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Genome-wide pathway-based association study implicates complement system in the development of Kashin-Beck disease in Han Chinese.
Bone. 2015 Feb; 71:36-41.BONE

Abstract

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 (P value=3.09×10(-5), false-discovery rate=0.042). Within the CACC pathway, the most significant association was observed at rs1656966 (P value=1.97×10(-4)) of KNG1 gene. Further replication study observed that rs1656966 (P value=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 (P value=0.038). Our study is the first to suggest that complement system-related CACC pathway contributed to the development of KBD.

Authors+Show Affiliations

Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace Elements and Endemic Diseases of Ministry of Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, P. R. China.Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace Elements and Endemic Diseases of Ministry of Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, P. R. China.Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace Elements and Endemic Diseases of Ministry of Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, P. R. China. Electronic address: guox@mail.xjtu.edu.cn.Department of Orthopedics, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.Key Laboratory of Environment and Gene Related Diseases of Ministry Education, Key Laboratory of Trace Elements and Endemic Diseases of Ministry of Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, P. R. China.Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P.R. China.Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA; Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA, USA.Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, P. R. China.Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, P. R. China.Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA; Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA, USA.Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA; Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25305519

Citation

Zhang, Feng, et al. "Genome-wide Pathway-based Association Study Implicates Complement System in the Development of Kashin-Beck Disease in Han Chinese." Bone, vol. 71, 2015, pp. 36-41.
Zhang F, Wen Y, Guo X, et al. Genome-wide pathway-based association study implicates complement system in the development of Kashin-Beck disease in Han Chinese. Bone. 2015;71:36-41.
Zhang, F., Wen, Y., Guo, X., Zhang, Y., Wang, S., Yang, T., Shen, H., Chen, X., Tan, L., Tian, Q., & Deng, H. W. (2015). Genome-wide pathway-based association study implicates complement system in the development of Kashin-Beck disease in Han Chinese. Bone, 71, 36-41. https://doi.org/10.1016/j.bone.2014.09.025
Zhang F, et al. Genome-wide Pathway-based Association Study Implicates Complement System in the Development of Kashin-Beck Disease in Han Chinese. Bone. 2015;71:36-41. PubMed PMID: 25305519.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genome-wide pathway-based association study implicates complement system in the development of Kashin-Beck disease in Han Chinese. AU - Zhang,Feng, AU - Wen,Yan, AU - Guo,Xiong, AU - Zhang,Yingang, AU - Wang,Sen, AU - Yang,Tielin, AU - Shen,Hui, AU - Chen,Xiangding, AU - Tan,Lijun, AU - Tian,Qing, AU - Deng,Hong-Wen, Y1 - 2014/10/16/ PY - 2014/03/14/received PY - 2014/09/06/revised PY - 2014/09/30/accepted PY - 2014/10/12/entrez PY - 2014/10/12/pubmed PY - 2015/8/22/medline KW - Complement system KW - Kashin-Beck disease KW - Microarray KW - Pathway-based association study SP - 36 EP - 41 JF - Bone JO - Bone VL - 71 N2 - 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 (P value=3.09×10(-5), false-discovery rate=0.042). Within the CACC pathway, the most significant association was observed at rs1656966 (P value=1.97×10(-4)) of KNG1 gene. Further replication study observed that rs1656966 (P value=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 (P value=0.038). Our study is the first to suggest that complement system-related CACC pathway contributed to the development of KBD. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/25305519/Genome_wide_pathway_based_association_study_implicates_complement_system_in_the_development_of_Kashin_Beck_disease_in_Han_Chinese_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(14)00364-0 DB - PRIME DP - Unbound Medicine ER -