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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

Farias, Fabiana H.G. ; Dahlqvist, Johanna ; Kozyrev, Sergey V. ; Leonard, Dag ; Wilbe, Maria ; Abramov, Sergei N. ; Alexsson, Andrei ; Pielberg, Gerli R. ; Hansson-Hamlin, Helene and Andersson, Göran , et al. (2019) In European Journal of Human Genetics 27(3). p.432-441
Abstract

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... (More)

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.

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European Journal of Human Genetics
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27
issue
3
pages
432 - 441
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Nature Publishing Group
external identifiers
  • pmid:30459414
  • scopus:85057004433
ISSN
1018-4813
DOI
10.1038/s41431-018-0297-x
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English
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yes
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38dd5a12-9a2a-416a-9911-5f27332bf67d
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2018-12-05 11:08:45
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2020-01-16 03:39:42
@article{38dd5a12-9a2a-416a-9911-5f27332bf67d,
  abstract     = {<p>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 &gt; 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 &gt; 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.</p>},
  author       = {Farias, Fabiana H.G. and Dahlqvist, Johanna and Kozyrev, Sergey V. and Leonard, Dag and Wilbe, Maria and Abramov, Sergei N. and Alexsson, Andrei and Pielberg, Gerli R. and Hansson-Hamlin, Helene and Andersson, Göran and Tandre, Karolina and Bengtsson, Anders A. and Sjöwall, Christopher and Svenungsson, Elisabet and Gunnarsson, Iva and Rantapää-Dahlqvist, Solbritt and Syvänen, Ann Christine and Sandling, Johanna K. and Eloranta, Maija Leena and Rönnblom, Lars and Lindblad-Toh, Kerstin},
  issn         = {1018-4813},
  language     = {eng},
  number       = {3},
  pages        = {432--441},
  publisher    = {Nature Publishing Group},
  series       = {European Journal of Human Genetics},
  title        = {A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts},
  url          = {http://dx.doi.org/10.1038/s41431-018-0297-x},
  doi          = {10.1038/s41431-018-0297-x},
  volume       = {27},
  year         = {2019},
}