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Exploring the CLEC16A gene reveals a MS-associated variant with correlation to the relative expression of CLEC16A isoforms in thymus

Genes & Immunity volume 12, pages 191–198 (2011)Cite this article

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Abstract

Genomewide association studies have implicated the CLEC16A gene in several autoimmune diseases, including multiple sclerosis (MS) and type 1 diabetes. However, the most associated single-nucleotide polymorphism (SNP) varies, and causal variants are still to be defined. In MS, two SNPs in partial linkage disequilibrium with each other, rs6498169 and rs12708716, have been validated at genomewide significance level. To explore the CLEC16A association in MS in more detail, we genotyped 57 SNPs in 807 Norwegian MS patients and 1027 Norwegian controls. Six highly associated SNPs emerged and were then replicated in two large independent sample sets (Norwegian and British), together including 1153 MS trios, 2308 MS patients and 4044 healthy controls. In combined analyses, SNP rs12708716 gave the strongest association signal in MS (P=5.3 × 10−8, odds ratio 1.18, 95% confidence interval=1.11–1.25), and was found to be superior to the other SNP associations in conditional logistic regression analyses. Expression analysis revealed that rs12708716 genotype was significantly associated with the relative expression levels of two different CLEC16A transcripts in thymus (P=0.004), but not in blood, possibly implying a thymus- or cell-specific splice regulation.

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Acknowledgements

We would like to thank all MS patients and healthy controls for their participation in the study. The study is funded by grants from The South-Eastern Norway Regional Health Authority, the Research Council of Norway; Scientific Advisory Council Ullevål, Oslo University Hospital; Norwegian Foundation for Health and Rehabilitation, the Norwegian Diabetes Association, the Oslo MS Association and the Odd Fellow MS society. We thank all contributors to the collection of samples and clinical data in the Norwegian MS Registry and Biobank. The Norwegian MS Registry and Biobank is supported by the Research Council of Norway, Haukeland University Hospital and Western Norway Regional Health Authority. The Norwegian Bone Marrow Donor Registry, Rikshospitalet, Oslo University Hospital are acknowledged for providing Norwegian controls. Harald Lindberg is thanked for collection of thymus samples. The Centre for interactive genetics; Cigene, Norwegian University of Life Sciences (UMB) AAs is thanked for performing Sequenom analyses. The University of Cambridge and colleagues at the Department of Clinical Neuroscience Addenbrooke's hospital are acknowledged for laboratory assistance and much appreciated collaboration in connection with the research stay of IL Mero in this department. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council Grant G0000934 and the Wellcome Trust Grant 068545/Z/02. This work was also supported by the Medical Research Council (G0700061), the Wellcome Trust (084702/Z/08/Z) and the Cambridge NIHR Biomedical Research Centre.

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  1. B A Lie and H F Harbo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Oslo University Hospital, Oslo, Norway

    I-L Mero, C Smestad, E G Celius & H F Harbo

  2. Institute of Immunology, Oslo University Hospital, Oslo, Norway

    I-L Mero, Å R Lorentzen, H Sæther, H Saeedi, M K Viken & B A Lie

  3. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's, Cambridge, UK

    M Ban, S Sawcer & A Compston

  4. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Å R Lorentzen & H F Harbo

  5. Department and Institute of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway

    B Skinningsrud & D E Undlien

  6. Department of Neurology, The Norwegian multiple sclerosis registry and biobank, Haukeland University Hospital, Bergen, Norway

    J Aarseth & K-M Myhr

  7. Institute of Basal Medical Science, University of Oslo, Oslo, Norway

    S Granum & A Spurkland

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  1. I-L Mero
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Correspondence to I-L Mero.

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Mero, IL., Ban, M., Lorentzen, Å. et al. Exploring the CLEC16A gene reveals a MS-associated variant with correlation to the relative expression of CLEC16A isoforms in thymus. Genes Immun 12, 191–198 (2011). https://doi.org/10.1038/gene.2010.59

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