GWAS-identified hyperuricemia-associated IGF1R variant rs6598541 has a limited role in urate mediated inflammation in human mononuclear cells.

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.

Regulation of SOCS3-STAT3 in urate-induced cytokine production in human myeloid cells.

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.

Prevalence of Azole-Resistant Aspergillus Section Fumigati Strains Isolated from Romanian Vineyard Soil Samples.

The relationship between fungal species and their resistance patterns in vineyard soils has important implications for agriculture and medicine. This study explored the prevalence of Aspergillus section Fumigati species and their resistance to azole compounds in Romanian vineyard soils. METHODS: A total of 265 soil samples from various Romanian vineyards were screened for fungi resistant to azoles. RESULTS: Aspergillus section Fumigati isolates exhibited significant resistance to itraconazole and voriconazole, but no azole-resistant Aspergillus fumigatus strains were detected. Six percent of the samples were positive for Aspergillus section Fumigati strains, all of which were azole-resistant. The strains were mainly Aspergillus udagawae (93.75%) and Aspergillus lentulus (6.25%). The predominant azole-resistant Aspergillus species were Aspergillus section Nigri strains, which were found in 75 soil samples. CONCLUSIONS: This study highlights the importance of understanding fungal resistance in vineyard soils for both the agricultural and clinical sectors. The presence of resistant strains may affect vine health and wine production while also constituting a challenge in the selection of effective treatments against severe and potentially fatal fungal infections in humans, stressing the importance of species-specific antifungal resistance knowledge.

Enhanced Innate and Acquired Immune Responses in Systemic Sclerosis Primary Peripheral Blood Mononuclear Cells (PBMCs).

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.

Hyperuricemia remodels the serum proteome toward a higher inflammatory state.

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.

The association between the CCDC88A gene polymorphism at rs1437396 and alcohol use disorder, with or without major depression disorder.

Girdin is a protein involved in neuronal migration and hippocampal development. It is encoded by the coiled-coil domain-containing 88A (CCDC88A) gene, located on the short arm of chromosome 2 (2p). The CCDC88A gene is modulated by the intergenic single-nucleotide polymorphism (SNP) of the rs1437396, situated 9.5 kb downstream from its transcription stop site. As recent genome-wide research has associated the T allele of the SNP with increased risk of alcohol use disorder (AUD), we wanted to validate this finding in an independent cohort and to test further for an association with comorbid major depressive disorder (MDD). The study included 226 AUD patients (AUD group), 53 patients with comorbid MDD, and 391 controls selected randomly. The participants were genotyped for the rs1437396 polymorphism using the real-time polymerase chain reaction. The association between the rs1437396 polymorphism and increased risk of AUD and AUD+MDD was tested with logistic regression. Our results show significantly higher frequency of the T risk allele in the AUD group (p=0.027) and even higher in the AUD+MDD group (p=0.016). In conclusion, this is the first study that has validated the association between the rs1437396 polymorphism of the CCDC88A gene and AUD with or without MDD. Studies on larger samples of patients are needed to further investigate the mechanism of this association.

MBOAT7 rs641738 variant in metabolic-dysfunction-associated fatty liver disease and cardiovascular risk.

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.

Copy number variation analysis in 189 Romanian patients with global developmental delay/intellectual disability.

BACKGROUND: Developmental delay and intellectual disability represent a common pathology in general population, involving about 3% of the pediatric age population, the genetic etiology being often involved. The aim of this study was to determine the clinically relevant copy number variants in patients diagnosed with global developmental delay/intellectual disability in our population, using the chromosomal microarray analysis. METHODS: We analyzed 189 patients diagnosed with global developmental delay/intellectual disability, presented in Clinical Emergency Hospital for Children, Cluj-Napoca. The patients were completely clinically investigated, including dysmorphic and internal malformations evaluation, psychiatric, neuropsychological and metabolic evaluation, standard karyotyping. Genomic analysis was done using chromosomal microarray analysis. RESULTS: Pathogenic findings (including uniparental disomy) and variants of unknown significance were detected in 53 of 189 patients (28.04%). Pathogenic copy number variants and uniparental disomy were observed in 35 of 189 patients (18.51%). Two patients presented uniparental disomy for chromosome 15, one with clinical phenotype of Prader-Willi syndrome and the other with clinical phenotype with Angelman syndrome. Within the category of pathogenic findings, the recurrent copy number variants were seen in 21 of 35 patients (60%). CONCLUSIONS: The increased percentage of pathogenic structural variants observed in patients with global developmental delay/intellectual disability analyzed by chromosomal microarray technique supports its use in patients with a non-specific phenotype such as these neurodevelopmental disorders. The high percentage of recurrent pathogenic variants between these findings is a finding that support their initial evaluation when a genetic testing algorithm could be a useful option.

The future clinical implications of trained immunity.

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.

Trained immunity and inflammation in rheumatic diseases.

