Frequency of Gene Polymorphisms in Admixed Venezuelan Women with Recurrent Pregnancy Loss: Microsomal Epoxy Hydroxylase (rs1051740) and Enos (rs1799983).

Recurrent pregnancy loss (RPL) affects around 2% of women of reproductive age. Primary RPL is defined by ≥2 pregnancy losses and no normal birth delivery. In secondary RPL, the losses are after a normal pregnancy and delivery. Most cases have no clear aetiology, although primary cases are the most complex. Several gene single nucleotide polymorphisms (SNPs) have been associated with RPL. The frequency of some SNPs is increased in women suffering from RLP from Asian or Caucasian races; however, in admixed populations, the information on possible genetic links is scarce and contradictory. This study aimed to assess the frequency of two SNPs present in two different enzymes involved in medical conditions observed during pregnancy. It is a case-control study. Microsomal epoxy hydrolase (mEPH) is involved in detoxifying xenobiotics, is present in the ovaries, and is hormonally regulated. The endothelial nitric oxide synthase (NOS3) that forms nitric is involved in vascular tone. Two SNPs, rs1051740 (mEPH) and rs1799983 (NOS3), were assessed. The study included 50 controls and 63 primary RPL patients. The frequency of mutated alleles in both SNPs was significantly higher in patients (p < 0.05). Double-mutated homozygotes were encountered only in RPL patients (p < 0.05). Genetic polymorphisms rs1051740 and rs1799983 may be involved in primary RPL in the Venezuelan admix population. Genetic studies could provide crucial information on the aetiology of primary RPL.

miR604A>G gene polymorphism is associated with recurrent pregnancy loss in Turkish women

SUMMARY OBJECTIVE: Recurrent pregnancy loss is considerably a reproductive health problem for couples. Genetic, epigenetic, and environmental factors play an important role in the development of recurrent pregnancy loss. While there are many causes, genetic and epigenetic factors are common. In this study, we aimed to examine the association between miR604 (rs2368393) A>G gene polymorphism and the risk of recurrent miscarriage in the Turkish population. METHODS: The study included 250 participants (i.e., 150 patients and 100 controls). DNA samples were isolated from peripheral blood, and polymerase chain reactions and restriction fragment length polymorphism methodologies were applied. RESULTS: The genotype distribution and allele frequencies of miR604A>G gene showed statistically significant differences between patients and control groups (p=0.002 and p<0.002, respectively). CONCLUSION: As a result of the study, we found that the AA genotype and A allele of the miR604A>G gene were statistically significant for the risk of recurrent pregnancy loss in Turkish women.

Influence of Environmental Exposure to Steel Waste on Endocrine Dysregulation and PER3 Gene Polymorphisms.

OBJECTIVE: To evaluate the association between environmental exposure to the following chemical substances: cadmium (Cd), lead (Pb), nickel (Ni), manganese (Mn), benzene (BZN), and toluene (TLN), and Period Circadian Regulator 3 (PER3) gene variable number of tandem repeats (VNTR) polymorphisms, according to chronotype in a population living in a steel residue-contaminated area. METHODS: This assessment comprises a study conducted from 2017 to 2019 with 159 participants who completed health, work, and Pittsburgh sleep scale questionnaires. Cd, Pb, Ni, Mn, BZN, and TLN concentrations in blood and urine were determined by Graphite Furnace Atomic Absorption Spectrometry (GFAAS) and Headspace Gas Chromatography (GC), and genotyping was carried out using Polymerase Chain Reaction (PCR). RESULTS: A total of 47% of the participants were afternoon chronotype, 42% were indifferent, and 11% were morning chronotype. Insomnia and excessive sleepiness were associated with the indifferent chronotype, while higher urinary manganese levels were associated with the morning chronotype (Kruskal-Wallis chi-square = 9.16; p < 0.01). In turn, the evening chronotype was associated with poorer sleep quality, higher lead levels in blood, and BZN and TLN levels in urine (χ2 = 11.20; p < 0.01) in non-occupationally exposed individuals (χ2 = 6.98; p < 0.01) as well as the highest BZN (χ2 = 9.66; p < 0.01) and TLN (χ2 = 5.71; p < 0.01) levels detected in residents from the influence zone 2 (far from the slag). CONCLUSION: Mn, Pb, benzene, and toluene contaminants may have influenced the different chronotypes found in the steel residue-exposed population.

