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Trained immunity is a process in which innate immune cells undergo functional reprogramming in response to pathogens or damage-associated molecules leading to an enhanced non-specific immune response to subsequent stimulation. While this capacity to respond more strongly to stimuli is beneficial for host defense, in some circumstances it can lead to maladaptive programming and chronic inflammation. Gout is characterized by persistent low-grade inflammation and is associated with an increased number of comorbidities. Hyperuricemia is the main risk factor for gout and is linked to the development of comorbidities. Several experimental studies have shown that urate can mechanistically alter the inflammatory capacity of myeloid cells, while observational studies have indicated an association of hyperuricemia to a wide spectrum of common adult inflammatory diseases. In this review, we argue that hyperuricemia is a main culprit in the development of the long-term systemic inflammation seen in gout. We revisit existing evidence for urate-induced transcriptional and epigenetic reprogramming that could lead to an altered functional state of circulating monocytes consisting in enhanced responsiveness and maladaptive immune responses. By discussing specific functional adaptations of monocytes and macrophages induced by soluble urate or monosodium urate crystals and their contribution to inflammation in vitro and in vivo, we further enforce that urate is a metabolite that can induce innate immune memory and we discuss future research and possible new therapeutic approaches for gout and its comorbidities.
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Artritis Gotosa/inmunología , Hiperuricemia/inmunología , Inflamación/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Ácido Úrico/metabolismo , Animales , Reprogramación Celular , Epigénesis Genética , Humanos , Inmunidad Innata , Memoria InmunológicaRESUMEN
Chronic immune activation in systemic sclerosis is supported by the production of a plethora of cytokines with proven regulatory activities of the immune responses. This study aimed to explore PBMCs' cytokine profiles in SSc patients versus controls, as well as to investigate the balance between pro- and anti-inflammatory cytokines in association with disease duration. PBMCs were isolated from 18 SSc patients and 17 controls and further subjected to in vitro stimulation with lipopolysaccharide and heat-killed Candida albicans. Cytokine production was measured after 24 h and 7 days, respectively, using ELISA kits for interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1Ra), IL-6, tumor necrosis factor (TNF), IL-10, IL-17, and interferon-gamma (IFN-gamma). IL-1 ß, IL-6, and TNF levels were increased in SSc patients compared with healthy volunteers irrespective of the stimulus used. IL-1Ra and Il-17 concentrations were not statistically different between groups, even though a trend toward higher levels in patients compared with their matched controls was also observed. Most cytokines demonstrated a stable course with disease progression, except for IL-10 levels, which declined over time. In conclusion, the results of this pilot study reveal that in patients with SSc a persistently enhanced immune response is established and maintained regardless of stimulus or disease duration.
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Leucocitos Mononucleares , Esclerodermia Sistémica , Humanos , Interleucina-10 , Interleucina-17/farmacología , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Interleucina-6/farmacología , Proyectos Piloto , Citocinas , Factor de Necrosis Tumoral alfa/farmacología , InmunidadRESUMEN
Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub-types, especially those CALR-mutated (OR = 1.4; 95% CI = 1.1-1.8; P-value = .005). HBS1L-MYB rs9376092 associated only with JAK2 V617F-mutated ET (OR = 1.4; 95% CI = 1.1-1.7; P-value = .003). THRB-RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1-2.1; P-value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F-mutated MPN, but also with CALR-mutated MPN (OR = 1.4; 95% CI = 1.1-1.8; P-value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub-type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN.
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Trastornos Mieloproliferativos/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Adulto JovenRESUMEN
Polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) represent typical myeloproliferative neoplasms (MPN), usually characterized by specific somatic driver mutations (JAK2 V617F, CALR and MPL). JAK2 46/1 haplotype and telomerase reverse transcriptase gene (TERT) rs2736100 A>C single nucleotide polymorphism (SNP) could represent a large fraction of the genetic predisposition seen in MPN. The rs10974944 C>G SNP, tagging the JAK2 46/1 haplotype, and the TERT rs2736100 A>C SNP were genotyped in 529 MPN patients with known JAK2 V617F, CALR and MPL status, and 433 controls. JAK2 46/1 haplotype strongly correlated to JAK2 V617F-positive MPN and, to a lesser extent, CALR-positive MPN. The TERT rs2736100 A>C SNP strongly correlated to all MPN, regardless of the phenotype (PV, ET or PMF) and major molecular subtype (JAK2 V617F- or CALR-positive). While both variants have a significant contribution, they have nuanced consequences, with JAK2 46/1 predisposing essentially to JAK2 V617F-positive MPN, and TERT rs2736100 A>C having a more general, non-specific effect on all MPN, regardless of phenotype or major molecular subtype.
