Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and important joint commitment, being the most common systemic autoimmune disease worldwide. RA displays important genetic background with a variety of genes contributing to the immune balance breakdown. Recent studies have demonstrated that vitamin D, through its receptor (VDR), is able to regulate the immune balance and suppress the autoimmunity process, being a potential target in autoimmune diseases. In the present genetic association study, we assessed 5 Tag single nucleotide polymorphisms (SNPs) (rs11168268, rs2248098, rs1540339, rs4760648 and rs3890733), which cover most of the VDR gene, in three different Brazilian populations (from Northeast, Southeast and South Brazil). We also evaluated the VDR expression profile in whole blood and monocytes from RA patients. For genotyping study, 428 RA patients and 616 healthy controls were genotyped with fluorogenic allele specific probes on an ABI7500 platform. For gene expression study, VDR mRNA levels of 15 RA patients and 26 healthy individuals were assessed by RT-PCR. Our results showed that SNPs rs4760648 and rs3890733 are associated to RA susceptibility (p value = 0.0026, OR 1.31 and p value = 0.0091, OR 1.28 with statistical power = 0.999 and 0.993, respectively). Regarding RA clinical features, the studied SNPs did not show significant associations. The gene expression assays showed that VDR mRNA levels were down regulated in both whole blood (-3.3 fold) and monocytes (-3.2 fold) of RA patients when compared to healthy controls. Our results, the first reported for distinct Brazilian populations, support a role of the VDR gene in the susceptibility to RA.
Background HLA-G may exert long-term immunotolerogenic effects through the generation of suppressor cells [reviewed in [1]]. Such features render HLA-G an attractive candidate gene for susceptibility to immune mediated diseases. Indeed, our group has observed a positive association of a 3’UTR haplotype encompassing the 14bp locus and the +3142C/G (rs1063320) and disease susceptibility in patients with systemic lupus erythematosus [2]. Objectives To investigate the genetic influence of the two HLA-G 3’UTR polymorphisms – the 14 bp insertion/deletion (rs1704) and the +3142C>G (rs1063320) – in the susceptibility to rheumatoid arthritis in a double-center study comprising a Southern-Brazilian cohort from Porto Alegre and Northern-Brazilian cohort from the city of Belém. Methods A total number of 546 RA patients and 531 controls was PCR genotyped for the two polymorphisms. Results Haplotype frequencies differed significantly between control groups from the Northern and Southern cohorts. After adjusting for city of origin and gender, we observed that female patients presented a higher frequency of the deletion-G (D/G) haplotype (OR=1.634, 95% CI=1.128–2.368, P=0.009). After stratifying for RF positivity, only the female RF+ group of patients presented statistical significance (OR=1.829, 95%C.I =1.243–2.690, P=0.002) - Table 1. Table 1.HLA-G D/G carrier frequencies in patients and comparison with controls AllFemalesMales N/Total (freq)N/Total (freq)N/Total (freq) Porto Alegre (South) Controls0.206 (59/287)0.133 (16/120)a,b0.257 (43/167) Patients (all)0.235 (80/340)0.242 (67/277)a0.206 (13/63) RF+0.238 (67/281)0.247 (56/227)b0.204 (11/54) RF–0.232 (13/56)0.234 (11/47)0.222 (2/9) Belém (North) Controls0.338 (75/222)0.302 (38/126)c0.385 (37/96) Patients (all)0.360 (71/197)0.374 (68/182)0.200 (3/15) RF+0.405 (60/148)0.414 (58/140)c0.250 (2/8) RF–0.242 (8/33)0.286 (8/28)0.0 (0/5) aP=0.015, bP=0.017, cP=0.072. Conclusions Our results suggest a differential influence of HLA-G 3’UTR polymorphisms in disease susceptibility, with the D/G haplotype as a risk factor for RA in RF+ females. References Carosella ED, HoWangYin K-Y, Favier B, LeMaoult J. Hla-g-dependent suppressor cells: Diverse by nature, function, and significance. Human immunology 2008;69:700-7. Consiglio CR, Veit TD, Monticielo OA, et al. Association of the hla-g gene +3142c>g polymorphism with systemic lupus erythematosus. Tissue Antigens 2011;77:540-5. Disclosure of Interest None Declared
Background In recent years, a convincing body of scientific evidence has indicated that the expression of human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, plays a role in regulation of inflammation in autoimmune diseases [1]. Polymorphisms in this gene, therefore, are reasonable candidates for susceptibility and pharmacogenetics studies in RA. Objectives We sought to determine whether the 14-bp insertion/deletion polymorphism in exon 8 of the HLA-G gene is associated with susceptibility to RA, clinical features, or response to MTX therapy. Methods We determined the HLA-G 14-bp insertion/deletion polymorphism genotypes in a prospective cohort of 309 consecutive RA patients and 294 healthy controls, and looked for associations between genotype and clinical features of RA. Multivariate analyses were performed to investigate the effect of homozygosity for the -14/-14 bp genotype on changes in DAS28 in response to MTX therapy in a subgroup of 188 RA patients. Results Among the 309 RA patients, no correlations were observed between allele or genotype frequencies of the HLA-G gene polymorphism and clinical features, including disease activity scores and functional scores. No significant differences were observed in the genotype and allele frequencies between RA patients and controls. In the subgroup evaluated for clinical response to MTX, we observed a decrease in mean DAS28 over the course of the study. Furthermore, a better response to MTX treatment, measured by adjusted mean of DAS28 change, was observed in those patients with the HLA-G -14/-14-bp genotype, which was not observed among other genotypes (table 1). Table 1.Multivariate analyses for disease activity scores changes GenotypesMean DAS28 change MTX treatedNon-MTX treated –14bp/–14bp¶n=55n=7 50.071 –1.4±0.3–0.4±0.5 Others¶n=99n=120.496 –1.1±0.2–1.3±0.4 Al§n=154n=190.155 –1.2±0.1–0.7±0.3 Data are presented as means±SE. *P values for “MTX use” as predictor of response; ¶P significance and adjusted means were obtained in ANCOVA model stratified by the presence of homozygosis for deletion in the HLA-G 14 pb polymorphism with sex, and MTX use as factors and age and baseline DAS28 as covariates; §P significance and adjusted means were obtained in the ANCOVA model adding homozygosis for deletion in the HLA-G 14 pb polymorphism as factor without stratification. Conclusions Homozygosity for the 14 bp deletion polymorphism within exon 8 of the HLA-G gene was associated with a better response to MTX in a prospective cohort of patients with RA. This is a plausible genetic marker for predicting response to MTX therapy in RA. References Baricordi, O.R., et al., HLA-G and inflammatory diseases. Inflamm Allergy Drug Targets. 2008, 7(2): p. 67-74. Disclosure of Interest None Declared
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.