Cytokine Networks as Targets for Preventing and Controlling Chagas Heart Disease.

Chagas disease, a neglected disease caused by the protozoan Trypanosoma cruzi, is endemic in 21 Latin American countries, affecting 6-8 million people. Increasing numbers of Chagas disease cases have also been reported in non-endemic countries due to migration, contamination via blood transfusions or organ transplantation, characterizing Chagas as an emerging disease in such regions. While most individuals in the chronic phase of Chagas disease remain in an asymptomatic clinical form named indeterminate, approximately 30% of the patients develop a cardiomyopathy that is amongst the deadliest cardiopathies known. The clinical distinctions between the indeterminate and the cardiac clinical forms are associated with different immune responses mediated by innate and adaptive cells. In this review, we present a collection of studies focusing on the human disease, discussing several aspects that demonstrate the association between chemokines, cytokines, and cytotoxic molecules with the distinct clinical outcomes of human infection with Trypanosoma cruzi. In addition, we discuss the role of gene polymorphisms in the transcriptional control of these immunoregulatory molecules. Finally, we discuss the potential application of cytokine expression and gene polymorphisms as markers of susceptibility to developing the severe form of Chagas disease, and as targets for disease control.

Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

Genetic polymorphisms are not associated with energy intake 1 year after Roux-en-Y gastric bypass in women.

BACKGROUND: The present study aimed to investigate the influence of food intake on body weight loss (WL) and the association of gene polymorphisms, 1 year after Roux-en-Y gastric bypass (RYGB) surgery. METHODS: In total, 95 obese women (age ranged 20-50 years) in a Brazilian cohort underwent RYGB surgery and completed the study. Anthropometric measurements and food intake were assessed before and 1 year after surgery. Twelve gene polymorphisms (GHRL rs26802; GHSR rs572169; LEP rs7799039; LEPR rs1137101; 5-HT2C rs3813929; UCP2 rs659366; UCP2 rs660339; UCP3 rs1800849; SH2B1 rs7498665; TAS1R2 rs35874116; TAS1R2 rs9701796; and FTO rs9939609) were determined using a real-time polymerase chain reaction and a TaqMan assay. The subjects were divided into quartiles regarding percentage of excess weight loss (%EWL). The effect of genetic variants on energy and macronutrient intake was evaluated by simple logistic regression, followed by multiple logistic regression. RESULTS: Subjects in the first and second quartiles showed a higher initial body mass index. Energy and macronutrient intake before and 1 year after RYGB surgery did not differ between the %EWL quartiles. None of gene polymorphisms investigated showed an association with the estimated energy intake 1 year after surgery. CONCLUSIONS: In conclusion, the estimate energy and food intake did not predict a greater body WL 1 year after RYGB surgery. In addition, the 12 gene polymorphism investigated did not affect the energy intake among female patients.

ADIPOQ-rs2241766 polymorphism is associated with changes in cholesterol levels of Mexican adolescents.

BACKGROUND: The ADIPOQ gene encodes a fat-derived protein hormone with a preponderant role in the homeostasis of glucose and fatty acids. However, previous association studies between ADIPOQ genetic variants and metabolic disorders have shown controversial results. In this study, we evaluated the effect of the ADIPOQ-rs2241766 polymorphism on diverse biochemical parameters (i.e., insulin resistance, atherogenic index, overweight and obesity) in an adolescent population from Mexico. METHODS: A cross-sectional study with convenience sampling was carried out in 356 adolescents from Northern Mexico. They were classified by sex and BMI-z score. The biochemical parameters were measured from blood samples using conventional methods. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: In low and normal weight groups, GG carriers had a significantly higher cholesterol level (P ≤ 0.05) than TG and TT carriers. However, there was no association between ADIPOQ-rs2241766 polymorphism and atherogenic index, overweight, or obesity. CONCLUSIONS: Our findings suggest that the cholesterol levels are under the influence of the ADIPOQ-rs2241766 polymorphism in Mexican adolescents and may explain how ADIPOQ variants increase the risk of developing metabolic disorders. Nevertheless, further studies are required to rule out the influence of other genetic and non-genetic factors.

The Impact of ACTN3 Gene Polymorphisms on Susceptibility to Exercise-Induced Muscle Damage and Changes in Running Economy Following Downhill Running.

