Department of Rheumatology, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands.
Ann Rheum Dis. 2013 May;72(5):769-75. doi: 10.1136/annrheumdis-2012-202184. Epub 2012 Oct 5.
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.
To study variants in the genes encoding these proteins in relation to progression of joint destruction.
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.
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).
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.
类风湿关节炎（RA）的关节破坏进展在一定程度上是可遗传的；对遗传因素的了解可能会增加我们对关节破坏机制的理解。Wnt/β-连环蛋白通路的活性影响成骨细胞分化。Dickkopf-1（DKK-1）和骨硬化蛋白（SOST）是负调节剂，脂蛋白受体相关蛋白-5（LRP-5）和 Kremen-1 是参与该通路的跨膜受体。
研究编码这些蛋白的基因中的变异与关节破坏进展的关系。
对来自四个队列的 1418 例 RA 患者的 4885 组手部和足部 X 射线进行了研究。对来自莱顿的 600 例 RA 患者进行了单核苷酸多态性（SNP）标记 DKK-1、SOST、Kremen-1 和 LRP-5 的探索性分析。与关节损伤进展显著相关的 SNP 随后在来自格罗宁根（NL）、谢菲尔德（英国）和隆德（瑞典）的队列中进行了基因分型。数据在荟萃分析中进行了总结。测量了功能性 DKK-1 和骨硬化蛋白的血清水平，并研究了与基因型的关系。
在第一队列中，有 6 个 DKK-1、3 个 SOST、1 个 Kremen-1 和 10 个 LRP-5 SNP 与关节破坏的放射学进展显著相关。在荟萃分析中，三个 DKK-1 SNP 与关节损伤的进展显著相关，即使在经过多次测试校正后也是如此（rs1896368、rs1896367 和 rs1528873）。两个 SOST SNP 也有显著趋势（rs4792909 和 rs6503475，经虚假发现率校正后为 p=0.07）。在 DKK-1 和 SOST 的 SNP 之间观察到基因-基因相互作用。rs1896368 中的基因型与血清 DKK-1 水平显著相关（p=0.02）。
携带 DKK-1 遗传变异风险等位基因的 RA 患者具有更高水平的功能性 DKK-1，且随时间推移关节破坏进展更为明显。
