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Genetic association, mRNA and protein expression analysis identify ATG4C as a susceptibility gene for Kashin-Beck disease.
Osteoarthritis Cartilage. 2017 02; 25(2):281-286.OC

Abstract

OBJECTIVE

Recent study observed defective autophagy in chondrocytes with Kashin-Beck Disease (KBD). To clarify the potential role of autophagy-related ATG4C gene in the development of KBD, we conducted an integrative analysis of genetic association, messenger ribonucleic acid (mRNA) and protein expression of ATG4C in KBD patients.

METHODS

1026 subjects (559 KBD patients and 467 healthy cases) were enrolled in discovery association study. Four single nucleotide polymorphisms (SNPs) of ATG4C gene (rs11208030, rs4409690, rs12097658 and rs6587988) were genotyped by Sequenom MassARRAY platform. Association analysis was conducted by PLINK software. The significant SNPs of ATG4C were replicated using an independent sample of 899 subjects (including 90 KBD patients and 809 healthy controls). Ungenotyped SNPs in ATG4C gene were imputed by IMPUTE 2.0. Knee cartilage specimens were collected from five KBD patients and five healthy subjects. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were performed to compare the mRNA and protein expression levels of ATG4C between KBD cartilage and control cartilage.

RESULTS

We observed significant association between KBD and rs11208030 (P value = 0.003), rs4409690 (P value = 0.004), rs12097658 (P value = 0.003) and rs6587988 (P value = 0.003) in both discovery and replication samples. The mRNA expression level of ATG4C (ratio = 0.168, P value = 0.007) in KBD chondrocytes was significantly lower than that in normal chondrocytes. Western blot (P value < 0.001) further confirmed the reduced expression of ATG4C protein in both KBD cartilage and chondrocytes.

CONCLUSION

Our results strongly suggest that ATG4C was a novel autophagy-related susceptibility gene of KBD.

Authors+Show Affiliations

Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, PR China.Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, PR China.Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, PR 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, PR 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, PR 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, PR 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.Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, PR China. Electronic address: fzhxjtu@mail.xjtu.edu.cn.

Pub Type(s)

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

Language

eng

PubMed ID

27742532

Citation

Wu, C, et al. "Genetic Association, mRNA and Protein Expression Analysis Identify ATG4C as a Susceptibility Gene for Kashin-Beck Disease." Osteoarthritis and Cartilage, vol. 25, no. 2, 2017, pp. 281-286.
Wu C, Wen Y, Guo X, et al. Genetic association, mRNA and protein expression analysis identify ATG4C as a susceptibility gene for Kashin-Beck disease. Osteoarthr Cartil. 2017;25(2):281-286.
Wu, C., Wen, Y., Guo, X., Yang, T., Shen, H., Chen, X., Tian, Q., Tan, L., Deng, H. W., & Zhang, F. (2017). Genetic association, mRNA and protein expression analysis identify ATG4C as a susceptibility gene for Kashin-Beck disease. Osteoarthritis and Cartilage, 25(2), 281-286. https://doi.org/10.1016/j.joca.2016.09.019
Wu C, et al. Genetic Association, mRNA and Protein Expression Analysis Identify ATG4C as a Susceptibility Gene for Kashin-Beck Disease. Osteoarthr Cartil. 2017;25(2):281-286. PubMed PMID: 27742532.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetic association, mRNA and protein expression analysis identify ATG4C as a susceptibility gene for Kashin-Beck disease. AU - Wu,C, AU - Wen,Y, AU - Guo,X, AU - Yang,T, AU - Shen,H, AU - Chen,X, AU - Tian,Q, AU - Tan,L, AU - Deng,H-W, AU - Zhang,F, Y1 - 2016/10/11/ PY - 2016/02/20/received PY - 2016/08/06/revised PY - 2016/09/24/accepted PY - 2016/10/30/pubmed PY - 2018/2/21/medline PY - 2016/10/16/entrez KW - ATG4C KW - Autophagy KW - Cartilage KW - Kashin–Beck disease SP - 281 EP - 286 JF - Osteoarthritis and cartilage JO - Osteoarthr. Cartil. VL - 25 IS - 2 N2 - OBJECTIVE: Recent study observed defective autophagy in chondrocytes with Kashin-Beck Disease (KBD). To clarify the potential role of autophagy-related ATG4C gene in the development of KBD, we conducted an integrative analysis of genetic association, messenger ribonucleic acid (mRNA) and protein expression of ATG4C in KBD patients. METHODS: 1026 subjects (559 KBD patients and 467 healthy cases) were enrolled in discovery association study. Four single nucleotide polymorphisms (SNPs) of ATG4C gene (rs11208030, rs4409690, rs12097658 and rs6587988) were genotyped by Sequenom MassARRAY platform. Association analysis was conducted by PLINK software. The significant SNPs of ATG4C were replicated using an independent sample of 899 subjects (including 90 KBD patients and 809 healthy controls). Ungenotyped SNPs in ATG4C gene were imputed by IMPUTE 2.0. Knee cartilage specimens were collected from five KBD patients and five healthy subjects. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were performed to compare the mRNA and protein expression levels of ATG4C between KBD cartilage and control cartilage. RESULTS: We observed significant association between KBD and rs11208030 (P value = 0.003), rs4409690 (P value = 0.004), rs12097658 (P value = 0.003) and rs6587988 (P value = 0.003) in both discovery and replication samples. The mRNA expression level of ATG4C (ratio = 0.168, P value = 0.007) in KBD chondrocytes was significantly lower than that in normal chondrocytes. Western blot (P value < 0.001) further confirmed the reduced expression of ATG4C protein in both KBD cartilage and chondrocytes. CONCLUSION: Our results strongly suggest that ATG4C was a novel autophagy-related susceptibility gene of KBD. SN - 1522-9653 UR - https://www.unboundmedicine.com/medline/citation/27742532/Genetic_association_mRNA_and_protein_expression_analysis_identify_ATG4C_as_a_susceptibility_gene_for_Kashin_Beck_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1063-4584(16)30303-X DB - PRIME DP - Unbound Medicine ER -