Polymorphism in rs2229783 of the Alpha 1(XI

The purpose of this study was to explore whether genomic polymorphisms in the alpha 1(XI) collagen gene (COL11A1) were associated with the risk and severity of Kashin-Beck disease (KBD). Twenty-two single nucleotide polymorphisms (SNPs) in COL11A1 were genotyped in 274 KBD cases and 249 healthy controls using the Sequenom MassARRAY system. The expression of type XI collagen (COL11A) in the knee articular cartilage of 22 KBD patients and 21 controls was analyzed by immunohistochemistry. Our results showed that the frequency distribution of genotypes of the rs polymorphism in COL11A1 was significantly different between the KBD and control groups (P = 0.0003). Moreover, the expression level of COL11A in cartilage was significantly lower in the KBD group than in the controls (t = 2.637, P = 0.02). However, no association was found between the rs and the severity of KBD, suggesting a role of COL11A1 in the susceptibility to but not the severity of KBD.

Kashin-Beck disease (KBD) is an endemic and chronic osteochondropathy mainly distributed over a limited area from southeastern Siberia extending to northeast and southwest China. A key pathological feature of KBD is chondrocyte necrosis in the deep zone of the growth plate of cartilage and articular cartilage[1]. The etiology of KBD remains unclear; recent epidemiological and genetic study results suggest that the interaction between environmental factors and susceptibility genes might play a role in the disease[2]. Certain susceptibility genes may affect susceptibility to environmental factors, such as selenium de?ciency or other biologic factors[3].

Type XI collagen (COL11A), a cartilage-specific extracellular matrix (ECM) protein, is important for cartilage-collagen fibril formation and for ECM organization. It participates in fibril formation with other cartilage-specific collagens (type II and IX collagens) and regulates the diameter of cartilage collagen fibrils. Polymorphisms in the COL11A1 gene have been shown to associate with lumbar disc herniation (LDH)[4]. Mutations in COL11A1 have also been shown to result in relatively mild chondrodysplasias associated with osteoarthritis (OA). Given that KBD has been found to have overlapping phenotypes and pathologic changes similar to those of OA and rheumatoid arthritis (RA)[5], we hypothesized that, as in OA and RA, genetic variants, in addition to environmental factors, may play an important role in the etiology and pathogenesis of KBD, and phenotypic expression of types I, II, III, and X collagen in chondrocytes cultured in vitro were significantly different between KBD and control cultures[6]. However, the role of COL11A in the pathology of KBD remains unknown. In this study, for the first time, we evaluate the impact of genomic polymorphisms in COL11A1 on the risk and progression of KBD.

KBD was diagnosed according to the national diagnostic criteria of China (WS/T 207-2010). Patients with clinical symptoms, radiographic changes, or other osteochondropathies were excluded. A healthy control was defined as no KBD and no primary or secondary OA. A total of 274 KBD patients and 249 age- (53.37 ± 10.79 years vs. 51.81 ± 17.85 years, t = 1.27, P > 0.05) and sex-matched (male/female, 125/149 vs. 124/125, χ2 = 0.91, P > 0.05) controls were collected from KBD-endemic areas of the Linyou and Yongshou Counties of Shaanxi Province. In addition, the 274 KBD patients were classified as clinical stages I, II, and III, which comprised 57.66% (158/274), 31.02% (85/274), and 11.32% (31/274) of the total, respectively. Fresh blood (5 mL) was collected from each subject.

Knee articular cartilage was collected from 22 KBD patients and 21 healthy controls. The KBD patients, consisting of 10 males and 12 females with an average age of 51.00 ± 8.30 (32-66) years, underwent knee debridement or arthroplasty at a hospital. The healthy control subjects, consisting of 11 males and 10 females with an average age of 48.23 ± 7.65 (33-61) years, had no history of osteochondropathy, but they had undergone amputation because of traffic accidents. No significant differences were observed between KBD and control group in age (t = 1.13, P > 0.05) and sex (χ2 = 0.21, P > 0.05). None of the KBD patients or controls were diagnosed with bone or cartilage genetic diseases or RA.

The study was performed in accordance with the Declaration of Helsinki and approved by the Human Ethics Committee of Xi’an Jiaotong University, China. Written informed consent was also obtained from the subjects or their relatives.

Based on the available information on SNPs in COL11A1 that are considered predisposing factors in osteochondropathy[7-8], 22 SNPs were selected from the NCBI SNP and HapMap database and evaluated in this study. The selected SNPs were required to have a minor allele frequency (MAF) ≥ 5%. Genomic DNA was extracted from the peripheral blood of the 274 KBD patients and 249 healthy controls using a blood DNA extraction kit (TIANGEN, Beijing, China). Genotyping was performed using the Sequenom MassARRAY system. Primers were designed using Sequenom SNP Assay Design software version 3.0 for iPLEX reactions. The protocol and reaction conditions were as outlined by the manufacturer. Data management and analysis were conducted by Sequenom Typer 4.0 Software (

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