Genetic Variants and Protein Alterations of Selenium- and T-2 Toxin-Responsive Genes Are Associated With Chondrocytic Damage in Endemic Osteoarthropathy

Yujie Ning; Minhan Hu; Jiayu Diao; Yi Gong; Ruitian Huang; Sijie Chen; Feiyu Zhang; Yanli Liu; Feihong Chen; Pan Zhang; Guanghui Zhao; Yanhai Chang; Ke Xu; Rong Zhou; Cheng Li; Feng Zhang; Mikko Lammi; Xi Wang; Xiong Guo

doi:10.3389/fgene.2021.773534

Genetic Variants and Protein Alterations of Selenium- and T-2 Toxin-Responsive Genes Are Associated With Chondrocytic Damage in Endemic Osteoarthropathy

Front Genet. 2022 Jan 11:12:773534. doi: 10.3389/fgene.2021.773534. eCollection 2021.

Authors

Yujie Ning¹, Minhan Hu¹, Jiayu Diao², Yi Gong¹, Ruitian Huang¹, Sijie Chen¹, Feiyu Zhang¹, Yanli Liu¹, Feihong Chen¹, Pan Zhang¹, Guanghui Zhao³, Yanhai Chang², Ke Xu³, Rong Zhou^{1

4}, Cheng Li^{1

4}, Feng Zhang¹, Mikko Lammi^{1

5}, Xi Wang¹, Xiong Guo¹

Affiliations

¹ Key Laboratory of Trace Elements and Endemic Diseases, School of Public Health, Health Science Center, Xi'an Jiaotong University, National Health Commission of the People's Republic of China, Xi'an, China.
² Shaanxi Provincial People's Hospital, Xi'an, China.
³ Xi'an Honghui Hospital, Xi'an, China.
⁴ Shaanxi Provincial Institute for Endemic Disease Control, Xi'an, China.
⁵ Department of Integrative Medical Biology, University of Umeå, Umeå, Sweden.

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.

Keywords: Kashin–Beck disease; T-2 toxin; chondrocyte damage; selenium; single nucleotide polymorphism.