Background Several autoimmune chronic inflammatory diseases have been associated with a polymorphism of the HS1,2A enhancer located in the 3' regulatory region of the locus for the immunoglobulin heavy chain (IgH 3'RR-1) (1,2). Its main biologic role resides in the immunoglobulin isotype switching and somatic hypermutation, but the interest in the regulatory region relies also on the demonstration that the allele*2 has a binding site for NF-kB, not present in allele*1.
Objectives To study the HS1,2A enhancer polymorphism as a possible biomarker of disease, disease activity and of response to therapy in the earliest phases of Rheumatoid Arthritis (ERA). To evaluate whether the polymorphism is related to a different NF-kB pathway activation on B cells of ERA patients carrying 2/2 or 1/1 genotypes.
Methods Three-hundred and twenty nine ERA patients, treated according to a tight control strategy were enrolled in the study. At each visit, clinical improvement and remission were evaluated according to ACR/EULAR criteria (3). ERA patients were genotyped for HS1,2A enhancer polymorphism, as previously described (4). At diagnosis, circulating B cells were isolated from PB of 8 naïve RA patients (4 with the 2/2 genotype and 4 with the 1/1 genotype) and analysed for specific genes expression through Real-Time PCR (PCR Array). The Ingenuity Pathway Analysis (IPA) software was used to examine biological networks associated with the polymorphism and to identify functionally related genes that correspond to specific canonical pathways.
Results Twenty-eight percent of ERA patients had the HS1,2A enhancer 2/2 genotype and 10.9% the 1/1 genotype, comparable with the already published data on RA (1). ERA patients carrying the 2/2 genotype had more active disease at baseline compared to 1/1 genotype (in terms of ESR, CRP, circulating IL6 and DAS), reaching less likely a good-EULAR response and remission at 3 months FU (good-EULAR response: 35.9% vs 56.4%, OR (95%CIs): 0.43 (0.24–0.78); EULAR-remission: 14.1% vs 34.6%, OR (95%CIs): 0.31 (0.14–0.67), respectively). Moreover, at 6 months FU, a higher percentage of subjects carrying the 2/2 genotype needed TNF-blockers addition compared to patients without the 2/2 genotype (26.1% vs 12.2%, p=0.01). Finally, we performed the IPA analysis of PB derived B cells from ERA patients carrying the 2/2 and 1/1 genotypes, finding that the focus genes were mapped to 3 networks related mainly to cell death and survival, immunological disease and cell-to-cell signaling and interaction. Moreover, the 2/2 genotype was linked to the top canonical pathway “NF-kB signaling” with TNF-alpha, CD40 and CD40 ligand as top upstream regulators.
Conclusions We demonstrate that carrying allele*2 of HS1,2A enhancer influences the disease activity and the response to therapy in RA already at the earlier phases of the disease and that this genetic background is strongly related to NF-kB activation. Based on these findings we suggest that the enhancer HS1,2A polymorphism is a genetic biomarker that should be included in an individual matrix able to define a possible personalized therapy in RA.
Tolusso B et al. Ann Rheum Dis 2009;
Frezza D et al. Ann Rheum Dis 2012;
Felson DT et al. Arthritis Rheum 2011;
Giambra V et al Gene 2005
Disclosure of Interest None declared
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