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Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis

de Rooy, Diederik P. C.; Yeremenko, Nataliya G.; Wilson, Anthony Gerard; Knevel, Rachel; Lindqvist, Elisabet LU ; Saxne, Tore LU ; Krabben, Annemarie; Leijsma, Martha K.; Daha, Nina A. and Tsonaka, S., et al. (2013) In Annals of the Rheumatic Diseases 72(5). p.769-775
Abstract
Background Progression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/beta-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway. Objective To study variants in the genes encoding these proteins in relation to progression of joint destruction. Methods 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from... (More)
Background Progression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/beta-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway. Objective To study variants in the genes encoding these proteins in relation to progression of joint destruction. Methods 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from Leiden on single nucleotide polymorphisms (SNPs) tagging Dkk-1, Sost, Kremen-1 and LRP-5. SNPs significantly associating with joint damage progression were subsequently genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). Data were summarised in meta-analyses. Serum levels of functional Dkk-1 and sclerostin were measured and studied in relation to genotypes. Results In the first cohort, six Dkk-1, three Sost, one Kremen-1 and 10 LRP-5 SNPs were significantly associated with radiological progression of joint destruction. Three Dkk-1 SNPs were associated significantly with progression of joint damage in the meta-analysis, also after correction for multiple testing (rs1896368, rs1896367 and rs1528873). Two Sost SNPs tended to significance (rs4792909 and rs6503475, p=0.07 after false discovery rate correction). Gene-gene interactions between SNPs on Dkk-1 and Sost were seen. Serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 (p=0.02). Conclusions Patients with RA carrying risk alleles of genetic variants in Dkk-1 have higher serum levels of functional Dkk-1 and more progressive joint destruction over time. (Less)
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Annals of the Rheumatic Diseases
volume
72
issue
5
pages
769 - 775
publisher
British Medical Association
external identifiers
  • wos:000317050400032
  • scopus:84875920469
ISSN
1468-2060
DOI
10.1136/annrheumdis-2012-202184
language
English
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yes
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6ca28c3f-e3a0-4808-91db-532d435f35e4 (old id 3748272)
date added to LUP
2013-06-03 08:35:22
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2019-05-21 02:11:35
@article{6ca28c3f-e3a0-4808-91db-532d435f35e4,
  abstract     = {Background Progression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/beta-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway. Objective To study variants in the genes encoding these proteins in relation to progression of joint destruction. Methods 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from Leiden on single nucleotide polymorphisms (SNPs) tagging Dkk-1, Sost, Kremen-1 and LRP-5. SNPs significantly associating with joint damage progression were subsequently genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). Data were summarised in meta-analyses. Serum levels of functional Dkk-1 and sclerostin were measured and studied in relation to genotypes. Results In the first cohort, six Dkk-1, three Sost, one Kremen-1 and 10 LRP-5 SNPs were significantly associated with radiological progression of joint destruction. Three Dkk-1 SNPs were associated significantly with progression of joint damage in the meta-analysis, also after correction for multiple testing (rs1896368, rs1896367 and rs1528873). Two Sost SNPs tended to significance (rs4792909 and rs6503475, p=0.07 after false discovery rate correction). Gene-gene interactions between SNPs on Dkk-1 and Sost were seen. Serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 (p=0.02). Conclusions Patients with RA carrying risk alleles of genetic variants in Dkk-1 have higher serum levels of functional Dkk-1 and more progressive joint destruction over time.},
  author       = {de Rooy, Diederik P. C. and Yeremenko, Nataliya G. and Wilson, Anthony Gerard and Knevel, Rachel and Lindqvist, Elisabet and Saxne, Tore and Krabben, Annemarie and Leijsma, Martha K. and Daha, Nina A. and Tsonaka, S. and Zhernakova, A. and Houwing-Duistermaat, J. J. and Huizinga, Tom W. J. and Toes, Rene E. M. and Baeten, Dominique L. P. and Brouwer, E. and van der Helm-van Mil, Annette H. M.},
  issn         = {1468-2060},
  language     = {eng},
  number       = {5},
  pages        = {769--775},
  publisher    = {British Medical Association},
  series       = {Annals of the Rheumatic Diseases},
  title        = {Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis},
  url          = {http://dx.doi.org/10.1136/annrheumdis-2012-202184},
  volume       = {72},
  year         = {2013},
}