Trans-omics pathway analysis suggests that eQTLs contribute to chondrocyte apoptosis of Kashin–Beck disease through regulating apoptosis pathway expression
Introduction
Kashin–Beck disease (KBD) is a chronic osteochondropathy (Moreno-Reyes et al., 1998, Stone, 2009), affecting more than 2.5 million people in China (Duan et al., 2010). The major clinical features of KBD include joint pain, joint deformities, continually aggravated osteoarthritis and growth retardation (Downey et al., 2009, Lu et al., 2011). Based on the severity of joint lesions, KBD is clinically classified into three grades (Duan et al., 2010). Comparing with grade I KBD patients, grade II and III KBD patients have serious multi-joint deformities and distinctive growth retardation, such as shortened phalanges and humeri, short stature and other features caused by impaired epiphyseal growth and ossification.
Excessive chondrocyte apoptosis is one of the primary pathological changes of KBD (Wang et al., 2006, Liu et al., 2010a). The molecular signaling pathways underlying KBD excessive chondrocyte apoptosis remain unclear, leading to a lack of effective medical interventions now. For instance, the prevalence of KBD in children reached 50.43% and 32.93% at KBD prevalent areas of Tibet and Shaanxi province of China (Wang et al., 2008). Recent studies demonstrated the involvement of genetic factors in the development of KBD (Lu et al., 2011, Xiong et al., 2010, Shi et al., 2011). Microarray studies of KBD observed significant abnormal expression of apoptosis-related genes, gene ontology and pathways in KBD articular cartilage (Wang et al., 2009, Zhang et al., 2011). It is interesting to clarify whether expression quantitative trait loci (eQTLs) contribute to excessive chondrocyte apoptosis of KBD through regulating the expression of apoptosis-related pathways.
Inspired by genome-wide pathway association analysis of complex diseases (Wang et al., 2007, Liu et al., 2010b), we conducted a genome-wide eQTL-based pathway association analysis of KBD in this study. The KBD-associated pathways were compared with abnormally expressed pathways in KBD articular cartilage, identified by microarray study of KBD.
Section snippets
eQTL-based pathway association analysis of KBD
To ensure the statistical power, extreme phenotype sampling was used here. 90 grade II or III KBD patients with extreme KBD phenotypes (including serious multiple-joint deformities and growth retardation) were recruited from Xi'an city of China (Table 1, Fig. 1). 1627 healthy subjects were collected from Xi'an city and Changsha city of China. All of study subjects underwent careful clinical and radiological examinations. KBD was diagnosed according to the KBD clinical diagnosis criteria of
Results
eQTL-based pathway association analysis identified 6 KBD-associated pathways with P values < 0.01 (Fig. 2), mainly involved in apoptosis, peroxisome and interleukin-1A mediated inflammation. Comparing with microarray pathway expression analysis results of KBD articular cartilage, we identified 4 eQTLs pathways, which were not only significantly associated with KBD, but also abnormally expressed in KBD articular cartilage, including REACTOME_INTRINSIC_PATHWAY_FOR_APOPTOSIS (P = 0.008), MAHAJAN
Discussion
Excessive chondrocyte apoptosis is one of major pathological changes of KBD (Wang et al., 2006, Wu et al., 2014). But little is known about the molecular mechanism underlying KBD excessive chondrocyte apoptosis. Wang et al. found that the percentage of apoptotic chondrocytes (33.60%) in KBD articular cartilage was much larger than that (1.33%) in healthy articular cartilage (Wang et al., 2006). Our result is consistent with that of previous study, supporting the key role of apoptosis in KBD
Acknowledgments
The study was supported by the National Natural Scientific Fund of China (81102086), the Science and Technology Research and Development Program of in Shaanxi Province of China (2013KJXX-51) and the Fundamental Research Funds for the Central Universities.
References (28)
- et al.
Oxygen and reactive oxygen species in cartilage degradation: friends or foes?
Osteoarthr. Cartil.
(2005) - et al.
Mitochondrial function is altered in articular chondrocytes of an endemic osteoarthritis, Kashin–Beck disease
Osteoarthr. Cartil.
(2010) - et al.
Kashin–Beck disease and Sayiwak disease in China: prevalence and a comparison of the clinical manifestations, familial aggregation, and heritability
Bone
(2011) - et al.
PLINK: a tool set for whole-genome association and population-based linkage analyses
Am. J. Hum. Genet.
(2007) - et al.
Evidence linking chondrocyte lipid peroxidation to cartilage matrix protein degradation. Possible role in cartilage aging and the pathogenesis of osteoarthritis
J. Biol. Chem.
(2000) - et al.
Hypoxia potentiates nitric oxide-mediated apoptosis in endothelial cells via peroxynitrite-induced activation of mitochondria-dependent and -independent pathways
J. Biol. Chem.
(2004) - et al.
Pathway-based approaches for analysis of genomewide association studies
Am. J. Hum. Genet.
(2007) - et al.
Comparative analysis of gene expression profiles between the normal human cartilage and the one with endemic osteoarthritis
Osteoarthr. Cartil.
(2009) - et al.
Oxidative stress and status of antioxidant enzymes in children with Kashin–Beck disease
Osteoarthr. Cartil.
(2013) - et al.
Expression profiles of genes involved in apoptosis and selenium metabolism in articular cartilage of patients with Kashin–Beck osteoarthritis
Gene
(2014)
Association study between polymorphisms in selenoprotein genes and susceptibility to Kashin–Beck disease
Osteoarthr. Cartil.
Nitric oxide-mediated chondrocyte cell death requires the generation of additional reactive oxygen species
Arthritis Rheum.
Osteo-chondroprogenitor-specific deletion of the selenocysteine tRNA gene, Trsp, leads to chondronecrosis and abnormal skeletal development: a putative model for Kashin–Beck disease
PLoS Genet.
Comparative analysis of gene expression profiles between primary knee osteoarthritis and an osteoarthritis endemic to Northwestern China, Kashin–Beck disease
Arthritis Rheum.
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The two authors contributed equally to this work.