HLA-G 3' Untranslated Region Polymorphisms Are Associated with Systemic Lupus Erythematosus in 2 Brazilian Populations (original) (raw)
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Tissue antigens, 2015
This study aims to comprehensively analyze human leucocyte antigen (HLA)-G polymorphisms association with susceptibility to systemic lupus erythematosus (SLE) development and clinical manifestations. The HLA-G 5' upstream regulatory region (URR), 3' untranslated region (UTR) and a cytosine deletion at exon 3 (ΔC, HLA-G*0105N allele) were analyzed in 114 SLE patients and 128 healthy controls from North East Brazil. The +3003T>C (rs1707) C allele and the HG010101c extended HLA-G allele were significantly more frequent in SLE patients than healthy controls (+3003C allele frequency: 12% in SLE patients vs 6% in controls; odds ratio (OR), 2.10, 95% confidence interval (CI), 1.06-4.28, P = 0.026; HG010101c frequency: 11.8% in SLE patients and 6.3% in controls; OR, 2.14, 95% CI, 1.01-4.51, P = 0.046) and were associated with susceptibility for disease development. Other polymorphisms were associated with different clinical manifestations. Although HLA-G role in SLE disease is fa...
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.
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.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that has been associated with HLA-G in previous studies on immunological diseases. This study aimed to investigate the association between three HLA-G gene polymorphisms (rs1632947, rs1233334, and rs371194629) and their impact on HLA-G mRNA expression and soluble HLA-G levels in serum. Genotyping was performed using TaqMan probe PCR. RNA extraction, reverse transcription PCR, and real-time PCR assay were conducted to assess the expression of microRNAs in serum and tissue samples. Soluble HLA-G was mesurede using ELISA in serum. Statistical analyses were performed using GraphPad Prism software with a significance level of p-value of 0.05. Results show a significant difference in the frequency of the G allele for two 5' untranslated region (UTR) polymorphisms of the HLA-G gene (rs1632947 and rs1233334) located at position − 964 and − 725, respectively, between the lupus patients and controls, with p-values of 0.009...
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.
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.
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 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.
Lupus, 2018
The aim of this case-control study was to investigate the association of human leukocyte antigen (HLA) Class II alleles with the susceptibility and phenotypic heterogeneity in systemic lupus erythematosus (SLE) in South Indian patients. A total of 439 individuals (212 SLE cases and 227 age-and ethnicity-matched controls) were included in the study. The genotyping of HLA-DRb1 and-DQb1 was conducted by the PCR-SSP method. HLA-DRb1*07 was significantly associated with SLE (OR: 2.02; 95% CI: 1.34-3.04, p ¼ 1.50 Â 10 À4 , p c ¼ 1.95 Â 10 À3), whereas the DRb1*14 allele was negatively associated with SLE (OR: 0.49; 95% CI: 0.31-0.76, p ¼ 1.70 Â 10 À2 , p c ¼ 0.221). In addition, the HLA-DRb1*07/15 genotype tended to be positively associated with SLE (OR: 3.23, 95% CI: 1.57-6.63, p ¼ 0.0009). Amino acid residues residing in the peptide-binding pocket of HLA-DRb1 play a significant role in peptide recruitment and antigen presentation. Our results demonstrated that amino acid glycine 11 (OR: 2.11, 95% CI: 1.42-3.12, p c ¼ 0.00093), tyrosine 13 (OR: 2.11, 95% CI: 1.42-3.12, p c ¼ 0.00062) and glutamine 74 (OR: 2.11, 95% CI: 1.42-3.12, p c ¼ 0.00077) showed a significant positive association with SLE. Certain haplotype combinations, DRB1*07-DQb1*03 (OR: 2.21; 95% CI:1.29-3.79, p c ¼ 0.06, p ¼ 0.00036) and DRb1*07-DQb1*05 (OR: 2.51, 95% CI: 1.34-4.71, p c ¼ 0.07, p ¼ 0.00039), had positive associations whereas DRb1*14-DQb1*03 (OR: 0.14, 95% CI: 0.061-0.36, p c ¼ 2.34 Â 10 À5 , p ¼ 1.30 Â 10 À6) were found to have a significant negative association with SLE. So far, the present study is the first attempt to investigate the association of HLA-DRb1 and-DQb1 allele, genotype and haplotype combinations with the risk of SLE in South Indian patients. In conclusion, the HLA-DRb1*07 allele is associated with risk of SLE whereas a protective association of HLA-DRb1*14 alleles with SLE was observed. Lupus (2018) 0, 1-10.
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.