Comprehensive analysis of polymorphisms in the HLA-G 5' upstream regulatory and 3' untranslated regions in Brazilian patients with systemic lupus erythematosus (original) (raw)
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The Journal of Rheumatology, 2013
Objective.HLA-G has well recognized tolerogenic properties in physiological and nonphysiological conditions. The 3′ untranslated region (3′UTR) of the HLA-G gene has at least 3 polymorphic sites (14-bpINS/DEL, +3142C/G, and +3196C/G) described as associated with posttranscriptional influence on messenger RNA production; however, only the 14-bpINS/DEL and +3142C/G sites have been studied in systemic lupus erythematosus (SLE).Methods.We investigated the HLA-G 3′UTR polymorphic sites (14-bpINS/DEL, +3003C/T, +3010C/G, +3027A/C, +3035C/T, +3142C/G, +3187A/G, and +3196C/G) in 190 Brazilian patients with SLE and 282 healthy individuals in allele, genotype, and haplotype analyses. A multiple logistic regression model was used to assess the association of the disease features with the HLA-G 3′UTR haplotypes.Results.Increased frequencies were observed of the 14-bpINS (p = 0.053), +3010C (p = 0.008), +3142G (p = 0.006), and +3187A (p = 0.013) alleles, and increased frequencies of the 14-bpINS...
Association of the HLA-G gene +3142C>G polymorphism with systemic lupus erythematosus
Tissue Antigens, 2011
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease that affects several organs and systems. Its etiology remains unknown, although it is probably multifactorial. The human leukocyte antigen G (HLA-G) is a nonclassic major histocompatibility complex I molecule characterized by restricted expression and low DNA polymorphism. HLA-G plays a role in immunosuppression through different mechanisms. In inflammatory diseases, it has been postulated that HLA-G expression may be a possible mechanism of tissue protection against exacerbated inflammatory response. On the 3 untranslated region (3 UTR) of the HLA-G gene, there is an insertion/deletion polymorphism of 14 bp (rs1704) that was shown to influence the mRNA stability. The influence of this polymorphism in disease susceptibility is controversial. Also in the 3 UTR there is a single nucleotide polymorphism C/G (rs1063320) on the position +3142, at a possible binding site for microRNAs (miRNAs) and having an influence on miRNA affinity. In this study, we analyzed the +3142C>G and the 14 bp polymorphisms in 195 SLE European-derived female patients. Our findings show a significant increase of the +3142G allele frequency among patients as compared with controls (0.58 vs 0.47, P = 0.011). Also, patients presented a higher frequency of the GG genotype (OR = 1.90, 95% CI: 1.08-3.42). Double heterozygotes for the two polymorphisms presented a milder mean systemic lupus erythematosus disease activity index (SLEDAI) than heterozygotes for only one of the variants or non-heterozygous individuals (1.56 vs 3.15 and 3.26, respectively, corrected P = 0.044). These results suggest the involvement of the HLA-G molecule on SLE susceptibility and outcome.
Journal of the Selva Andina Research Society, 2020
La susceptibilidad individual en autoinmunidad puede estar determinada por una combinación de polimorfismos específicos de genes que codifican para múltiples proteínas, citoquinas, antígenos del complejo principal de histocompatibilidad, moléculas de adhesión, y proteínas celulares. Esta condición puede conducir a la expresión anormal de moléculas inmunoreguladoras y finalmente resultar en el desarrollo o exacerbación de la enfermedad autoinmune. HLA-G es una molécula glicoprotéica del MHC de clase I, la cual cumple con funciones muy importante al momento de activar y regular el sistema inmune. Por lo tanto, lo que se pretende con este estudio es determinar la asociación genética entre el polimorfismo de 14 pb del gen HLA-G con la susceptibilidad a contraer LES y las manifestaciones clínicas de la enfermedad. La población de estudio consistió de 120 pacientes con LES y 112 pacientes sin la enfermedad (grupo control), 94% procedía de la ciudad de La Paz, quienes asistieron al Instituto SELADIS. Para el estudio se obtuvo el DNA humano a partir de sangre periférica, se realizó la PCR para la tipificación molecular de los genotipos y alelos que fueron revelados por medio de electroforesis en gel de agarosa. Al mismo tiempo se realizaron pruebas serológicas por ELISA para determinar la presencia de anticuerpos IgG anti-DNA de doble cadena en los pacientes lúpicos. Los resultados de la PCR mostraron que los pacientes lúpicos tienen mayor frecuencia de expresión del genotipo Ins/Del (OR=1.72, p<0.05); mientras que, la presencia del genotipo homocigoto Ins/Ins es más frecuente en el grupo control (OR=0.29, p<0.001), mostrándose de esta forma que el primer genotipo es un factor de riesgo y el segundo, un factor de protección a padecer LES respectivamente. Se observó también que entre pacientes y controles no existe diferencia significativa en la frecuencia de presentación del genotipo Del/Del en homocigosis. En cuanto a las frecuencias alélicas se obtuvo que el alelo deleción en más frecuente en el grupo de pacientes lúpicos, a comparación del grupo control donde ambos alelos presentaron el mismo porcentaje. Con respecto a las manifestaciones clínicas se observó que el polimorfismo Ins/Del (O.R=8.64) es factor de riesgo para el desarrollo de manifestaciones dermatológicas. 2020. Journal of the Selva Andina Research Society®. Bolivia. Todos los derechos reservados.