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Calreticulina/genética , Haplotipos/genética , Janus Quinasa 2/genética , Trastornos Mieloproliferativos/genética , Telomerasa/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Policitemia Vera/genética , Polimorfismo de Nucleótido Simple , Mielofibrosis Primaria/genética , Trombocitemia Esencial/genética , Adulto JovenRESUMEN
Arterial and venous thrombosis are the most frequent complications in patients with polycythemia vera and essential thrombocythemia. We sought to demonstrate a possible contribution of the factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) 677 C > T and 1298 A > C mutations to the thrombotic risk in patients with polycythemia vera and essential thrombocythemia along with other biological features of these patients. We included 86 patients with polycythemia vera, of which 34 (39.5 %) had major thrombosis and 95 patients with essential thrombocythemia, of which 22 (23.1 %) had major thrombosis. In the whole cohort of patients, only the factor V Leiden mutation was significantly associated with both arterial and venous thrombosis in univariate and multivariate analysis (odds ratio (OR) = 4.3; 95 % confidence interval (CI) = 1.5-12.5; p = 0.008 and OR = 4.3; 95 % CI = 1.2-15.9; p = 0.02, respectively). Other factors significantly associated with thrombosis in both univariate and multivariate analysis were male sex (OR = 2.8, 95 % CI = 1.4-5.4, p = 0.002 and OR = 3.5, 95 % CI = 1.6-7.6, p = 0.002, respectively) and the JAK2 V617F mutation (OR = 5.5, 95 % CI = 2.1-15, p = 0.0001 and OR = 6.9, 95 % CI = 2.2-21.2, p = 0.001, respectively). In conclusion, among the four mutations analyzed (factor V Leiden, prothrombin G20210A, and MTHFR 677 C > T and 1298 A > C), only factor V Leiden is a major contributor to thrombosis in polycythemia vera and essential thrombocythemia.
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Factor V/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Mutación Missense , Policitemia Vera/genética , Protrombina/genética , Trombocitemia Esencial/genética , Trombosis/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , Policitemia Vera/complicaciones , Estudios Retrospectivos , Factores de Riesgo , Trombocitemia Esencial/complicaciones , Trombosis/etiologíaRESUMEN
The mRNA vaccine against COVID-19 protects against severe disease by the induction of robust humoral and cellular responses. Recent studies have shown the capacity of some vaccines to induce enduring non-specific innate immune responses by the induction of trained immunity, augmenting protection against unrelated pathogens. This study aimed to assess whether the mRNA vaccine BNT162b2 can induce lasting non-specific immune responses in myeloid cells following a three-dose vaccination scheme. In a sample size consisting of 20 healthy individuals from Romania, we assessed inflammatory proteins using the Olink® Target 96 Inflammation panel, as well as ex vivo cytokine responses following stimulations with unrelated PRR ligands. We assessed the vaccine-induced non-specific systemic inflammation and functional adaptations of myeloid cells. Our results revealed the induction of a stimulus- and cytokine-dependent innate immune memory phenotype that became apparent after the booster dose and was maintained eight months later in the absence of systemic inflammation.
