Contributions
Abstract: P448
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 14 Genetics/Epigenetics
More than a hundred genetic risk loci for multiple sclerosis (MS) have been identified. Functional analyses of these variants are needed to better understand the biological processes related to disease pathogenesis. We explored whether MS-associated single nucleotide polymorphisms (SNPs) within the first intron of the CD58 gene influence the expression of the intronic primate-specific microRNA hsa-mir-548ac.
Expression quantitative trait locus (eQTL) analyses were performed using public microarray data of HapMap populations (n=726 individuals), public RNA-sequencing data of the Geuvadis project (n=465 individuals) and own real-time PCR data (n=32 MS patients). Analysis of variance (ANOVA) was used to test the relationship between CD58 gene expression, hsa-miR-548ac levels and the number of MS risk alleles (defined either by SNP rs1335532 or SNP rs1414273) carried by each individual. Welch t-tests were calculated for pairwise comparisons of genotype groups. Statistical significance was defined as p-value< 0.05.
The genetic susceptibility variant for MS was associated with significantly lower CD58 mRNA levels in the HapMap cohort and in the Geuvadis cohort. On the other hand, significantly increased levels of hsa-miR-548ac were seen in risk allele carriers in the real-time PCR data and in the Geuvadis data. The inverse eQTL effect suggests a genotype-dependent processing of both mRNA and microRNA from the same primary transcript. Moreover, CD58 and hsa-miR-548ac were not strictly coexpressed across different immune cell populations, with elevated levels of the microRNA seen in CD4+ T helper cells.
To conclude, we provide evidence that the causal SNP of the CD58 gene locus is located in the hsa-mir-548ac stem-loop sequence. Further experiments are currently performed to quantify the effect of the respective alleles on the kinetics of Drosha processing and to screen for target genes of this microRNA. We postulate similar eQTL effects for other members of this microRNA family.
Disclosure:
NI, BF, DK, NB, IS and HJT declare no conflicts of interest.
MH received speaking fees and travel funds from Bayer HealthCare, Biogen, Novartis and Teva.
UKZ received speaking fees and financial support for research activities from Almirall, Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi and Teva.
Abstract: P448
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 14 Genetics/Epigenetics
More than a hundred genetic risk loci for multiple sclerosis (MS) have been identified. Functional analyses of these variants are needed to better understand the biological processes related to disease pathogenesis. We explored whether MS-associated single nucleotide polymorphisms (SNPs) within the first intron of the CD58 gene influence the expression of the intronic primate-specific microRNA hsa-mir-548ac.
Expression quantitative trait locus (eQTL) analyses were performed using public microarray data of HapMap populations (n=726 individuals), public RNA-sequencing data of the Geuvadis project (n=465 individuals) and own real-time PCR data (n=32 MS patients). Analysis of variance (ANOVA) was used to test the relationship between CD58 gene expression, hsa-miR-548ac levels and the number of MS risk alleles (defined either by SNP rs1335532 or SNP rs1414273) carried by each individual. Welch t-tests were calculated for pairwise comparisons of genotype groups. Statistical significance was defined as p-value< 0.05.
The genetic susceptibility variant for MS was associated with significantly lower CD58 mRNA levels in the HapMap cohort and in the Geuvadis cohort. On the other hand, significantly increased levels of hsa-miR-548ac were seen in risk allele carriers in the real-time PCR data and in the Geuvadis data. The inverse eQTL effect suggests a genotype-dependent processing of both mRNA and microRNA from the same primary transcript. Moreover, CD58 and hsa-miR-548ac were not strictly coexpressed across different immune cell populations, with elevated levels of the microRNA seen in CD4+ T helper cells.
To conclude, we provide evidence that the causal SNP of the CD58 gene locus is located in the hsa-mir-548ac stem-loop sequence. Further experiments are currently performed to quantify the effect of the respective alleles on the kinetics of Drosha processing and to screen for target genes of this microRNA. We postulate similar eQTL effects for other members of this microRNA family.
Disclosure:
NI, BF, DK, NB, IS and HJT declare no conflicts of interest.
MH received speaking fees and travel funds from Bayer HealthCare, Biogen, Novartis and Teva.
UKZ received speaking fees and financial support for research activities from Almirall, Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi and Teva.