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Cited by 69Multiple Sclerosis Research StudiesGenetic Associations and EpidemiologyGenomics and Chromatin Dynamics

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

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Alcina, Antonio, Fedetz, Maria, Fernández, Óscar, Saiz, Albert, Izquierdo, Guillermo, Lucas, Miguel, Leyva, Laura, García-León, Juan-Antonio +17 more·2013·Journal of Medical Genetics
DOI 10.1136/jmedgenet-2012-101085PMC PMC3538279
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Abstract

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.

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Authors
Alcina, A., Fedetz, M., Fernández, Ó., Saiz, A., Izquierdo, G., Lucas, M., Leyva, L., García-León, J.-A., Abad-Grau, M. D. M., Alloza, I., Antigüedad, A., Garcia-Barcina, M. J., Vandenbroeck, K., Varadé, J., de la Hera, B., Arroyo, R., Comabella, M., Montalban, X., Petit-Marty, N., Navarro, A., Otaegui, D., Olascoaga, J., Blanco, Y., Urcelay, E., & Matesanz, F.
Affiliations
  • Consejo Superior de Investigaciones Científicas (ES)
  • Department of Cell Biology and Immunology Instituto de Parasitología y Biomedicina ‘López Neyra’, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain
  • Hospital Regional Universitario de Málaga (ES)
  • Hospital Clínic de Barcelona (ES)
  • Hospital Universitario Virgen Macarena (ES)
  • Laboratorio de Investigación, Instituto de Neurociencias Clínicas, Hospital Regional Universitario Carlos Haya, Málaga, Spain
  • Departamento de Lenguajes y Sistemas Informáticos, CITIC, Universidad de Granada, Granada, Spain
  • University of the Basque Country (ES)
  • Hospital de Basurto (ES)
  • Servicio de Genética, Hospital de Basurto, Bilbao, Spain
  • Ikerbasque (ES)
  • Hospital Clínico San Carlos (ES)
  • Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
  • Vall d'Hebron Hospital Universitari (ES)
  • Centre d'Esclerosi Múltiple de Catalunya, CEM-Cat, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d´Hebron (HUVH), Barcelona, Spain
  • Institute of Evolutionary Biology (UPF-CSIC), PRBB, Barcelona, Spain
  • Institució Catalana de Recerca i Estudis Avançats (ES)
  • Biogipuzkoa Health Research Institute (ES)
  • Donostiako Unibertsitate Ospitalea (ES)
Corresponding author
  • Alcina, Antonio
  • Matesanz, Fuencisla
ORCID
Venue
Journal of Medical Genetics
Publisher
BMJ
Published
2012-11-17
Volume
50
Issue
1
Pages
25-33
ISSN
  • 0022-2593 (ISSN-L)
  • 1468-6244
DOI
10.1136/jmedgenet-2012-101085
PMC
PMC3538279
OpenAlex
W2155661622
Cited by
69
References
3
Citations by year
2026: 4 · 2025: 5 · 2024: 3 · 2023: 7 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 7 · 2018: 4 · 2017: 6 · 2016: 5 · 2015: 7 · 2014: 2 · 2013: 5
FWCI
3.20
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Journal of Medical Genetics (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (acceptedVersion, other-oa)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion, other-oa)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by-nc)
  • Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, cc-by-nc-nd)
Funders
  • Ministerio de Economía y Competitividad
  • Ikerbasque, Basque Foundation for Science
  • Junta de Andalucía
  • European Regional Development Fund
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
multiple sclerosis, functional variants, enhancer activity, gene expression regulation, expression quantitative trait loci, enhancer-promoter interactions, KIF5A, CYP27B1, linkage disequilibrium
MeSH terms
Chromosome Mapping, Chromosomes, Human, Pair 12, Enhancer Elements, Genetic, Humans, Methyltransferases, Multiple Sclerosis, Transcription, Genetic, 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, Kinesins, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study

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