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Gout is a common autoinflammatory joint diseases characterized by deposition of monosodium urate (MSU) crystals which trigger an innate immune response mediated by inflammatory cytokines. IGF1R is one of the loci associated with both urate levels and gout susceptibility in GWAS to date, and IGF-1-IGF-1R signaling is implicated in urate control. We investigate the role of IGF-1/IGF1R signaling in the context of gouty inflammation. Also, we test the gout and urate-associated IGF1R rs6598541 polymorphism for association with the inflammatory capacity of mononuclear cells. For this, freshly isolated human peripheral blood mononuclear cells (PBMCs) were exposed to recombinant IGF-1 or anti-IGF1R neutralizing antibody in the presence or absence of solubilized urate, stimulated with LPS/MSU crystals. Also, the association of rs6598541 with IGF1R and protein expression and with ex vivo cytokine production levels after stimulation with gout specific stimuli was tested. Urate exposure was not associated with IGF1R expression in vitro or in vivo. Modulation of IGF1R did not alter urate-induced inflammation. Developing urate-induced trained immunity in vitro was not influenced in cells challenged with IGF-1 recombinant protein. Moreover, the IGF1R rs6598541 SNP was not associated with cytokine production. Our results indicate that urate-induced inflammatory priming is not regulated by IGF-1/IGF1R signaling in vitro. IGF1R rs6598541 status was not asociated with IGF1R expression or cytokine production in primary human PBMCs. This study suggests that the role of IGF1R in gout is tissue-specific and may be more relevant in the control of urate levels rather than in inflammatory signaling in gout.
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Gota , Hiperuricemia , Humanos , Ácido Úrico/metabolismo , Hiperuricemia/complicaciones , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Leucocitos Mononucleares/metabolismo , Estudio de Asociación del Genoma Completo , Gota/genética , Gota/complicaciones , Inflamación/metabolismo , Citocinas/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismoRESUMEN
OBJECTIVE: Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation. METHODS: Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24h with varying concentrations of soluble urate, followed by 24h restimulation with lipopolysaccharides (LPS)±monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium® MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients with JAK2 V617F tyrosine kinase mutation. RESULTS: PBMCs pre-treated with urate produced more interleukin-1beta (IL-1ß) and interleukin-6 (IL-6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced SOCS3 expression in control monocytes but no DNA methylation changes were observed at the SOCS3 gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (JAK2 V617F mutation) could not be primed by urate. CONCLUSION: In vitro, urate exposure increased SOCS3 expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3.
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Citocinas , Gota , Factor de Transcripción STAT3 , Proteína 3 Supresora de la Señalización de Citocinas , Ácido Úrico , Humanos , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/genética , Ácido Úrico/farmacología , Factor de Transcripción STAT3/metabolismo , Citocinas/metabolismo , Gota/genética , Gota/metabolismo , Células Cultivadas , Masculino , Células Mieloides/metabolismo , Células Mieloides/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Hiperuricemia/metabolismo , Femenino , Persona de Mediana Edad , Metilación de ADN , Janus Quinasa 2/metabolismoRESUMEN
Introduction: Although metabolic-dysfunction-associated fatty liver disease (MAFLD) is associated with an increased cardiovascular risk, MAFLD predisposing genetic variants were not steadily related to cardiovascular events. Therefore, we aimed to assess whether membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) rs641738 variant is associated with an increased cardiovascular risk in in MAFLD patients. Methods: We conducted an observational cross-sectional study including 77 subjects (38 MAFLD patients, 39 controls), between January-September 2020 using hepatic ultrasonography and SteatoTestTM to assess hepatic steatosis. Echocardiographic and Doppler ultrasound parameters were evaluated. Genomic DNA was extracted and rs641738 SNP was genotyped using TaqMan assays. Results: The rs641738 variant was not significantly associated with MAFLD, with a p-value of 0.803, 0.5265, 0.9535, and 0.5751 for codominant, dominant, recessive, and overdominant genotypes, respectively. The rs641738 variant overdominant genotype significantly predicted atherosclerotic cardiovascular disease (ASCVD) risk algorithm in univariate analysis (-4.3 [95% CI -8.55 - -0.55, p-value= 0.048]), but lost significance after multivariate analysis (-3.98 [95% CI -7.9 - -0.05, p-value= 0.053]). The rs641738 variant recessive genotype significantly predicted ActiTest in univariate analysis (0.0963 [95% CI 0.0244 - 0.1681, p-value= 0.009]), but lost significance after multivariate analysis (0.0828 [95% CI -0.016 - 0.1816, p-value= 0.105]). Conclusion: No significant association was observed between rs641738 variant and MAFLD in the studied population. The rs641738 variant was found to predict ASCVD risk score and ActiTest in univariate linear regression analysis. However, the significance of both associations was lost after performing multivariate analysis.
