Genetic variant in SPAG16 is associated with the susceptibility of ACPA-positive rheumatoid arthritis possibly via regulation of MMP-3

• Published in: Journal of orthopaedic surgery and research Vol. 17; no. 1; pp. 511 - 7
• Main Authors: Lin, Qingxi, Zhou, Bingxiang, Song, Xiaoxiao, Ye, Wei, Li, Qinglong, Shi, Tong, Cheng, Chen, Li, Yetian, Wei, Xing
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 24.11.2022; BioMed Central; BMC
• Subjects: ACPA-positive; Alleles; Analysis; Arthritis; Arthritis, Rheumatoid - diagnostic imaging; Arthritis, Rheumatoid - genetics; Blood; Body mass index; C-reactive protein; Cartilage; Correlation analysis; Development and progression; Disease; Erythrocyte sedimentation rate; Gene expression; Gene frequency; Genetic aspects; Genetic diversity; Genetic research; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Genotype & phenotype; Genotypes; Genotyping; Health risk assessment; Humans; Male; Matrix metalloproteinase; Matrix Metalloproteinase 3 - genetics; Medical examination; Metalloproteinase; MMP-3; Orthopedics; Rheumatoid arthritis; Rheumatoid factor; Risk factors; RNA; RNA, Messenger; Semen; Single-nucleotide polymorphism; Sperm; Spermatozoa; Statistical analysis; Stromelysin 1; Susceptible; China; Japan; ACPA-positive; Susceptible; Rheumatoid arthritis; MMP-3
• ISSN: 1749-799X; 1749-799X
• DOI: 10.1186/s13018-022-03405-w

In two previously published genome-wide association studies, a cluster of variants of sperm-associated antigen16 (SPAG16) were reported to be associated with the radiological progression rate of ACPA-positive rheumatoid arthritis (RA) patients from North American and Southern European ancestry. In this study, we aimed to investigate whether the reported RA-risk loci in SPAG16 are associated with the disease in the Chinese population and to further validate the functional role of the susceptible locus in RA tissues. A total of 500 ACPA-positive RA patients and 1000 age-matched healthy subjects were recruited. Two SNPs of SPAG16, including rs7607479 (C/T) and rs6435818 (A/C), were genotyped, and the genotyping data were compared with chi-square test. Gene expression analysis was performed in synovial tissues obtained from 40 RA patients and 30 non-RA controls surgically treated for bone fracture. The tissue expression of SPAG16 and matrix metalloproteinase 3 (MMP-3) was compared between the two groups by the Student's t test. The relationship between serum indexes and mRNA expression of SPAG16 and MMP-3 were evaluated by Spearman's correlation analysis. For rs7607479, the frequency of genotype TT was significantly higher in RA patients than in the controls (49.0% vs. 40.4%, p = 0.002). The RA patients were found to have significantly lower frequency of allele C than the controls (30.9% vs. 36.8%, p = 0.001). As for rs6435818, there was no significant difference of genotype or allele frequency between the two groups. The mRNA expression of MMP-3 was 1.63-fold higher in the RA patients than in the controls (p < 0.001). The expression of SPAG16 was comparable between the two groups (p = 0.43). The mRNA expression of MMP-3 was 1.39-fold higher in patients with genotype TT than in the patients with genotype CC (p = 0.006). The mRNA expression level of MMP-3 was significantly correlated with serum rheumatoid factor (r = 0.498, p < 0.001) and C-reactive protein (r = 0.272, p = 0.01), weakly correlated with erythrocyte sedimentation rate (r = 0.236, p = 0.09). We validated a common genetic risk factor in ACPA-positive patients with RA, which is associated with the tissue production of MMP-3 and disease progression. Further functional analysis into the role of rs7607479 in MMP-3 expression can shed new light on the genetic architecture of ACPA-positive RA.