Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associated with multiple sclerosis
Alcina, Antonio (Instituto de Parasitología y Biomedicina "López-Neyra")
Fedetz, Maria (Instituto de Parasitología y Biomedicina "López-Neyra")
Fernández, Óscar (Hospital Regional Universitario Carlos Haya (Málaga))
Saiz, Albert (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Izquierdo, Guillermo (Hospital Universitario Virgen Macarena (Sevilla, Andalusia))
Lucas, Miguel (Hospital Universitario Virgen Macarena (Sevilla, Andalusia))
Leyva, Laura (Hospital Regional Universitario Carlos Haya (Málaga))
García-León, Juan Antonio (Hospital Regional Universitario Carlos Haya (Málaga))
Abad-Grau, María del Mar (Universidad de Granada)
Alloza, Iraide (Universidad del País Vasco)
Antigüedad, Alfredo (Hospital de Basurto (Bilbao, Biscaia))
Garcia-Barcina, María J. (Hospital de Basurto (Bilbao, Biscaia))
Vandenbroeck, Koen (Universidad del País Vasco)
Varadé, Jezabel (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos)
de la Hera, Belén (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos)
Arroyo, Rafael (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos)
Comabella, Manuel (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Montalban, Xavier (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Petit-Marty, Natalia (Institut de Biologia Evolutiva (UPF-CSIC) (Barcelona))
Navarro, Arcadi 1969- (Institut de Biologia Evolutiva (UPF-CSIC) (Barcelona))
Otaegui, David (Biodonostia Osasun Ikerketako Institutura (País Basc))
Olascoaga, Javier (Hospital Universitario Donosti)
Blanco, Yolanda (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Urcelay, Elena (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos)
Matesanz, Fuencisla (Instituto de Parasitología y Biomedicina "López-Neyra")

Fecha:	2013
Resumen:	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.
Ayudas:	Ministerio de Ciencia e Innovación SAF2009-11491 Ministerio de Ciencia e Innovación RD07/0060 Ministerio de Ciencia e Innovación CP10/00526 Ministerio de Ciencia e Innovación PI10/1985 Ministerio de Ciencia e Innovación PS09/02105
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	Journal of medical genetics, Vol. 50, Issue 1 (May 2013) , p. 25-33, ISSN 1468-6244

DOI: 10.1136/jmedgenet-2012-101085
PMID: 23160276

9 p, 404.0 KB

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