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Gout is an autoinflammatory disease triggered by a complex innate immune response to MSU crystals and inflammatory triggers. While hyperuricemia is an obligatory risk factor for the development of gout, the majority of individuals with hyperuricemia never develop gout but have an increased risk of developing cardiometabolic disorders. Current management of gout aims at MSU crystal dissolution by lowering serum urate. We apply a targeted proteomic analysis, using Olink inflammation panel, to a large group of individuals with gout, asymptomatic hyperuricemia, and normouricemic controls, and we show a urate-driven inflammatory signature. We add in vivo evidence of persistent immune activation linked to urate exposure and describe immune pathways involved in the pathogenesis of gout. Our results support a pro-inflammatory effect of asymptomatic hyperuricemia and pave the way for new research into targetable mechanisms in gout and cardiometabolic complications of asymptomatic hyperuricemia.
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INTRODUCTION: Trained Immunity (TI) refers to the long-term modulation of the innate immune response, based on previous interactions with microbes, microbial ligands, or endogenous substances. Through metabolic and epigenetic reprogramming, monocytes, macrophages, and neutrophils develop an enhanced capacity to mount innate immune responses to subsequent stimuli and this is persistent due to alterations at the myeloid progenitor compartment. AREAS COVERED: The purpose of this article is to review the current understanding of the TI process and to discuss its potential clinical implications in the near future. We address the evidence of TI involvement in various diseases, the currently developed new therapy, and discuss how TI may lead to new clinical tools to improve existing standards of care. EXPERT OPINION: The state of the art in this domain has made considerable progress, linking TI-related mechanisms in multiple immune-mediated pathologies, starting with infections to autoimmune disorders and cancers. As a relatively new area of immunology, it has seen fast progress with many of its applications ready to be investigated in clinical settings.
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Enfermedades Autoinmunes , Neoplasias , Humanos , Ligandos , Inmunidad Innata , Monocitos , Enfermedades Autoinmunes/terapia , Memoria InmunológicaRESUMEN
BACKGROUND: Rheumatic diseases include a variety of autoimmune and autoinflammatory conditions that are characterised by musculoskeletal involvement and systemic disease. Both innate and adaptive immunity can contribute to the complex inflammatory processes that take part in the pathogenesis of these debilitating disorders. FINDINGS: Over the past decade, studies have led to a paradigm-shift around the concept of immune memory, generating the knowledge that cells of the innate immune system can develop a de facto memory mediated by epigenetic reprograming and metabolic changes (trained immunity). Here we provide an overview of current data that describe features of trained immunity in rheumatic diseases. We link evidence on inflammatory mediators and cytokine production, immunometabolism and epigenetic regulation of immunological programs, and outline the fact that trained immunity could play mechanistic roles in rheumatic diseases such as gout, rheumatoid arthritis, systemic lupus erythematosus or systemic sclerosis. CONCLUSION: This review describes recent findings in several important rheumatic disorders and emphasizes changes in the functional program of innate immune cells that are reminiscent of a trained immune phenotype. Further assessment of trained immunity in rheumatic disease can provide targetable mechanisms that could potentially alter the disease symptomatology and evolution.
