Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Analysis of the Association of CDA (Cytidin Deaminase) (K27Q), TNF- (-308G>A) and PTPN22 R620W Genetic Polymorphisms with Auto-Antibody Seropositive RA and the Response to B Cell Depletion.
Tolusso3, Barbara, Di Pietro7, Fabio, Pallavicini4, Francesca Bobbio, Ravagnani1, Viviana, Benucci5, Maurizio, Podesta'2, Edoardo, Atzeni6, Fabiola
Department of Clinical and Experimental Medicine, Section of Rheumatology & Internal Medicine, University of Verona, Verona, Italy
Division of Clinical Immunology and Rheumatology, S. Andrea University Hospital, "Sapienza" University of Rome, II School of Medicine, Rome, Italy
Division of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy
Division of Rheumatology, University of Pavia, IRCCS S. Matteo Foundation, Pavia, Italy
Rheumatology Unit, Department of Internal Medicine, Ospedale di S. Giovanni di Dio, Florence, Italy
Rheumatology Unit, University Hospital L. Sacco, Milan, Italy
School of Biosciences and Biotechnology, University of Camerino, Camerino (MC), Italy
To evaluate the genetic relationship between the two functional polymorphism of CDA (22G>A) and TNF-a (-308G>A) gene, and PTPN22 R620W respectively, in Rheumatoid Arthritis (RA) and their possible association with B cell depletion therapy.
One hundred and twenty three (82% female) RA patients who did not respond to previous DMARDs and/or TNFa blockers were enrolled in a multicenter italian study to evaluate the efficacy of RTX therapy. All RA were seropositive for at least one (RF-IgG,RF-IgA,RF-IgM,MCVA,ACPA) autoantibody. 181 healthy subjects living in the same geographical area entered in the study as a control group. DNA from patients and controls was genotyped for the PTPN22 R620W, TNFa-308 G/A and CDA K27Q polymorphisms by RLFP methods. The EULAR response criteria were used to assess the disease activity (DAS 44 <= 2.4: good response) at 6 months follow-up. Exact HWE tests were performed for each SNP independently among cases and controls. Logistic regression models (SAS V9.1.3) were used to assess the effects of each of the 4 SNPs on RA with adjusting for sex and age at disease onset. Multifactor dimensionality reduction (MDR,) was used to verify our interaction results. Models are evaluated on the testing balanced accuracy statistic (TBA), the cross-validation consistency (CVC) and the statistical significance of the model. These data were also analyzed using the G-MDR (V0.7) software package, an algorithm that includes adjustment for covariates (sex and age).
All SNPs were in HWE except CDAK27Q (p=0.000011). Considering the TNFa-308A SNP, we showed an increased frequency of the allele A (19.8%) in the RA cohort compared to controls (9.1%; OR (95% CIs): 2.23 (1.403.60). The analysis of the CDA K27Q SNP showed a significant increased frequency of the genotype Q*/Q* (40.2%) and a decreased frequency of the genotype K*/Q* (31.2%) in RA patients compared to controls (Q*/Q*: 29.9%; OR: 1.58 (1.022.44); K*/Q*: 42.3%; OR: 0.62 (0.400.96). We found no difference in genotype distribution nor in allele frequencies of PTPN22 R620W between RA patients and controls. Based on the multilocus MDR approach, CDA K27Q SNP was the strongest risk factor for RA, with an average prediction accuracy of 57.9% (p=0.008). When we allowed for two genes in the analysis, the TNFa-308 G/A was identified in addition to CDA K27Q SNP and predicted disease status correctly 58.9% of the time (p=0.002); the prediction accuracy reached the value of 59.6% considering also the contribution of the PTPN22 R620W (p=0.001). Instead, the G-MDR method that includes sex and age in the analysis, showed that TNFa-308 G/A was the strongest risk factor for RA, with an average prediction accuracy of 57.6% (p<0.0001). No association was seen between PTPN22 R620W, TNFa-308 G/A and CDA K27Q polymorphisms and EULAR good response to RTX after 6th months FU.
Aggressive-progressive RA prone to receive RTX associates to -308 allele*A of the TNFa gene which is linked to high TNFalpha synthesis and to the QQ CDA genotype which is linked to a lower inhibition of the GM-CSF synthesis.
To cite this abstract, please use the following information:
Tolusso, Barbara, Di Pietro, Fabio, Pallavicini, Francesca Bobbio, Ravagnani, Viviana, Benucci, Maurizio, Podesta', Edoardo, et al; Analysis of the Association of CDA (Cytidin Deaminase) (K27Q), TNF- (-308G>A) and PTPN22 R620W Genetic Polymorphisms with Auto-Antibody Seropositive RA and the Response to B Cell Depletion. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1582