Prakash J, Williams F M K, Trofimov S, Surdulescu G, Spector T, Livshits G
Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
Department of Twin Research and Genetic Epidemiology, King's College London, Strand, London, UK.
Osteoporos Int. 2016 Jun;27(6):2065-75. doi: 10.1007/s00198-016-3486-x. Epub 2016 Jan 13.
Dickkopf-related protein 1 (DKK1) is a major inhibitor of Wnt signalling pathway but also plays an important role in bone formation. Its circulating levels appear to correlate significantly with plasma levels of inflammatory factors, fractalkine and IL-6. This study, using a large sample of UK twins, showed that the variation of each of these factors and correlation between them was explained by the genetic factors, and indicated possible association with DKK1 gene variants.
DKK1 is involved in the development of several inflammatory conditions related to bone and joint degradation. Our objectives were to explore the genetic contribution (heritability) to circulating DKK1 variation and its correlation with other inflammatory cytokines, interleukin 6 (IL-6) and fractalkine, and to test whether the DKK1 heritability could be attributable to single nucleotide polymorphisms (SNPs) mapped to DKK1, IL-6 and FRCT genes.
The study included a large community-based sample of 4939 women drawn from the general UK population. Plasma samples were analysed for circulating levels of DKK1, IL-6 and fractalkine (FRCT); 65 SNPs of DKK1, IL-6 and FRCT candidate genes, with MAF >0.1, were examined. We applied variance component analysis to evaluate contribution of putative genetic (including above SNPs) and environmental factors to variation of DKK1, and its correlation with IL-6 and FRCT.
Putative genetic factors explained 42.2 ± 2 % of the total variation of circulating DKK1 levels, and were also significant for fractalkine and IL-6 variations. Most importantly, we report significant phenotypic (0.208 ± 0.006-0.459 ± 0.007) and genetic (0.338 ± 0.069-0.617 ± 0.033) correlations between these molecules. We found evidence suggestive of association between the DKK1 and its structural genes variants.
Circulating DKK1 levels correlated significantly with levels of IL-6 and FRCT, known risk factors for several inflammatory processes suggesting a potential role of DKK1 in inflammation and tissue injury. Our results suggest the contribution of genetic factors in inter-individual variation of DKK1 levels in human population. However, further studies are required to determine genetic polymorphisms affecting DKK1 variation and its correlation with IL-6 and FRCT.
Dickkopf相关蛋白1（DKK1）是Wnt信号通路的主要抑制剂，但在骨形成中也发挥重要作用。其循环水平似乎与炎症因子、趋化因子和白细胞介素-6（IL-6）的血浆水平显著相关。本研究使用大量英国双胞胎样本，表明这些因素各自的变异及其之间的相关性可由遗传因素解释，并提示可能与DKK1基因变异有关。
DKK1参与了几种与骨和关节退变相关的炎症性疾病的发展。我们的目标是探讨循环DKK1变异的遗传贡献（遗传度）及其与其他炎症细胞因子、白细胞介素-6（IL-6）和趋化因子的相关性，并测试DKK1的遗传度是否可归因于定位到DKK1、IL-6和FRCT基因的单核苷酸多态性（SNP）。
该研究纳入了来自英国普通人群的4939名女性的大型社区样本。分析血浆样本中DKK1、IL-6和趋化因子（FRCT）的循环水平；检测了DKK1、IL-6和FRCT候选基因的65个MAF>0.1的SNP。我们应用方差成分分析来评估假定的遗传因素（包括上述SNP）和环境因素对DKK1变异的贡献及其与IL-6和FRCT的相关性。
假定的遗传因素解释了循环DKK1水平总变异的42.2±2%，对趋化因子和IL-6变异也有显著影响。最重要的是，我们报告了这些分子之间显著的表型相关性（0.208±0.006 - 0.459±0.007）和遗传相关性（0.338±0.069 - 0.617±0.033）。我们发现了DKK1与其结构基因变异之间存在关联的证据。
循环DKK1水平与IL-6和FRCT水平显著相关，IL-6和FRCT是几种炎症过程的已知危险因素，这表明DKK1在炎症和组织损伤中可能发挥作用。我们的结果表明遗传因素对人群中DKK1水平个体间变异有贡献。然而，需要进一步研究来确定影响DKK1变异及其与IL-6和FRCT相关性的基因多态性。
