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. 2022 Jun;10(6):e1950.
doi: 10.1002/mgg3.1950. Epub 2022 Apr 12.

Analysis of TNFSF13B polymorphisms and BAFF expression in rheumatoid arthritis and primary Sjögren's syndrome patients

Enrique Santillán-López  1 , José Francisco Muñoz-Valle  2 , Edith Oregon-Romero  2 , Noemí Espinoza-García  3 , Beatriz Alejandra Treviño-Talavera  1 , Diana Celeste Salazar-Camarena  4 , Miguel Marín-Rosales  4   5 , Alvaro Cruz  2 , Jhonatan Antonio Alvarez-Gómez  3 , Nefertari Sagrero-Fabela  1 , Sergio Cerpa-Cruz  6 , Claudia Azucena Palafox-Sánchez  2   4
Affiliations

Analysis of TNFSF13B polymorphisms and BAFF expression in rheumatoid arthritis and primary Sjögren's syndrome patients

Enrique Santillán-López et al. Mol Genet Genomic Med. 2022 Jun.

Abstract

Background: The increased expression of B cell-activating factor (BAFF) has been linked to autoantibody production in autoimmune diseases (ADs). The aim of this study was to investigate the association among TNFSF13B gene (OMIM: 603969) single nucleotide polymorphisms (SNPs), TNFSF13B mRNA, and soluble BAFF (sBAFF) expression in patients with rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS). The diagnostic value of sBAFF also was evaluated by the area under the curve (AUC) of receiver operating characteristic or receptor (ROC) curves.

Methods: Genotypes of the TNFSF13B rs9514827 (-2841 T > C), rs1041569 (-2701 A > T) and rs9514828 (-871 C > T) SNPs were determined by PCR-RFLP assay. TNFSF13B mRNA and sBAFF expression were performed by RT-qPCR and ELISA, respectively. The study included 320 RA patients, 101 pSS patients, and 309 healthy subjects (HS).

Results: The rs9514828 T allele and the TAT haplotype were associated with an increased risk to develop RA. In both ADs, the TNFSF13B mRNA levels were increased in comparison with HS. The rs9514828 (-871 C > T) polymorphism was associated with increased gene expression in RA patients. Also, sBAFF levels were higher in both ADs, however pSS patients showed the highest sBAFF levels. sBAFF showed higher diagnostic performance for pSS with an AUC of 0.968, with a similar accuracy of anti-SSA/Ro antibody diagnosis (AUC = 0.974).

Conclusions: Our findings demonstrate that the TNFSF13B rs9514828 (-871 C > T) polymorphism is a risk factor for RA in the western Mexican population. sBAFF levels may be a potential diagnosis biomarker in pSS.

Keywords: TNFSF13B polymorphisms; primary Sjogren's syndrome; rheumatoid arthritis; sBAFF levels.

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Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this paper.

Figures

FIGURE 1
FIGURE 1
Association of TNFSF13B gene expression according to rheumatic diseases and ‐871C > T polymorphism. The TNFSF13B gene expression was higher in RA and pSS than in HS (a and b). When comparing the gene expression between both rheumatic diseases no statistical difference was found (b). The sBAFF concentration was higher in both autoimmune disorders than in HS, mainly in pSS (c). TNFSF13B expression showed high expression in RA patients with CT and TT genotypes of the ‐871C > T polymorphism [2.77 and 6.82‐fold more, respectively (d)]. RA patients were classified according to dominant and recessive genotyping models, the carriers with the mutant alleles showed 3.51 and 4.43‐fold more expression (e and f). Also, TNFSF13B gene expression according to genetic models, showed that being a carrier of two copies of the T allele was associated with higher TNFSF13B mRNA expression (g–i). sBAFF concentration did not show a difference in RA patients, independently of genotypes (j). The TNFSF13B gene expression and sBAFF levels were similar in patients with pSS carriers of the risk allele with respect to the most frequent (k and l). Qualitative and quantitative TNFSF13B gene expression analysis was evaluated through the 2–ΔΔCt and 2–ΔCt methods. Data are shown in median and percentiles (25–75). HS: Healthy subjects, pSS: Primary Sjögren's syndrome, RA: Rheumatoid arthritis. p‐Values were obtained through the Mann–Whitney U tests or Kruskal‐Wallis H test (Dunn's post hoc test, when appropriate) according to the case. p‐Value < .05 *, p‐value < .01 **, p‐value < .001***. Statistically significant difference, p‐value < .05
FIGURE 2
FIGURE 2
Association and correlation of sBAFF levels, autoantibodies, and clinimetric measures in RA and pSS patients. RA patients showed positive correlation between ACPAs and RF with a statistical difference (r = 0.380, p = .001). Also, the clinimetric tools had a positive correlation with variables directly related to its calculation (a). RA patients classified according to ACPAs and RF status did not show statistical difference (b). Otherwise, classified as low or high, the formers showed higher sBAFF levels (p < .05), (c). No statistical differences were found in pSS patients among TNFSF13B mRNA relative expression units (REU), sBAFF, FS, and clinimetrical tools (d). However, anti‐SSA/Ro and anti‐SSB/La showed a positive correlation with SSDAI (e), and the focus score (FS) was higher in pSS seropositive to anti‐SSA/Ro (f). The diagnostic performance of sBAFF was evaluated in RA (g) and pSS (h), with higher efficiency in pSS than in RA (AUC = 0.968 vs 0.811, respectively). Also, the diagnostic efficiency of sBAFF was compared with anti‐SSA/Ro and sBAFF showed a similar performance with no statistical difference (i). Data is shown in median and percentiles (25–75). REU was obtained through the 2–ΔCt method. ROC curves with AUC were used and compared through the Delong method. ACPA: Anti‐citrullinated protein antibodies, AUC: Area under the curve, DAS28: Disease activity score of 28 joints, ESR: Erythrosedimentation rate, FS: Focus score, HAQ: Health assessment Questionary, RA: Rheumatoid arthritis, pSS: Primary Sjögren's syndrome, REU: Relative expression units, RF: Rheumatoid factor, SSDAI: Sjögren's syndrome disease activity index, SSDDI: Sjögren's syndrome disease damage index. p‐Values were obtained through the Mann–Whitney U tests and Spearman's rank‐order correlation test. p‐value < .01 **, p‐value < .001***. Statistically significant difference, p‐value < .05
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