Genome-wide pathway-based association study implicates complement system in the development of Kashin-Beck disease in Han Chinese.
Genome-wide pathway-based association study implicates complement system in the development of Kashin-Beck disease in Han Chinese.
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DOI：
10.1016/j.bone.2014.09.025
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发表时间：
2015-02
期刊：
影响因子：
4.1
通讯作者：
Feng Zhang;Y. Wen;Xiong Guo;Yin-gang Zhang;Sen Wang;Tielin Yang;Hui Shen;Xiangding Chen
中科院分区：
文献类型：
--
作者：
Feng Zhang;Y. Wen;Xiong Guo;Yin-gang Zhang;Sen Wang;Tielin Yang;Hui Shen;Xiangding Chen
大骨节病是一种慢性骨软骨病。大骨节病的发病机制尚不清楚。为了明确大骨节病的相关生物学通路，我们对2743名中国汉族成年人进行了全基因组通路关联研究（GWPAS）。一个改进的基因集富集算法被用来检测大骨节病和963个生物学途径之间的关联。通过对KBD患者血清补体水平的检测和基因表达分析，探讨了KBD发病机制。我们发现，补体和凝血级联（CACC）途径与大骨节病显著相关（P值= 3.09 × 10− 5，错误发现率= 0.042）。在CACC通路中，在KNG1基因的rs1656966（P值= 1.97 × 10− 4）处观察到最显著的关联。进一步的重复研究发现，在1026名受试者的独立验证样本中，rs1656966（P值= 0.037）与大骨节病显著相关。基因表达分析发现，CACC通路的CFD（ratio = 3.39 ± 2.68）、A2M（ratio = 3.67 ± 5.63）、C5（ratio = 2.65 ± 2.52）和CD46（ratio = 2.29 ± 137）基因在大骨节病关节软骨中表达上调。大骨节病患者血清补体C5水平显著高于健康对照组（P值= 0.038）。本研究首次提示补体系统相关的CACC通路参与了大骨节病的发生发展。
Kashin-Beck disease (KBD) is a chronic osteochondropathy. The pathogenesis of KBD remains unknown. To identify relevant biological pathways for KBD, we conducted a genome-wide pathway-based association study (GWPAS) following by replication analysis, totally using 2743 Chinese Han adults. A modified gene set enrichment algorithm was used to detect association between KBD and 963 biological pathways. Cartilage gene expression analysis and serum complement measurement were performed to evaluate the functional relevance of identified pathway with KBD. We found that the Complement and Coagulation Cascades (CACC) pathway was significantly associated with KBD (Pvalue = 3.09 × 10− 5, false-discovery rate = 0.042). Within the CACC pathway, the most significant association was observed at rs1656966 (Pvalue = 1.97 × 10− 4) of KNG1 gene. Further replication study observed that rs1656966 (Pvalue = 0.037) was significantly associated with KBD in an independent validation sample of 1026 subjects. Gene expression analysis observed that CFD (ratio = 3.39 ± 2.68), A2M (ratio = 3.67 ± 5.63), C5 (ratio = 2.65 ± 2.52) and CD46 (ratio = 2.29 ± 137) genes of the CACC pathway were up-regulated in KBD articular cartilage compared to healthy articular cartilage. The serum level of complement C5 in KBD patients were significantly higher than that in healthy controls (Pvalue = 0.038). Our study is the first to suggest that complement system-related CACC pathway contributed to the development of KBD.