RESUMEN
BACKGROUND: Rheumatoid arthritis (RA) is a complex autoimmune disease that negatively affects synovial joints, leading to the deterioration of movement and mobility of patients. This chronic disease is considered to have a strong genetic inheritance, with genome-wide association studies (GWAS) highlighting many genetic loci associated with the disease. Moreover, numerous confounding and non-genetic factors also contribute to the risk of the disease. AIMS: This study investigates the association of selected genetic polymorphisms with rheumatoid arthritis risk and develops a polygenic risk score (PRS) based on selected genes. METHODS: A case-control study recruited fully consenting participants from the East Midlands region of the UK. DNA samples were genotyped for a range of polymorphisms and genetic associations were calculated under several inheritance models. PRS was calculated at crude (unweighted) and weighted levels, and its associations with clinical parameters were determined. RESULTS: There were significant associations with the risk of RA at six genetic markers and their associated risk alleles (TNRF2*G, TRAF1*A, PTPN22*T, HLA-DRB1*G, TNFα*A, and IL4-590*T). The TTG haplotype at the VDR locus increased the risk of RA with an OR of 3.05 (CI 1.33-6.98, p = 0.009). The GA haplotype of HLADRB1-TNFα-308 was a significant contributor to the risk of RA in this population (OR = 2.77, CI 1.23-6.28, p = 0.01), although linkage disequilibrium was low. The polygenic risk score was significantly higher in cases over controls in both unweighted (mean difference = 1.48, t285 = 5.387, p < 0.001) and weighted (mean difference = 2.75, t285 = 6.437, p < 0.001) results. CONCLUSION: Several genetic loci contribute to the increased risk of RA in the British White sample. The PRS is significantly higher in those with RA and can be used for clinical applications and personalised prevention of disease.
Asunto(s)
Artritis Reumatoide , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Humanos , Artritis Reumatoide/genética , Femenino , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , Reino Unido/epidemiología , Estudio de Asociación del Genoma Completo , Población Blanca/genética , Anciano , Adulto , Haplotipos , Cadenas HLA-DRB1/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Herencia Multifactorial , Receptores de Calcitriol/genéticaRESUMEN
Genetic associations of TNFR2, VDR (Bsm I and Fok I), A2M, GSTT(1), GSTM(1) and ACE in South Asian and Caucasian patients with rheumatoid arthritis (RA) were assessed in this study. DNA samples from South Asians (134 cases, 149 controls) and Caucasians (137 cases, 150 controls) from the East Midlands of the United Kingdom were genotyped for seven polymorphisms. All cases were rheumatoid-factor positive. Significant genetic associations were observed with TNFR2 R-R (OR = 3.16, CI 1.20-9.26, P < 0.05), A2M 1-1 (OR = 2.09, CI 1.21-3.64, P < 0.05) and GST T(1)null (OR = 1.97, CI 1.07-3.68, P < 0.05) among Caucasian patients. In South Asians, VDR Bsm I B-B genotype (OR = 2.08, CI 1.23-3.52, P < 0.05), A2M 2-2 genotype (OR = 3.99, CI 1.19-17.18, P < 0.05), and GST T(1)null genotype (OR = 2.81, CI 1.40-5.77, P < 0.002) genotypes were associated with RA. In the majority of cases, recessive and multiplicative modes of inheritance explained the observed associations. This study demonstrates that ethnicity affects the genetic associations in RA.
Asunto(s)
Artritis Reumatoide/genética , Estudios de Asociación Genética/métodos , Glutatión Transferasa/genética , Peptidil-Dipeptidasa A/genética , Receptores de Calcitriol/genética , Receptores Tipo II del Factor de Necrosis Tumoral/genética , alfa-Macroglobulinas/genética , Adulto , Anciano , Artritis Reumatoide/enzimología , Artritis Reumatoide/etnología , Asia/epidemiología , Asia/etnología , Pueblo Asiatico/etnología , Pueblo Asiatico/genética , Humanos , Persona de Mediana Edad , Reino Unido/epidemiología , Reino Unido/etnología , Población Blanca/etnología , Población Blanca/genéticaRESUMEN
OBJECTIVE: To compare the distribution and assess genetic associations of the PTPN22 R620W single-nucleotide polymorphism among South Asian (Asiatic Indian) patients with rheumatoid arthritis (RA) and ethnically matched controls. METHODS: DNA samples from 133 rheumatoid factor-positive South Asian RA patients and 149 control subjects from the East Midlands of the UK were genotyped for PTPN22 R620W polymorphism. Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The PTPN22 *T allele frequency was lower than in the Caucasian populations, but the disease association was significant (odds ratio 5.87, 95% confidence interval 1.68-20.52). Similar association was observed for genotypes containing *T allele. CONCLUSION: Our results suggest that the T variant acts as a susceptibility allele for autoantibody-positive RA among South Asians.