title: Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis.
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/β-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.
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands. d.p.c.de_rooy@lumc.nl
authors.forename: Diederik P C
authors.initials: DP
authors.lastname: de Rooy
authors.forename: Nataliya G
authors.initials: NG
authors.lastname: Yeremenko
authors.forename: Anthony Gerard
authors.initials: AG
authors.lastname: Wilson
authors.forename: Rachel
authors.initials: R
authors.lastname: Knevel
authors.forename: Elisabet
authors.initials: E
authors.lastname: Lindqvist
authors.forename: Tore
authors.initials: T
authors.lastname: Saxne
authors.forename: Annemarie
authors.initials: A
authors.lastname: Krabben
authors.forename: Martha K
authors.initials: MK
authors.lastname: Leijsma
authors.forename: Nina A
authors.initials: NA
authors.lastname: Daha
authors.forename: S
authors.initials: S
authors.lastname: Tsonaka
authors.forename: A
authors.initials: A
authors.lastname: Zhernakova
authors.forename: J J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Dominique L P
authors.initials: DL
authors.lastname: Baeten
authors.forename: E
authors.initials: E
authors.lastname: Brouwer
authors.forename: Annette H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007596:Joints / Q000378:metabolism / Q000473:pathology; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012720:Severity of Illness Index; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; C495270:CTNNB1 protein, human; C501126:DKK1 protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; C486075:KREMEN1 protein, human; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008565:Membrane Proteins; C422903:SOST protein, human; D051176:beta Catenin; D004720:Endonucleases; C406922:CEL I nuclease