RESUMEN
Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Quinasa I-kappa B/genética , Interleucina-10/genética , Antígenos Comunes de Leucocito/genética , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab/uso terapéutico , Artritis Reumatoide/genética , Femenino , Estudios de Asociación Genética , Marcadores Genéticos , Humanos , Infliximab/uso terapéutico , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , RiesgoRESUMEN
BACKGROUND: The aim of this study was to explore the impact of arthritis on liver function using different approaches in vivo and in vitro. METHODS: A cross-sectional study was performed on 330 non-obese/non-T2DM subjects: 180 RA patients, 50 NAFLD non-RA patients, and 100 healthy donors (HDs). A longitudinal study was conducted on 50 RA patients treated with methotrexate for six months. Clinical and laboratory parameters and markers of liver disease were collected. Mechanistic studies were carried out in both the CIA mouse model and hepatocytes treated with anti-citrullinated protein antibodies (ACPAs). RESULTS: RA patients have an increased risk of suffering from liver disease independent of obesity or T2DM. This risk was associated with factors such as insulin resistance, autoantibodies, inflammation, and component C3. Methotrexate treatment for six months was associated with liver abnormalities in those newly-diagnosed patients having CV risk factors. ACPAs induced a defective hepatocyte function, promoting IR and inflammation. The induction of arthritis in mice caused the infiltration of immune cells in the liver and increased inflammatory, apoptotic, and fibrotic processes. CONCLUSION: RA patients may experience mild to moderate liver inflammation due to the infiltration of T, B cells, and macrophages, and the action of ACPAs. This is independent of obesity or diabetes and linked to systemic inflammation, and disease activity levels. The negative effects of methotrexate on liver function could be restricted to the concomitant presence of cardiovascular risk factors.
Asunto(s)
Artritis Reumatoide , Hepatopatías , Humanos , Animales , Ratones , Metotrexato/uso terapéutico , Estudios Longitudinales , Estudios Transversales , Péptidos Cíclicos , Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Autoanticuerpos , Inflamación , ObesidadRESUMEN
OBJECTIVE: To examine genetic association between rheumatoid arthritis (RA) and known polymorphisms in core genes of the nuclear factor (NF)kappaB pathway, the major intracellular pathway in RA pathogenesis. METHODS: Discovery and replication sample sets of Spanish patients with RA and controls were studied. A total of 181 single nucleotide polymorphisms (SNPs) uniformly spaced along the genomic sequences of 17 core genes of the NFkappaB pathway (REL, RELA, RELB, NFKB1, NFKB2, NFKBIA, NFKBIB, NFKBIE, IKBKA, IKBKB, IKBKE, IKBKAP, KBRAS1, KBRAS2, MAP3K1, MAP3K14, TAX1BP1) were studied by mass spectrometry analysis complemented with 5'-nuclease fluorescence assays in the discovery set, 458 patients with RA and 657 controls. SNPs showing nominal significant differences were further investigated in the replication set of 1189 patients with RA and 1092 controls. RESULTS: No clear reproducible association was found, although 12 SNPs in IKBKB, IKBKE and REL genes showed significant association in the discovery set. Interestingly, two of the SNPs in the IKBKE gene, weakly associated in the discovery phase, showed a trend to significant association in the replication phase. Pooling both sample sets together, the association with these two SNPs was significant. CONCLUSION: We did not find any major effect among the explored members of the NFkappaB pathway in RA susceptibility. However, it is possible that variation in the IKBKE gene could have a small effect that requires replication in additional studies.
Asunto(s)
Artritis Reumatoide/genética , FN-kappa B/genética , Polimorfismo de Nucleótido Simple , Adulto , Estudios de Casos y Controles , Susceptibilidad a Enfermedades , Femenino , Frecuencia de los Genes , Variación Genética , Haplotipos , Humanos , Quinasa I-kappa B/genética , Funciones de Verosimilitud , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
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