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Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus

Sigurdsson, Snaevar; Goering, Harald H H; Kristjansdottir, Gudlaug; Milani, Lili; Nordmark, Gunnel; Sandling, Johanna K; Eloranta, Maija-Leena; Feng, Di; Sangster-Guity, Niquiche and Gunnarsson, Iva, et al. (2008) In Human Molecular Genetics 17(6). p.872-881
Abstract
We analyzed a comprehensive set of single-nucleotide polymorphisms (SNPs) and length polymorphisms in the interferon regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. We found 16 SNPs and two length polymorphisms that display association with SLE (P < 0.0005, OR > 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3' of IRF5, and a novel CGGGG insertion-deletion... (More)
We analyzed a comprehensive set of single-nucleotide polymorphisms (SNPs) and length polymorphisms in the interferon regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. We found 16 SNPs and two length polymorphisms that display association with SLE (P < 0.0005, OR > 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3' of IRF5, and a novel CGGGG insertion-deletion (indel) polymorphism located 64 bp upstream of the first untranslated exon (exon 1A) of IRF5. The CGGGG indel explains the association signal from multiple SNPs in the IRF5 gene, including rs2004640, rs10954213 and rs729302 previously considered to be causal variants in SLE. The CGGGG indel contains three or four repeats of the sequence CGGGG with the longer allele containing an additional SP1 binding site as the risk allele for SLE. Using electrophoretic mobility shift assays we show increased binding of protein to the risk allele of the CGGGG indel and using a minigene reporter assay we show increased expression of IRF5 mRNA from a promoter containing this allele. Increased expression of IRF5 protein was observed in peripheral blood mononuclear cells from SLE patients carrying the risk allele of the CGGGG indel. We have found that the same IRF5 allele also confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases. (Less)
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Contribution to journal
publication status
published
subject
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Human Molecular Genetics
volume
17
issue
6
pages
872 - 881
publisher
Oxford University Press
external identifiers
  • wos:000253832700011
  • scopus:40649121122
ISSN
0964-6906
DOI
10.1093/hmg/ddm359
language
English
LU publication?
yes
id
b4d9676e-4c35-4a34-8778-52432f3afd22 (old id 1186087)
date added to LUP
2008-09-03 12:31:58
date last changed
2017-08-27 03:55:02
@article{b4d9676e-4c35-4a34-8778-52432f3afd22,
  abstract     = {We analyzed a comprehensive set of single-nucleotide polymorphisms (SNPs) and length polymorphisms in the interferon regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. We found 16 SNPs and two length polymorphisms that display association with SLE (P &lt; 0.0005, OR &gt; 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3' of IRF5, and a novel CGGGG insertion-deletion (indel) polymorphism located 64 bp upstream of the first untranslated exon (exon 1A) of IRF5. The CGGGG indel explains the association signal from multiple SNPs in the IRF5 gene, including rs2004640, rs10954213 and rs729302 previously considered to be causal variants in SLE. The CGGGG indel contains three or four repeats of the sequence CGGGG with the longer allele containing an additional SP1 binding site as the risk allele for SLE. Using electrophoretic mobility shift assays we show increased binding of protein to the risk allele of the CGGGG indel and using a minigene reporter assay we show increased expression of IRF5 mRNA from a promoter containing this allele. Increased expression of IRF5 protein was observed in peripheral blood mononuclear cells from SLE patients carrying the risk allele of the CGGGG indel. We have found that the same IRF5 allele also confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases.},
  author       = {Sigurdsson, Snaevar and Goering, Harald H H and Kristjansdottir, Gudlaug and Milani, Lili and Nordmark, Gunnel and Sandling, Johanna K and Eloranta, Maija-Leena and Feng, Di and Sangster-Guity, Niquiche and Gunnarsson, Iva and Svenungsson, Elisabet and Sturfelt, Gunnar and Jönsen, Andreas and Truedsson, Lennart and Barnes, Betsy J and Alm, Gunnar and Roennblom, Lars and Syvaenen, Ann-Christine},
  issn         = {0964-6906},
  language     = {eng},
  number       = {6},
  pages        = {872--881},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus},
  url          = {http://dx.doi.org/10.1093/hmg/ddm359},
  volume       = {17},
  year         = {2008},
}