title: Profile of differential promoter activity by nucleotide substitution at GWAS signals for multiple sclerosis.
abstract: This experimental study was conducted with completely randomized design. Genome-wide association studies (GWAS) have revealed a large number of genetic associations of nucleotide sequence variants with susceptibility to multiple sclerosis (MS). Nevertheless, studies to identify the functional relevance of these variants lag far behind identification of the GWAS signals. Expression quantitative trait loci (eQTLs) analysis and promoter activity analysis with the variants filtered by GWAS were conducted to identify their functional alleles and haplotypes. The promoter activity was assayed with reporter constructs containing variants at 8 MS GWAS signals resulted from 18 GWAS. The promoter activity differed by alternative sequence variants at upstream regions of the CYP24A1, CYP27B1, SYK, RAD21L1, PVR, ODF3B, and RGS14 genes (P<0.05). The transcriptional regulations of sequence variants were also found by identifications of eQTLs for their corresponding genes with lymphoblastoid cells in the current study (SYK, ODF3B, RGS14, and PVR, P<8.33×10⁻³) and with dendritic cells in a previous study (CYP27B1, P=1.84×10⁻⁶). This study identified regulatory nucleotide sequences in the promoters of the CYP24A1, CYP27B1, SYK, RAD21L1, PVR, ODF3B, and RGS14 genes, and their variants differentially affected gene expression. This might result in their associations with MS susceptibility in previous GWAS. Further functional studies are required to understand the process of transcriptional regulation of the variants identified in the current study and the mechanisms underlying susceptibility to MS.
authors.affiliation: From the School of Systems Biomedical Science, Soongsil University, 511 Sangdo-dong, Dongjak-gu, Seoul 156-743, Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Ryu
authors.forename: Jeyoung
authors.initials: J
authors.lastname: Woo
authors.forename: Jimin
authors.initials: J
authors.lastname: Shin
authors.forename: Hyunju
authors.initials: H
authors.lastname: Ryoo
authors.forename: Younyoung
authors.initials: Y
authors.lastname: Kim
authors.forename: Chaeyoung
authors.initials: C
authors.lastname: Lee
mesh_terms: D000483:Alleles; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009711:Nucleotides / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
chemical_list: D009711:Nucleotides