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Enfermedades Autoinmunes , Enfermedades Reumáticas , Inmunidad Adaptativa , Epigénesis Genética , Humanos , Inmunidad Innata , InflamaciónRESUMEN
Polycythemia vera, essential thrombocythemia, and primary myelofibrosis are myeloproliferative neoplasms, characterized in a majority of cases by a unique somatic point mutation, JAK2 V617F. Recently, it was shown that JAK2 V617F occurs more frequently on a specific JAK2 haplotype, named JAK2 46/1. We genotyped 149 myeloproliferative neoplasms patients (69 had polycythemia vera, 65 had essential thrombocythemia, and 15 had primary myelofibrosis) with a known JAK2 V617F mutational status and 150 controls for the JAK2 rs10974944 (C/G) single nucleotide polymorphism, in which the G allele tags the 46/1 haplotype. We found that the rs10974944 GG/CG genotypes were significantly enriched in patients compared to controls (p < 0.0001). After stratifying for the JAK2 V617F mutational status and for the mutant allele burden, we demonstrated that GG/CG genotypes were significantly more frequent in V617F positive compared to V617F negative patients (p = 0.001), but not in V617F negative patients compared to controls (p = 0.29). Similarly, the GG/CG genotypes were significantly enriched in V617F positive patients with a mutant allele burden >50% compared to those with a mutant allele burden <50% (p = 0.0006). Our results indicate that the G allele, part of the JAK2 46/1 haplotype, contributes significantly to the occurrence of JAK2 V617F-positive myeloproliferative neoplasms. Moreover, JAK2 46/1 seems to be associated with mutant allele burden >50% in JAK2 V617F-positive myeloproliferative neoplasms patients.
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Alelos , Haplotipos , Neoplasias Hematológicas , Janus Quinasa 2/genética , Trastornos Mieloproliferativos , Polimorfismo de Nucleótido Simple , Genotipo , Neoplasias Hematológicas/enzimología , Neoplasias Hematológicas/genética , Humanos , Persona de Mediana Edad , Mutación , Trastornos Mieloproliferativos/enzimología , Trastornos Mieloproliferativos/genéticaRESUMEN
BACKGROUND: The complexity of myeloproliferative neoplasms (MPNs) cannot be characterized by acquired somatic mutations alone. Individual genetic background is thought to contribute to the development of MPNs. The aim of our study was to assess the association between the TET2 rs1548483 single nucleotide polymorphism (SNP) and the susceptibility to polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) or chronic myeloid leukemia (CML). METHODS: We evaluated the TET2 rs1548483 SNP through real-time PCR in 1601 MPN patients out of which 431 with PV, 688 with TE, 233 with PMF, 249 with CML and 197 controls. We included only patients with a molecularly proven driver mutation, such as JAK2 V617F, CALR or BCR-ABL1. RESULTS: Significant association between TET2 rs154843 variant allele and JAK2 V617F-positive PV and PMF (OR = 1.70; 95% CI: 1.01-2.91; p-value = 0.046, and OR = 2.04; 95% CI: 1.10-3.77; p-value = 0.024, respectively), and type 2 CALR-positive PMF (OR = 2.98; 95% CI: 1.12-7.93; p-value = 0.035) was noted. CONCLUSIONS: The TET2 rs1548483 SNP is associated with the susceptibility to molecularly annotated PV and PMF.
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PURPOSE: Osteopathy/osteoporosis in Gaucher disease type 1 (GD1) shows variable responses to enzyme replacement therapy (ERT); the pathogenesis is incompletely understood. We aimed to investigate the effects of several gene variants on bone mineral density (BMD) and serum markers of bone metabolism in GD1. PATIENTS AND METHODS: Fifty adult Caucasian patients with GD1/117 controls were genotyped for gene variants in the osteoprotegerin (TNFRSF11B; OPG), estrogen receptor alpha, calcitonin receptor (CALCR), and vitamin D receptor (VDR) genes. In patients and 50 matched healthy controls, we assessed clinical data, serum markers of bone metabolism, and subclinical inflammation. BMD was measured for the first time before/during ERT (median 6.7 years). RESULTS: Forty-two percent of patients were splenectomized. ERT led to variable improvements in BMD. Distribution of gene variants was comparable between patients/controls. The AA genotype (c.1024+283G>A gene variant; VDR gene) was associated with lower Z scores before ERT vs GA (P=0.033), was encountered in 82.3% of patients with osteoporosis and was more frequent in patients with pathological fractures. Z score increases during ERT were higher in patients with the CC genotype (c.9C>G variant, TNFRSF11B; OPG gene; P=0.003) compared with GC (P=0.003). The CC genotype (c.1340T>C variant, CALCR gene) was associated with higher Z scores before ERT than the TT genotype (P=0.041) and was absent in osteoporosis. Osteocalcin and OPG were lower in patients vs controls; beta crosslaps, interleukin-6, and ferritin were higher. CONCLUSIONS: We suggest for the first time a protective role against osteoporosis in GD1 patients for the CC genotype of the c.9C>G gene variant in the TNFRSFB11 (OPG) gene and for the CC genotype of the c.1340T>C gene variant (CALCR gene), while the AA genotype of the c.1024+283G>A gene variant in the VDR gene appears as a risk factor for lower BMDs. Serum markers suggest decreased osteosynthesis, reduced inhibition of osteoclast activation, increased bone resorption, and subclinical inflammation during ERT.
