Original Full Length ArticleGenome-wide pathway-based association study implicates complement system in the development of Kashin-Beck disease in Han Chinese
Introduction
Kashin-Beck disease (KBD) is a chronic osteochondropathy [1], [2], which first occurs in children (aged 3–12 years). KBD patients suffer from serious joint pain, joint deformities, osteoarthritis and growth retardation [3], [4]. Currently, KBD is mainly prevalent in some areas of China, Russia and North Korea. In China, there are more than 2.5 million KBD patients, and about 30 million people living in KBD prevalent areas are at the risk of KBD [5]. According to the extent of joint lesions, KBD is clinically classified into grade I, II and III KBD [5]. Because the pathogenesis of KBD remains unknown, there is not curative approach for KBD now.
Recent studies found that genetic factors played an important role in the development of KBD. Lv et al. observed significantly familial clustering of KBD patients in a large cohort of 10,823 subjects from 1361 Han Chinese families [4]. The estimated heritability of KBD varied from 35.10% to 41.76% in families [4], [6]. Candidate gene association studies reported several susceptibility genes for KBD [7], [8]. However, the genetic basis of KBD is largely unknown. Genome-wide interrogating the genetic variants affecting the risk of KBD can help to clarify the pathogenesis of KBD. Recently, genome-wide pathway-based association studies (GWPAS) were proposed [9], and successfully applied in the genetic studies of complex diseases [10], [11], [12], [13], [14]. Identifying disease-relevant biological pathways can provide novel insight into the pathogenesis of complex diseases [15]. To the best of our knowledge, no GWPAS of KBD has been reported by now, limiting our efforts to clarify the pathogenesis of KBD.
In this study, a GWPAS of KBD was first conducted in 1717 Chinese Han subjects. The most significant association signal in KBD-associated pathway was then validated in an independent validation sample containing 1026 subjects. Gene expression analysis of KBD articular cartilage and serum complement measurement were also 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. To the best of our knowledge, this study is the first to suggest that the CACC pathway contributed to the development of KBD.
Section snippets
Human subjects
Extreme phenotype sampling was used in the GWPAS [16]. Fifty-nine grade II and 31 grade III unrelated KBD patients with extreme KBD phenotypes were recruited from Linyou county of Xi'an city of Shaanxi province in China. All of the 90 KBD patients presented similar extreme KBD phenotypes, including shortened phalanges, shortened humeri and serious short stature (Fig. 1). A total of 1627 unrelated healthy subjects recruited from Xi'an city and Changsha city in China, were used as control samples
Results
STRUCTURE analysis observed that all GWPAS samples were clustered together as a homogeneous population. EIGENSTRAT analysis obtained a genomic control inflation factorλgc = 1.03, indicating no significant population stratification in our GWPAS samples.
Among the 963 pathways analyzed in this study, the CACC pathway showed the most significant association with KBD (P value = 3.09 × 10− 5) (Fig. S1). After adjusting for multiple testing, the CACC pathway was still significantly associated with KBD (FDR
Discussion
In this study, we conducted a GWPAS of KBD and found that the CACC pathway was significantly associated with KBD. Further replication study validated the most significant association signal observed in the CACC pathway. Gene expression analysis also found that A2M, CFD, C5 and CD46 genes of the CACC pathway were up-regulated in KBD articular cartilage compared to healthy articular cartilage. The serum C5 level of KBD patients appeared to increase compared to healthy controls. Our results
Acknowledgments
The study was supported by National Natural Scientific Fund of China (81102086), Science and Technology Research and Development Program of in Shaanxi Province of China (2013KJXX-51), Natural Science Basic Research Program Shaanxi Province (2011JQ4013).
References (29)
- 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.
Pathway-based approaches for analysis of genomewide association studies
Am J Hum Genet
(2007) - et al.
Pathway analysis of seven common diseases assessed by genome-wide association
Genomics
(2008) - et al.
Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn Disease
Am J Hum Genet
(2009) - et al.
PLINK: a tool set for whole-genome association and population-based linkage analyses
Am J Hum Genet
(2007) - et al.
Comparative analysis of gene expression profiles between the normal human cartilage and the one with endemic osteoarthritis
Osteoarthritis Cartilage
(2009) - et al.
Interactions of the complement system with molecules of extracellular matrix: relevance for joint diseases
Immunobiology
(2012) - et al.
Kashin-Beck osteoarthropathy in rural Tibet in relation to selenium and iodine status
N Engl J Med
(1998) Diseases. A medical mystery in middle China
Science
(2009)- et al.
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
(2009)
Comparative analysis of gene expression profiles between primary knee osteoarthritis and an osteoarthritis endemic to Northwestern China, Kashin-Beck disease
Arthritis Rheum
Heritability estimates and linkage analysis of 23 short tandem repeat loci on chromosomes 2, 11, and 12 in an endemic osteochondropathy in China
Scand J Rheumatol
Genetic variants in the HLA-DRB1 gene are associated with Kashin-Beck disease in the Tibetan population
Arthritis Rheum
Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility
Mol Psychiatry
Cited by (14)
The anaphylatoxin C5a: Structure, function, signaling, physiology, disease, and therapeutics
2023, International ImmunopharmacologyNetwork pharmacology and experimental validation-based approach to understand the effect and mechanism of Taohong Siwu Decoction against ischemic stroke
2022, Journal of EthnopharmacologyCitation Excerpt :It plays an important role in the occurrence of inflammatory response(Andrew et al., 2012). CFD can treat kashin-Beck disease (KBD) (Zhang et al., 2015) and cancer by regulating the complement pathway(Laverdière et al., 2016; Pascual et al., 1993). These six differential genes are all directly related to the complement cascade signaling pathway.
Integrating genome-wide association study, chromosomal enhancer maps and element-gene interaction networks detected brain regions related associations between elements and ADHD/IQ
2018, Behavioural Brain ResearchCitation Excerpt :The P value was finally calculated from the permuted empirical distribution of GSEA statistics for each element. Detailed description of analysis approach can be found in previous studies [49,50]. As shown by Fig. 1, we observed significant association signals between 4 elements and ADHD in different brain regions.
Complement involvement in bone homeostasis and bone disorders
2018, Seminars in ImmunologyCitation Excerpt :Although not classically classified as an arthritic disease, clinical manifestations of Kashin-Beck disease, a chronic osteochondropathy associated with growth retardation, are similar to OA, including joint pain and deformities. Interestingly, C5 serum levels were elevated in Kashin-Beck disease, thereby linking the disease with complement pathways [142]. In summary, findings from clinical studies and animal models demonstrate a crucial function of the complement system and specific complement proteins in arthritis disease development and progression, as illustrated in Fig. 4.
Integrative analysis of proteomics and metabolomics of anaphylactoid reaction induced by Xuesaitong injection
2015, Journal of Chromatography ACitation Excerpt :In addition, Kng1 was down-regulated in the XSTI group, indicating that XSTI induced mast cell degranulation to release the effect substances (such as histamine and purine metabolites) via direct stimulation and the complement and kallikrein–kinin pathways (Fig. 5). Gpx1, C4d and Kng1 could be used as biomarkers for the two pathways, respectively [21,30,31]. Furthermore, these results revealed that >10-kDa molecules are chiefly responsible for the anaphylactoid reaction of XSTI, and ginsenosides may antagonize anaphylactoid reactions.