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.

Non-Syndromic Hearing Loss in a Romanian Population: Carrier Status and Frequent Variants in the GJB2 Gene.

The genetic causes of autosomal recessive nonsyndromic hearing loss (ARNSHL) are heterogeneous and highly ethnic-specific. We describe GJB2 (connexin 26) variants and carrier frequencies as part of our study and summarize previously reported ones for the Romanian population. In total, 284 unrelated children with bilateral congenital NSHL were enrolled between 2009 and 2018 in northwestern Romania. A tiered diagnostic approach was used: all subjects were tested for c.35delG, c.71G>A and deletions in GJB6 (connexin 30) using PCR-based methods. Furthermore, 124 cases undiagnosed at this stage were analyzed by multiplex-ligation-dependent probe amplifications (MLPA), probe mix P163, and sequencing of GJB2 exon 2. Targeted allele-specific PCR/restriction fragment length polymorphism (RFLP) established definite ethio-pathogenical diagnosis for 72/284 (25.35%) of the cohort. Out of the 124 further analyzed, in 12 cases (9.67%), we found compound heterozygous point mutations in GJB2. We identified one case of deletion of exon 1 of the WFS1 (wolframin) gene. Carrier status evaluation used Illumina Infinium Global Screening Array (GSA) genotyping: the HINT cohort-416 individuals in northwest Romania, and the FUSE cohort-472 individuals in southwest Romania. GSA variants yielded a cumulated risk allele presence of 0.0284. A tiered diagnostic approach may be efficient in diagnosing ARNSHL. The summarized contributions to Romanian descriptive epidemiology of ARNSHL shows that pathogenic variants in the GJB2 gene are frequent among NSHL cases and have high carrier rates, especially for c.35delG and c.71G>A. These findings may serve in health strategy development.

Molecular and Cytogenetic Analysis of Romanian Patients with Differences in Sex Development.

Differences in sex development (DSD) are often correlated with a genetic etiology. This study aimed to assess the etiology of DSD patients following a protocol of genetic testing. MATERIALS AND METHODS: This study prospectively investigated a total of 267 patients with DSD who presented to Clinical Emergency Hospital for Children Cluj-Napoca between January 2012 and December 2019. Each patient was clinically, biochemically, and morphologically evaluated. As a first intervention, the genetic test included karyotype + SRY testing. A high value of 17-hydroxyprogesterone was found in 39 patients, in whom strip assay analysis of the CYP21A2 gene was subsequently performed. A total of 35 patients were evaluated by chromosomal microarray technique, and 22 patients were evaluated by the NGS of a gene panel. RESULTS: The karyotype analysis established the diagnosis in 15% of the patients, most of whom presented with sex chromosome abnormalities. Genetic testing of CYP21A2 established a confirmation of the diagnosis in 44% of patients tested. SNP array analysis was particularly useful in patients with syndromic DSD; 20% of patients tested presented with pathogenic CNVs or uniparental disomy. Gene panel sequencing established the diagnosis in 11 of the 22 tested patients (50%), and the androgen receptor gene was most often involved in these patients. The genes that presented as pathogenic or likely pathogenic variants or variants of uncertain significance were RSPO1, FGFR1, WT1, CHD7, AR, NIPBL, AMHR2, AR, EMX2, CYP17A1, NR0B1, GNRHR, GATA4, and ATM genes. CONCLUSION: An evaluation following a genetic testing protocol that included karyotype and SRY gene testing, CYP21A2 analysis, chromosomal analysis by microarray, and high-throughput sequencing were useful in establishing the diagnosis, with a spectrum of diagnostic yield depending on the technique (between 15 and 50%). Additionally, new genetic variants not previously described in DSD were observed.

Diagnostic Usefulness of MLPA Techniques for Recurrent Copy Number Variants Detection in Global Developmental Delay/Intellectual Disability.

BACKGROUND: Genetic testing has become a standardized practice in the diagnosis of patients with global developmental delay/intellectual disability (GDD/ID). The aim of this study is to observe the frequency of recurrent copy number variations (CNVs) in patients diagnosed with GDD/ID, using MLPA technique. METHODS: A total of 501 paediatric patients with GDD/ID were analysed using SALSA MLPA probemix P245 Microdeletion Syndromes-1A, and the technical steps were performed according to the MRC Holland MLPA general protocol. RESULTS: Twenty-five of 501 patients (5%) were diagnosed with a microdeletion/microduplication syndrome. Amongst them, 7 of 25 (30%) with clinical suggestion have a confirmed diagnosis, for the other cases the clinical features were not evocative for a specific syndrome. CONCLUSION: This study showed that in cases with a specific clinical diagnosis the MLPA technique could be a useful alternative, less expensive and more efficient to indicate as first intention of a targeted diagnostic test, as it is the case of Williams syndrome, Prader-Willi syndrome or DiGeorge syndrome.