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BACKGROUND AND AIM: Patients with Gaucher disease type 1 (GD1) show an altered lipid profile and a certain degree of insulin resistance, which might contribute to cholelithiasis (CL) and could possibly be associated with ABCG5/ABCG8 gene variants. We aimed to investigate the prevalence of CL in Caucasian adult patients with GD1 and the possible risk factors, including gene variants of the ABCG5/ABCG8 genes. METHODS: 61 Caucasian patients with GD1 (38 female/23male), aged 18-62 years and 61 healthy subjects matched for age, gender and BMI, without CL, for comparison of lipid profiles. Data before start of enzyme replacement therapy (ERT) were recorded: clinical, haematological, severity parameters, splenectomy, genotype. Fasting lipid profiles before ERT, glycemia, insulinaemia, HOMA-IR at the last visit were documented. Genotyping for the gene variants D19H, Y54C, T400K, A632V (ABCG8); Q604E (ABCG5) was performed. RESULTS: CL occurred in 45.9% of patients. Risk factors were: age, family history of CL, higher BMI values, LDL-cholesterol (LDL-C), disease severity, splenectomy. A specific dyslipidemia was found in patients vs. controls. Total serum cholesterol (TC) and LDL-C were higher in patients with CL than in those without; no obvious influence of insulin-resistance to lithogenesis was found. Patients with the GG genotype of D19H and the CC genotype of T400K (ABCG8 gene) had significantly higher levels of TC and LDL-C. CONCLUSION: Patients with GD1 showed an increased prevalence of CL, which was associated with common and disease-specific risk factors. Starting ERT soon after clinical onset and avoiding splenectomy might reduce the risk of CL in GD1.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Colelitiasis/genética , Enfermedad de Gaucher/genética , Variación Genética , Lipoproteínas/genética , Adolescente , Adulto , Estudios de Casos y Controles , Colelitiasis/diagnóstico , Colelitiasis/epidemiología , Estudios Transversales , Terapia de Reemplazo Enzimático , Femenino , Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/tratamiento farmacológico , Enfermedad de Gaucher/epidemiología , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Glucosilceramidasa/uso terapéutico , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Prevalencia , Factores de Riesgo , Rumanía/epidemiología , Población Blanca/genética , Adulto JovenRESUMEN
OBJECTIVES: To analyze the relationship between six polymorphisms in genes related to oxidative stress, namely CAT-262 C>T, MnSOD Ala16Val, GPX1 Pro198Leu, GSTM1 and GSTT1 null genotypes, and GSTP1 Ile105Val, and the occurrence of BCR-ABL negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, and primary myelofibrosis). METHODS: We genotyped for these polymorphisms 328 patients with a known mutation status for JAK2 V617F, MPL and CALR, and 363 controls, using molecular genetics assays. RESULTS: The CAT-262 C>T and GPX1 Pro198Leu polymorphisms were seen significantly less frequently, while the GSTP1 IleVal105 polymorphism was seen significantly more frequently in patients with BCR-ABL negative myeloproliferative neoplasms, regardless of the molecular sub-type (e.g. JAK2 V617F or CALR mutated). DISCUSSION AND CONCLUSION: Our study provides evidence that variation in genes related to oxidative stress might modulate the risk of developing BCR-ABL negative myeloproliferative neoplasms.