Tissue Antigens, 2008
Systemic lupus erythematosus (SLE) is an autoimmune disease mainly mediated by the deposit of immune complexes and defects in T lymphocytes and antigenpresenting cells along with a high production of T-helper 2 cytokines. A toleranceinducible function of nonclassical class Ib human leukocyte antigen (HLA)-G molecule in innate and adaptive cellular responses has been reported, suggesting a role in inflammatory diseases. A 14 bp sequence insertion/deletion polymorphism (rs16375) in the 3#-untranslated region of the HLA-G gene has been associated to the stability of HLA-G messenger RNA. The insertion of the 14 bp sequence seems to be associated with lower levels of soluble HLA-G (sHLA-G). The aim of this study was to evaluate the possible association of the presence of the 14 bp sequence (114 bp) with SLE. We have HLA-G genotyped 200 SLE patients and 451 healthy control subjects (HS; Italian) and analyzed the plasma levels of sHLA-G and interleukin-10 (IL-10) in a subset of SLE patients and healthy subjects (Italian and Danish). A significant increase of the 114 bp HLA-G allele was detected in the Italian SLE patients compared with HS [P ¼ 0.003, OR 1.44 (95% CI 1.13-1.82)]. A significant increased frequency of HLA-G 114/114 bp and a decreased frequency of HLA-G 214/214 bp were observed in SLE patients. There median concentration of sHLA-G was significantly lower in the plasma of SLE patients compared with that in the plasma of healthy controls (P < 0.0001). Furthermore, the results confirmed higher concentrations of IL-10-positive plasma in SLE patients. These results support a potential role for HLA-G in the susceptibility of SLE.
HLA Class II DNA Typing in a Large Series of European Patients with Systemic Lupus Erythematosus
Medicine, 2002
The etiopathogenesis of systemic lupus erythematosus (SLE) is complex and still largely unknown. Genetic, environmental, and hormonal factors contribute to disease susceptibility (1). The importance of genetic factors is documented by 1) the pronounced difference in concordance rates between monozygotic and dizygotic twins (15); 2) the higher disease prevalence in relatives of patients with SLE (14); 3) the higher prevalence of SLE in certain ethnic groups, like African Americans and some Native Americans (18); and 4) studies of murine SLE showing that some strains invariably develop the disease (23, 24). In humans, several genes contribute to lupus susceptibility. Their identification has been complicated by the fact that SLE is a heterogeneous disease, both clinically and immunologically (3); in addition, many of the susceptibility genes differ across the various populations (27), and it is well recognized that genetic
HLA class II haplotypes in Mexican systemic lupus erythematosus patients
Human Immunology, 2004
Systemic lupus erythematosus (SLE) is an autoimmune disease in which polymorphisms within the human leukocyte antigen (HLA) region have been associated to its etiology. For this study, HLA-DQB1, DQA1, and DRB1 genes were typed by polymerase chain reactionsequence-specific primer in 237 individuals, taken from 74 families, who had a member with SLE, and who had their residence in the western region of Mexico; as well as in 159 ethnically matched healthy volunteers taken from 32 families. Genotype and allele frequency analysis was performed in 74 SLE patients and 54 unrelated controls. Precise threeloci identification of independent haplotypes was performed in 48 patients and 54 controls by familial segregation. Genotype distribution at each loci was concordant with Hardy-Weinberg's equilibrium in the control group. In general, no genotype effect was observed in SLE patients.
Association of the HLA-G 14 bp polymorphism with systemic lupus erythematosus
Lupus, 2009
Human leukocyte antigen-G (HLA-G) is a nonclassical class I major histocompatibility complex molecule which is induced at the course of inflammatory pathologies, and its expression has been suggested as a possible mechanism of tissue protection against autoimmune inflammatory responses, therefore acting as a mechanism of immune surveillance. We investigated the influence of the 14 bp polymorphism of the HLA-G gene on systemic lupus erythematosus (SLE) by analyzing 293 patients with SLE and 460 healthy controls. The patient's group was not in Hardy-Weinberg equilibrium, presenting an excess of heterozygotes (P = 0.014). The heterozygote group exhibited lower systemic lupus erythematosus disease activity indexes than the homozygous deletion group and the homozygous insertion group (mean value = 2.29 against 2.97 and 3.4, respectively, P = 0.035). Photosensitive patients showed a higher frequency of heterozygotes and an equivalent lower frequency of homozygotes for deletion; on the other hand, patients without arthritis presented a higher frequency of heterozygotes than the arthritis group and also a lower frequency of the del/del genotype. Overall, our results support the idea of a role of the HLA-G insertion/deletion polymorphism and therefore a role for the HLA-G molecule, on the pathology of SLE. Lupus (2009) 18, 424-430.