Skeletal Abnormalities and VDR1 Gene Polymorphisms in Mucopolysaccharidosis Patients.

INTRODUCTION: Articular and bone damage, which is so disabling in Mucopolysaccharidosis (MPS), requires attention as to the explanatory bias of the pathogenetic mechanisms identified to date. The vitamin D receptor (VDR) has been investigated in many studies in correlation with bone metabolism, osteoporosis, and the impaired bone mineral density associated with certain polymorphisms of the VDR gene. AIM: This study aims to observe whether there is an association between clinical features, phospho-calcium metabolism parameters and the VDR gene polymorphisms in patients with MPS. PATIENTS AND METHOD: We evaluated six patients with MPS type I, 20 patients with MPS type II, two patients with MPS types IIIA and IIIB and three patients with MPS type IVB. In these patients, phospho-calcium metabolism, markers of bone formation, bone radiographs and bone densitometry were evaluated, as were four polymorphisms of the VDR gene (ApaI, BsmI, FokI and TaqI). RESULTS: There was a deficiency in 25 hydroxy vitamin D in MPS type I patients at the final evaluation and in MPS type II patients, both at ERT initiation and at the last evaluation. The analysed polymorphisms were not associated with modified calcium-phosphor levels, but some differences were observed regarding the level of 25 OH vitamin D. Thus, in the case of AA polymorphism, all patients have a 25 OH vitamin D deficiency, and one patient with the AA genotype and three with Aa have a 25 OH vitamin D deficiency and secondary hyperparathyroidism due to this deficiency (four patients), all of them having the Bb phenotype. CONCLUSION: In MPS patients, vitamin D deficiency is observed, as it is in some patients with secondary hyperparathyroidism, which indicates vitamin D supplementation to protect bone metabolism. There are no obvious correlations between VDR polymorphism and bone metabolism in MPS patients.

TET2 rs1548483 SNP Associating with Susceptibility to Molecularly Annotated Polycythemia Vera and Primary Myelofibrosis.

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.

Urate-induced immune programming: Consequences for gouty arthritis and hyperuricemia.

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.

Genomic study via chromosomal microarray analysis in a group of Romanian patients with obesity and developmental disability/intellectual disability.

Background Obesity with developmental disability/intellectual disability (DD/ID) is the most common association in syndromic obesity. Genomic analysis studies have allowed the decipherment of disease aetiology, both in cases of syndromic obesity as well as in cases of isolated or syndromic DD/ID. However, more data are needed to further elucidate the link between the two. The aim of this pangenomic study was to use single nucleotide polymorphism (SNP) array technology to determine the copy number variant (CNV) type and frequency associated with both obesity and DD/ID. Methods Thirty-six patients were recruited from the Clinical Emergency Hospital for Children, in Cluj-Napoca, Romania during the period 2015-2017. The main inclusion criterion was a diagnosis that included both obesity and DD/ID. Genomic analysis via SNP array technology was performed. Results Out of the 36 patients, 12 (33%) presented CNVs with a higher degree of pathogenicity (A group) and 24 (66%) presented benign CNVs (B group). The SNP array results for the A group were as follows: pathogenic CNVs in 8/12 patients (67%); variants of unknown significance (VOUS) in 2/12 patients (16%); and uniparental disomy (UPD) in 2/12 patients (16%). Conclusions Some of these CNVs have already been observed in patients with both obesity and DD/ID, but the others were noticed only in DD/ID patients and have not been described until now in association with obesity.

The influence of GSTT/GSTM null genotypes in scarring.

BACKGROUND AND AIMS: The process of scarring is a common denominator of interest for the medical field. From general medicine to dentistry, pathological scar tissue represents a challenge in providing optimal care to a patient. The present study aims to investigate whether a systemically reduced antioxidant potential, revealed by null isoforms of glutathione S transferase, affects the process of scarring in a group of female patients. METHODS: The study is based on a group of 54 patients with physiological scars after a 6-month observation period, as well as 18 patients with hypertrophic or atrophic scars. Peripheral venous blood was collected, from which DNA was extracted using a commercial kit. Genotyping followed a Multiplex PCR protocol for GSTT1/GSTM1. RESULTS: In a dominant model, the combination of wild type (heterozygous or homozygous) GSTT1 and GSTM1 was negatively associated with pathological scarring, with the wild type (heterozygous or homozygous) GSTM1 genotype being potentially responsible for this effect. Other factors affecting pathological scarring were investigated: family history, phototype, as well as scores on the POSAS and SCAR scales. CONCLUSIONS: The presence of GSTT1 and GSTM1 alleles brings forward an increased antioxidant capacity, serving as a protective factor for patients during scar formation.

Gene variants of osteoprotegerin, estrogen-, calcitonin- and vitamin D-receptor genes and serum markers of bone metabolism in patients with Gaucher disease type 1.

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.