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.
journal_name
Ann Rheum Disjournal_title
Annals of the rheumatic diseasesauthors
de Rooy DP,Yeremenko NG,Wilson AG,Knevel R,Lindqvist E,Saxne T,Krabben A,Leijsma MK,Daha NA,Tsonaka S,Zhernakova A,Houwing-Duistermaat JJ,Huizinga TW,Toes RE,Baeten DL,Brouwer E,van der Helm-van Mil AHdoi
10.1136/annrheumdis-2012-202184subject
Has Abstractpub_date
2013-05-01 00:00:00pages
769-75issue
5eissn
0003-4967issn
1468-2060pii
annrheumdis-2012-202184journal_volume
72pub_type
杂志文章,meta分析abstract::The cellular events underlying the pathogenesis of psoriatic arthritis (PsA) and psoriasis have not yet been fully elucidated. Nevertheless, some clues to these conditions are beginning to emerge. In particular, a growing body of data supports the role of proinflammatory cytokines, such as tumour necrosis factor (TNF)...
journal_title:Annals of the rheumatic diseases
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:Annals of the rheumatic diseases
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
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pub_type: 临床试验,杂志文章
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pub_type: 临床试验,杂志文章
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journal_title:Annals of the rheumatic diseases
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
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journal_title:Annals of the rheumatic diseases
pub_type: 临床试验,杂志文章
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/ard.61.11.1027
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/annrheumdis-2012-202658
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章,多中心研究
doi:10.1136/annrheumdis-2011-200901
更新日期:2012-07-01 00:00:00
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章,评审
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更新日期:2008-07-01 00:00:00
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2018-12-01 00:00:00