J Med Genet doi:10.1136/jmedgenet-2012-101085
  • Complex traits
  • Original article

Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associated with multiple sclerosis

Open Access
  1. Fuencisla Matesanz1,4
  1. 1Department of Cell Biology and Immunology Instituto de Parasitología y Biomedicina ‘López Neyra’, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain
  2. 2Servicio de Neurología, Instituto de Neurociencias Clínicas, Hospital Regional Universitario Carlos Haya, Málaga, Spain
  3. 3Neurology Service, Hospital Clinic and I. d'Investigació Biomèdica Pi iSunyer (IDIBAPS), Barcelona, Spain
  4. 4Unidad de Esclerosis Múltiple, Hospital Virgen Macarena, Sevilla, Spain
  5. 5Servicio de Biología Molecular, Hospital Virgen Macarena, Sevilla, Spain
  6. 6Laboratorio de Investigación, Instituto de Neurociencias Clínicas, Hospital Regional Universitario Carlos Haya, Málaga, Spain
  7. 7Departamento de Lenguajes y Sistemas Informáticos, CITIC, Universidad de Granada, Granada, Spain
  8. 8Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Leioa, Spain
  9. 9Servicio de Neurología, Hospital de Basurto, Bilbao, Spain
  10. 10Servicio de Genética, Hospital de Basurto, Bilbao, Spain
  11. 11IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
  12. 12Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
  13. 13Multiple Sclerosis Unit, Neurology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid. Spain
  14. 14Centre d'Esclerosi Múltiple de Catalunya, CEM-Cat, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Spain
  15. 15Institute of Evolutionary Biology (UPF-CSIC), PRBB, Barcelona, Spain
  16. 16National Institute for Bioinformatics, Universitat Pompeu Fabra, Barcelona, Spain
  17. 17Institució Catalana de Recerca i EstudisAvançats (ICREA), Catalonia, Spain
  18. 18Multiple Sclerosis Unit, Neuroscience Area, Biodonostia Health Research Institute, Donostia-San Sebastian, Spain
  19. 19Servicio de Neurología, Unidad de Esclerosis Múltiple, Hospital Donostia, San Sebastián, Spain
  1. Correspondence to Dr Fuencisla Matesanzor or Dr Antonio Alcina, Instituto de Parasitologia y Biomedicina ‘Lopez-Neyra’-CSIC, Avda. Conocimiento S/N. Parque Tecnologico Ciencias de la Salud, 18100 Armilla, Granada, Spain; lindo{at} (FM), pulgoso{at} (AA)
  • Received 29 May 2012
  • Revised 24 September 2012
  • Accepted 10 October 2012
  • Published Online First 17 November 2012


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.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: and

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