Whole-exome sequencing for the identification of susceptibility genes of Kashin-Beck disease

Zhenxing Yang; Yu Xu; Hongrong Luo; Xiaohong Ma; Qiang Wang; Yingcheng Wang; Wei Deng; Tao Jiang; Guangqing Sun; Tingting He; Jingchu Hu; Yingrui Li; Jun Wang; Tao Li; Xun Hu

doi:10.1371/journal.pone.0092298

Whole-exome sequencing for the identification of susceptibility genes of Kashin-Beck disease

PLoS One. 2014 Apr 28;9(4):e92298. doi: 10.1371/journal.pone.0092298. eCollection 2014.

Authors

Zhenxing Yang¹, Yu Xu², Hongrong Luo¹, Xiaohong Ma¹, Qiang Wang¹, Yingcheng Wang¹, Wei Deng¹, Tao Jiang², Guangqing Sun², Tingting He², Jingchu Hu², Yingrui Li², Jun Wang², Tao Li¹, Xun Hu³

Affiliations

¹ Psychiatric Laboratory & Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China.
² BGI-Shenzhen, Shenzhen, Guangdong, P R China.
³ State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China; Biobank Center, West China Hospital, Sichuan University, Chengdu, Sichuan, P R China.

Abstract

Objective: To identify and investigate the susceptibility genes of Kashin-Beck disease (KBD) in Chinese population.

Methods: Whole-exome capturing and sequencing technology was used for the detection of genetic variations in 19 individuals from six families with high incidence of KBD. A total of 44 polymorphisms from 41 genes were genotyped from a total of 144 cases and 144 controls by using MassARRAY under the standard protocol from Sequenom. Association was applied on the data by using PLINK1.07.

Results: In the sequencing stage, each sample showed approximately 70-fold coverage, thus covering more than 99% of the target regions. Among the single nucleotide polymorphisms (SNPs) used in the transmission disequilibrium test, 108 had a p-value of <0.01, whereas 1056 had a p-value of <0.05. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis indicates that these SNPs focus on three major pathways: regulation of actin cytoskeleton, focal adhesion, and metabolic pathways. In the validation stage, single locus effects revealed that two of these polymorphisms (rs7745040 and rs9275295) in the human leukocyte antigen (HLA)-DRB1 gene and one polymorphism (rs9473132) in CD2-associated protein (CD2AP) gene have a significant statistical association with KBD.

Conclusions: HLA-DRB1 and CD2AP gene were identified to be among the susceptibility genes of KBD, thus supporting the role of the autoimmune response in KBD and the possibility of shared etiology between osteoarthritis, rheumatoid arthritis, and KBD.

Publication types

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

MeSH terms

Adolescent
Adult
Aged
Asian People / genetics
Case-Control Studies
Exome / genetics*
Female
Genetic Predisposition to Disease / genetics*
Genotyping Techniques
Humans
Kashin-Beck Disease / genetics*
Male
Middle Aged
Polymorphism, Genetic
Sequence Analysis*
Young Adult

Grants and funding

This work was supported by National Key Technology R & D Program of the Ministry of Science and Technology of China during the 11th Five-Year Plan (2007BA125B02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.