PMID- 36434627 OWN - NLM STAT- MEDLINE DCOM- 20221129 LR - 20221213 IS - 1749-799X (Electronic) IS - 1749-799X (Linking) VI - 17 IP - 1 DP - 2022 Nov 24 TI - Genetic variant in SPAG16 is associated with the susceptibility of ACPA-positive rheumatoid arthritis possibly via regulation of MMP-3. PG - 511 LID - 10.1186/s13018-022-03405-w [doi] LID - 511 AB - OBJECTIVES: 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. METHODS: 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. RESULT: 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). CONCLUSIONS: 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. CI - (c) 2022. The Author(s). FAU - Lin, Qingxi AU - Lin Q AD - Department of Orthopedics, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, LinShan Road No. 188, Nanjing City, 210008, China. FAU - Zhou, Bingxiang AU - Zhou B AD - Department of Orthopedics, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, LinShan Road No. 188, Nanjing City, 210008, China. FAU - Song, Xiaoxiao AU - Song X AD - Department of Orthopedics, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, LinShan Road No. 188, Nanjing City, 210008, China. FAU - Ye, Wei AU - Ye W AD - Department of Orthopedics, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, LinShan Road No. 188, Nanjing City, 210008, China. FAU - Li, Qinglong AU - Li Q AD - Department of Orthopedics, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, LinShan Road No. 188, Nanjing City, 210008, China. FAU - Shi, Tong AU - Shi T AD - Department of Orthopedics, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, LinShan Road No. 188, Nanjing City, 210008, China. FAU - Cheng, Chen AU - Cheng C AD - Department of Orthopaedic Surgery, The JiangYan TCM Hospital of Taizhou City, JiangYan Road No. 699, Taizhou City, 225500, China. FAU - Li, Yetian AU - Li Y AD - Department of Orthopaedic Surgery, The First Affiliated Hospital of Anhui Medical University, Jixi Road No. 218, Hefei City, 230022, China. liyetian1984@163.com. FAU - Wei, Xing AU - Wei X AUID- ORCID: 0000-0003-2627-8281 AD - Department of Orthopedics, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, LinShan Road No. 188, Nanjing City, 210008, China. dave469889771@sina.com. LA - eng PT - Journal Article DEP - 20221124 PL - England TA - J Orthop Surg Res JT - Journal of orthopaedic surgery and research JID - 101265112 RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - 0 (RNA, Messenger) SB - IM MH - Humans MH - Male MH - *Matrix Metalloproteinase 3/genetics MH - Genome-Wide Association Study MH - Semen MH - *Arthritis, Rheumatoid/diagnostic imaging/genetics MH - Spermatozoa MH - RNA, Messenger PMC - PMC9701044 OTO - NOTNLM OT - ACPA-positive OT - MMP-3 OT - Rheumatoid arthritis OT - Susceptible COIS- The authors declare that they have no competing interests. EDAT- 2022/11/27 06:00 MHDA- 2022/11/30 06:00 PMCR- 2022/11/24 CRDT- 2022/11/26 11:50 PHST- 2022/02/20 00:00 [received] PHST- 2022/11/11 00:00 [accepted] PHST- 2022/11/26 11:50 [entrez] PHST- 2022/11/27 06:00 [pubmed] PHST- 2022/11/30 06:00 [medline] PHST- 2022/11/24 00:00 [pmc-release] AID - 10.1186/s13018-022-03405-w [pii] AID - 3405 [pii] AID - 10.1186/s13018-022-03405-w [doi] PST - epublish SO - J Orthop Surg Res. 2022 Nov 24;17(1):511. doi: 10.1186/s13018-022-03405-w.