A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts

Research output: Contribution to journalArticle


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.


  • Fabiana H.G. Farias
  • Johanna Dahlqvist
  • Sergey V. Kozyrev
  • Dag Leonard
  • Maria Wilbe
  • Sergei N. Abramov
  • Andrei Alexsson
  • Gerli R. Pielberg
  • Helene Hansson-Hamlin
  • Göran Andersson
  • Karolina Tandre
  • Christopher Sjöwall
  • Elisabet Svenungsson
  • Iva Gunnarsson
  • Solbritt Rantapää-Dahlqvist
  • Ann Christine Syvänen
  • Johanna K. Sandling
  • Maija Leena Eloranta
  • Lars Rönnblom
  • Kerstin Lindblad-Toh
External organisations
  • Uppsala University
  • Washington University in St. Louis
  • Kazan Federal University
  • Linköping University
  • Karolinska University Hospital
  • Umeå University
  • Broad Institute
  • Swedish University of Agricultural Sciences
  • Skåne University Hospital
  • Karolinska Institutet
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Rheumatology and Autoimmunity
  • Medical Genetics
Original languageEnglish
Pages (from-to)432-441
JournalEuropean Journal of Human Genetics
Issue number3
Early online date2018 Nov 20
Publication statusPublished - 2019
Publication categoryResearch