title: Genome-wide pathway-based association study implicates complement system in the development of Kashin-Beck disease in Han Chinese.
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.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wen
authors.affiliation: 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.
authors.forename: Xiong
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Orthopedics, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Yingang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Sen
authors.initials: S
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Tielin
authors.initials: T
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, P. R. China.
authors.forename: Xiangding
authors.initials: X
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, P. R. China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D001777:Blood Coagulation; D002358:Cartilage, Articular / Q000473:pathology; D002681:China; D003165:Complement System Proteins / Q000276:immunology*; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D057767:Kashin-Beck Disease / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008875:Middle Aged
chemical_list: D003165:Complement System Proteins
keywords: Complement system; Kashin-Beck disease; Microarray; Pathway-based association study