TY - JOUR T1 - Identification of a functional variant in the <em>KIF5A-CYP27B1-METTL1-FAM119B</em> locus associated with multiple sclerosis JF - Journal of Medical Genetics JO - J Med Genet SP - 25 LP - 33 DO - 10.1136/jmedgenet-2012-101085 VL - 50 IS - 1 AU - Antonio Alcina AU - Maria Fedetz AU - Óscar Fernández AU - Albert Saiz AU - Guillermo Izquierdo AU - Miguel Lucas AU - Laura Leyva AU - Juan-Antonio García-León AU - María del Mar Abad-Grau AU - Iraide Alloza AU - Alfredo Antigüedad AU - María J Garcia-Barcina AU - Koen Vandenbroeck AU - Jezabel Varadé AU - Belén de la Hera AU - Rafael Arroyo AU - Manuel Comabella AU - Xavier Montalban AU - Natalia Petit-Marty AU - Arcadi Navarro AU - David Otaegui AU - Javier Olascoaga AU - Yolanda Blanco AU - Elena Urcelay AU - Fuencisla Matesanz Y1 - 2013/01/01 UR - http://jmg.bmj.com/content/50/1/25.abstract N2 - Background and aim 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. ER -