Abstract
The mechanism of environmental factors in Kashin–Beck disease (KBD) remains unknown. We aimed to identify single nucleotide polymorphisms (SNPs) and protein alterations of selenium- and T-2 toxin–responsive genes to provide new evidence of chondrocytic damage in KBD. This study sampled the cubital venous blood of 258 subjects including 129 sex-matched KBD patients and 129 healthy controls for SNP detection. We applied an additive model, a dominant model, and a recessive model to identify significant SNPs. We then used the Comparative Toxicogenomics Database (CTD) to select selenium- and T-2 toxin–responsive genes with the candidate SNP loci. Finally, immunohistochemistry was applied to verify the protein expression of candidate genes in knee cartilage obtained from 15 subjects including 5 KBD, 5 osteoarthritis (OA), and 5 healthy controls. Forty-nine SNPs were genotyped in the current study. The C allele of rs6494629 was less frequent in KBD than in the controls (OR = 0.63, p = 0.011). Based on the CTD database, PPARG, ADAM12, IL6, SMAD3, and TIMP2 were identified to interact with selenium, sodium selenite, and T-2 toxin. KBD was found to be significantly associated with rs12629751 of PPARG (additive model: OR = 0.46, p = 0.012; dominant model: OR = 0.45, p = 0.049; recessive model: OR = 0.18, p = 0.018), rs1871054 of ADAM12 (dominant model: OR = 2.19, p = 0.022), rs1800796 of IL6 (dominant model: OR = 0.30, p = 0.003), rs6494629 of SMAD3 (additive model: OR = 0.65, p = 0.019; dominant model: OR = 0.52, p = 0.012), and rs4789936 of TIMP2 (recessive model: OR = 5.90, p = 0.024). Immunohistochemistry verified significantly upregulated PPARG, ADAM12, SMAD3, and TIMP2 in KBD compared with OA and normal controls (p < 0.05). Genetic polymorphisms of PPARG, ADAM12, SMAD3, and TIMP2 may contribute to the risk of KBD. These genes could promote the pathogenesis of KBD by disturbing ECM homeostasis.
Highlights
Kashin–Beck disease (KBD) is an endemic osteoarthropathy distributed throughout North Korea, Siberia, Japan, and China
Our results identify potential SNP biomarkers of selenium deficiency– and T-2 toxin–responsive genes to help reveal the pathogenesis of KBD
KBD was found to be significantly associated with SNPs rs12629751 T/C of PPARG on chromosome 3, rs3775296 A/C of TLR-3 on chromosome 4, rs1800796 G/C of IL6 on chromosome 7, rs1871054 T/C of ADAM12 on chromosome 10, rs6494629 C/ T of SMAD3 on chromosome 15, and rs4789936 T/C of TIMP2 on chromosome 17
Summary
Kashin–Beck disease (KBD) is an endemic osteoarthropathy distributed throughout North Korea, Siberia, Japan, and China. Monitoring data reported in the 2018 China Health Statistical Yearbook documents 535,878 patients, including 8,540 juvenile cases and more than 104 million residents at risk (http://www.nhfpc.gov.cn). The main pathogenic sites of KBD were irreversible coagulation necrosis and apoptosis in chondrocytes from articular cartilage, epiphyseal cartilage, and epiphyseal plate cartilage. Selenium deficiency and T-2 toxin (Guo et al, 2014; Sun et al, 2019; Wang et al, 2020) have been established and widely accepted as the main environmental risk factors for KBD that induce cartilage damage such as acceleration of chondrocyte apoptosis and an imbalance of the extracellular matrix (Wang et al, 2006; Li et al, 2012). The aetiology and pathogenesis of OA are poorly understood, but OA mainly occurs in elderly individuals, with chondrocyte apoptosis starting from the superficial zone of cartilage, whereas KBD mainly occurs in childhood, with chondrocyte apoptosis starting from the deep zone of cartilage (Guo et al, 2014; He et al, 2018; Wang et al, 2021)
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