HLA in Portuguese Systemic Lupus Erythematosus Patients and Their Relation to Clinical Features
Annals of The New York Academy of Sciences, 2009
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease translating the different genetic and environmental factors involved. Polymorphisms at several loci, including the major histocompatibility complex (MHC), have been associated worldwide with SLE, although inconsistencies exist among these studies mainly due to genetic heterogeneity between populations and sample characteristics. The aim of the present study was to investigate in Portuguese SLE the association of HLA-DRB1 alleles with clinical patterns of the disease and severity. Two hundred eighteen Portuguese patients with SLE—42% of whom had kidney involvement—were studied for HLA-DRB1. Clinical and laboratory manifestations were correlated with HLA allele frequencies. HLA-DRB1 * 03 allele frequency was significantly higher in SLE patients—as a whole and as either with or without renal involvement—compared to controls, while HLA-DRB1 * 09 and DRB1 * 13 allele frequencies were decreased. Regarding the relationship with the presence or absence of specific clinical manifestations, it was only found that HLA-DRB1 * 08 allele frequency was increased in patients with neurological involvement. No association with the presence or absence of anti-dsDNA, anti-sm or antiphospholipid antibodies, or antiphospholipid syndrome, was observed. These results were reproducible when analysis was repeated only with patients with more than 5 years of evolution. As in other populations HLA-DRB1 * 03 is a susceptibility allele in Portuguese SLE patients, while HLA-DRB1 * 09 and DRB1 * 13 alleles may be protective alleles, not only for the disease, but for the development of nephritis. No correlations with the different clinical manifestations were found, except with the neurological system.
Meta Gene, 2018
Background: Systemic Lupus Erythematosus (SLE) is a multisystem generalized chronic autoimmune disorder characterized by humoral autoimmunity. The etiology of SLE is thought to be multifactorial involving an interplay of environmental, humoral, and genetic factors. There is a strong association of the human leukocyte antigen (HLA) with SLE, however, the association is likely to be heterogeneous among different ethnic groups. The aim of this study was to determine the association of HLA-DRB1, HLA-DQA1 and HLA-DQB1 with SLE susceptibility and clinical manifestations in the western Indian population. Methods: A total of 250 SLE patients fulfilling the ACR criteria were recruited and an equal number of age sex and ethnically matched normal healthy controls were recruited for this study. HLA types were determined by the polymerase chain reaction on a Luminex platform with sequence-specific oligonucleotide primers (PCR-SSOP) method in 250 patients and 250 control subjects. Results: The following HLA alleles were found to be positively associated with SLE: HLA-DRB1*04 (P=.00380), HLA DRB1*11 (P=0.0001), HLA-DQB1*03 (P=.0008), HLA DQB1*05(P=0.040) and DQA1*01(P=0.
Autoimmunity Reviews, 2008
Objective: To estimate the common effect size of HLA-DRB1 and -DQB1 alleles on systemic lupus erythematosus (SLE) susceptibility across Latin America populations through a meta-analysis. Methods: Case-control studies on HLA class II association with SLE in Latin America were searched up to August 2007. The effect summary odds ratios (ORs) and 95% confidence intervals (CIs) were obtained by means of the random effect model. Results: Eleven studies were selected, which included 747 cases and 1180 controls. Associations with SLE susceptibility were found for HLA-DR2 (OR: 1.75; 95% CI: 1.40-2.19) and -DR3 (OR: 2.02; 95% CI: 1.44-2.83) groups. HLA-DRB1⁎0301 allele disclosed the strongest association (OR: 2.14; 95% CI: 1.28-3.56). HLA-DR3-DQ2 haplotype was a risk factor (OR: 2.92; 95% CI: 1.66-5.14). A protective effect was found for the HLA-DR5 group (OR: 0.43; 95% CI: 0.27-0.67), mainly due to a negative association between HLA-DRB1⁎1101 allele and disease (OR: 0.21; 95% CI: 0.06-0.72). Functional analysis of susceptibility and protective alleles revealed physicochemical differences of critical amino acids shaping the peptide-binding groove at DRβ chain allowing us to infer an approach to understand the role of HLA in SLE. No significant association was established for HLA-DQB1 alleles. Conclusions: HLA-DRB1 gene is a mayor factor for development of SLE in Latin Americans.