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A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab. (Rheumatology)
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2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, p. 432-441Article in journal (Refereed) Published
Abstract [en]

Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

Place, publisher, year, edition, pages
2019. Vol. 27, p. 432-441
National Category
Medical Genetics
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-368313DOI: 10.1038/s41431-018-0297-xISI: 000458626500013PubMedID: 30459414OAI: oai:DiVA.org:uu-368313DiVA, id: diva2:1267818
Funder
Swedish Research CouncilSwedish Research Council FormasSwedish Rheumatism AssociationKnut and Alice Wallenberg Foundation
Note

These authors contributed equally: Johanna Dahlqvist, Sergey V. Kozyrev, Dag Leonard, Maria Wilbe

Available from: 2018-12-04 Created: 2018-12-04 Last updated: 2019-03-11Bibliographically approved

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Farias, Fabiana H. G.Dahlqvist, JohannaKozyrev, Sergey V.Leonard, DagWilbe, MariaAbramov, SergeiAlexsson, AndreiPielberg, GerliTandre, KarolinaSyvänen, Ann-ChristineSandling, Johanna K.Eloranta, Maija-LeenaRönnblom, LarsLindblad-Toh, Kerstin

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Farias, Fabiana H. G.Dahlqvist, JohannaKozyrev, Sergey V.Leonard, DagWilbe, MariaAbramov, SergeiAlexsson, AndreiPielberg, GerliTandre, KarolinaSyvänen, Ann-ChristineSandling, Johanna K.Eloranta, Maija-LeenaRönnblom, LarsLindblad-Toh, Kerstin
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Department of Medical Biochemistry and MicrobiologyScience for Life Laboratory, SciLifeLabRheumatologyMolecular Medicine
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European Journal of Human Genetics
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