title: Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associated with multiple sclerosis.
abstract: OBJECTIVE
  Several studies have highlighted the association of the 12q13.3-12q14.1 region with coeliac disease, type 1 diabetes, rheumatoid arthritis and multiple sclerosis (MS); however, the causal variants underlying diseases are still unclear. The authors sought to identify the functional variant of this region associated with MS.
  
  
  METHODS
  Tag-single nucleotide polymorphism (SNP) analysis of the associated region encoding 15 genes was performed in 2876 MS patients and 2910 healthy Caucasian controls together with expression regulation analyses.
  
  
  RESULTS
  rs6581155, which tagged 18 variants within a region where 9 genes map, was sufficient to model the association. This SNP was in total linkage disequilibrium (LD) with other polymorphisms that associated with the expression levels of FAM119B, AVIL, TSFM, TSPAN31 and CYP27B1 genes in different expression quantitative trait loci studies. Functional annotations from Encyclopedia of DNA Elements (ENCODE) showed that six out of these rs6581155-tagged-SNPs were located in regions with regulatory potential and only one of them, rs10877013, exhibited allele-dependent (ratio A/G=9.5-fold) and orientation-dependent (forward/reverse=2.7-fold) enhancer activity as determined by luciferase reporter assays. This enhancer is located in a region where a long-range chromatin interaction among the promoters and promoter-enhancer of several genes has been described, possibly affecting their expression simultaneously.
  
  
  CONCLUSIONS
  This study determines a functional variant which alters the enhancer activity of a regulatory element in the locus affecting the expression of several genes and explains the association of the 12q13.3-12q14.1 region with MS.
authors.affiliation: Department of Cell Biology and Immunology Instituto de Parasitología y Biomedicina López Neyra, Consejo Superior de Investigaciones Científicas (IPBLNCSIC), Granada, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcina
authors.forename: Maria
authors.initials: M
authors.lastname: Fedetz
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernández
authors.forename: Albert
authors.initials: A
authors.lastname: Saiz
authors.forename: Guillermo
authors.initials: G
authors.lastname: Izquierdo
authors.forename: Miguel
authors.initials: M
authors.lastname: Lucas
authors.forename: Laura
authors.initials: L
authors.lastname: Leyva
authors.forename: Juan-Antonio
authors.initials: JA
authors.lastname: García-León
authors.forename: María Del Mar
authors.initials: Mdel M
authors.lastname: Abad-Grau
authors.forename: Iraide
authors.initials: I
authors.lastname: Alloza
authors.forename: Alfredo
authors.initials: A
authors.lastname: Antigüedad
authors.forename: María J
authors.initials: MJ
authors.lastname: Garcia-Barcina
authors.forename: Koen
authors.initials: K
authors.lastname: Vandenbroeck
authors.forename: Jezabel
authors.initials: J
authors.lastname: Varadé
authors.forename: Belén
authors.initials: B
authors.lastname: de la Hera
authors.forename: Rafael
authors.initials: R
authors.lastname: Arroyo
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.forename: Natalia
authors.initials: N
authors.lastname: Petit-Marty
authors.forename: Arcadi
authors.initials: A
authors.lastname: Navarro
authors.forename: David
authors.initials: D
authors.lastname: Otaegui
authors.forename: Javier
authors.initials: J
authors.lastname: Olascoaga
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Blanco
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
authors.forename: Fuencisla
authors.initials: F
authors.lastname: Matesanz
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D004742:Enhancer Elements, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008780:Methyltransferases / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014158:Transcription, Genetic
chemical_list: C500506:KIF5A protein, human; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; C120297:METTL1 protein, human; D008780:Methyltransferases; D016547:Kinesins