonstrated that the rs28445040 variant was the causal factor for skipping of exon 7. Western blots of peripheral blood mononuclear cells from MS patients showed a significant allele-dependent reduction of the SP140 protein expression. To confirm the association of this functional variant with MS and to compare it with the best-associated variant previously reported by GWAS (rs10201872), a case-control study including 4384 MS patients and 3197 controls was performed. Both variants, in strong LD (r(2) = 0.93), were found similarly associated with MS [P-values, odds ratios: 1.9E-9, OR = 1.35 (1.22-1.49) and 4.9E-10, OR = 1.37 (1.24-1.51), respectively]. In conclusion, our data uncover the causal variant for the SP140 locus and the molecular mechanism associated with MS risk. In addition, this study and others previously reported strongly suggest that this functional variant may be shared with other immune-mediated diseases as CD and CLL.

Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140

“…Here, we report on SP140, a previously uncharacterized immune-restricted epigenetic reader that has previously reported SNPs that associate with CD (16, 17), CLL (18), and MS (19). We show that individuals bearing CD-associated SP140 SNPs, most of which are intronic and in perfect LD with SP140 SNPs associated with CLL and MS, have alterations in SP140 mRNA splicing that ultimately result in loss of SP140 protein, consistent with the findings from a recent publication (45). Consequently, CD patients deficient in this epigenetic reader exhibited hyporesponsive innate immune responses to bacteria or viral ligands that stratified them from other CD patients.…”

“…4A) (16, 17), including those associated with CLL (rs13397985) (18) and MS (rs10201872) (19), and hence may act coordinately (hereafter collectively referred to as SNP +/+ ). All of these SP140 SNPs are intronic, except for a single SNP in exon 7 (rs28445040) that was recently suggested to be the causal SNP (45). Of the five known protein-coding mRNA isoforms of SP140 (Fig.…”

Characterization of candidate genes in inflammatory bowel disease–associated risk loci

“…SP140 and IKZF3 share similar patterns of tissue-specific expression, with the highest expression in the spleen, small intestine, and whole blood (24) as well as B cell subsets (25, 26). In addition to IBD, SNPs in both genes have been associated with risk for multiple sclerosis (27, 28). …”

The roles of RNA processing in translating genotype to phenotype

“…Having established that there is extensive variability in pre-mRNA splicing that is linked to genetic variation, several studies have gone further to demonstrate associations between disease risk and genetic variants that affect splicing 14,25,32–36 . There is a growing number of individual genes for which variant-specific splicing patterns have been directly linked with disease susceptibility, including splice variants of oxidized low-density lipoprotein receptor 1 ( OLR1 ) and low-density lipoprotein receptor ( LDLR ) that are linked with coronary artery disease and splice variants of interleukin-7 receptor ( IL7R ) that are linked with multiple sclerosis 37–39 .…”