This study aimed to investigate if ACTN3 gene polymorphism impacts the susceptibility to exercise-induced muscle damage (EIMD) and changes in running economy (RE) following downhill running. Thirty-five healthy men were allocated to the two groups based on their ACTN3 gene variants: RR and X allele carriers. Neuromuscular function [knee extensor isometric peak torque (IPT), rate of torque development (RTD), and countermovement, and squat jump height], indirect markers of EIMD [muscle soreness, mid-thigh circumference, knee joint range of motion, and serum creatine kinase (CK) activity], and RE (oxygen uptake, minute ventilation, blood lactate concentration, and perceived exertion) for 5-min of running at a speed equivalent to 80% of individual maximal oxygen uptake speed were assessed before, immediately after, and 1-4 days after a 30-min downhill run (-15%). Neuromuscular function was compromised (P < 0.05) following downhill running with no differences between the groups, except for IPT, which was more affected in the RR individuals compared with the X allele carriers immediately (-24.9 ± 6.9% vs. -16.3 ± 6.5%, respectively) and 4 days (-16.6 ± 14.9% vs. -4.2 ± 9.5%, respectively) post-downhill running. EIMD manifested similarly for both the groups except for serum CK activity, which was greater for RR (398 ± 120 and 452 ± 126 U L-1 at 2 and 4 days following downhill running, respectively) compared with the X allele carriers (273 ± 121 and 352 ± 114 U L-1 at the same time points). RE was compromised following downhill running (16.7 ± 8.3% and 11 ± 7.5% increases in oxygen uptake immediately following downhill running for the RR and X allele carriers, respectively) with no difference between the groups. We conclude that although RR individuals appear to be more susceptible to EIMD following downhill running, this does not extend to the changes in RE.

The association between vesicle-associated membrane protein - 8 A/G gene polymorphism and the risk of acute myocardial infarction / La relación entre el polimorfismo A/G del gen de la proteína de membrana asociada a vesículas-8 y el riesgo de infarto agudo de miocardio

Abstract Introduction Until now, only few studies have reported the correlation between vesicle-associated membrane protein-8 (VAMP-8) A/G gene polymorphism and acute myocardial infarction. Whereas, theoretically, VAMP-8 plays a pivotal role in the pathogenesis of acute myocardial infarction through platelet activation, secretion, and aggregation. Objective To investigate the association between VAMP-8 A/G gene polymorphism and the risk of acute myocardial infarction. Methods A cross-sectional study was carried out at Saiful Anwar General Hospital during June 2013 - May 2014. A Mae II enzyme with restriction fragment length polymorphism method was used to genotype VAMP-8 A/G gene polymorphisms in acute myocardial infarction and control groups. A multiple logistic regression test was used to analyze the association between VAMP-8 A/G gene polymorphism and the risk of acute myocardial infarction. Results A total of 35 controls and 97 acute myocardial infarction patients from our Hospital during the period were enrolled for our study. Our results found that VAMP-8 A/G gene polymorphism was not associated with the risk of acute myocardial infarction. Moreover, we also failed to confer the association between VAMP-8 A/G gene polymorphism and both smoking and hypertension among patients with acute myocardial infarction. Furthermore, in the setting of premature acute myocardial infarction, the correlation also failed to confirm. Conclusion In our population, there is no association between VAMP-8 A/G gene polymorphism and the risk of acute myocardial infarction.

Resumen Introducción Hasta la fecha, solo unos pocos estudios han reportado la correlación entre el polimorfismo A/G del gen de la proteína de membrana asociada a vesículas-8 (VAMP-8, por sus siglas en inglés) y el infarto agudo de miocardio. Si bien, en teoría, VAMP-8 juega un papel fundamental en la patogénesis del infarto agudo de miocardio a través de la activación, secreción y agregación plaquetaria. Objetivo Investigar la relación entre el polimorfismo A/G del gen VAMP-8 y el riesgo de infarto agudo de miocardio. Métodos: Se llevó a cabo un estudio transversal en Siful Anwar General Hospital entre junio del 2013 y mayo del 2014. Se utilizó la técnica de polimorfismos de longitud de fragmentos de restricción con la enzima Mae II para genotipificar los polimorfismos A/G del gen VAMP-8 en grupos de infarto agudo de miocardio y de control. Se aplicó una prueba de regresión logística múltiple para analizar la relación entre el polimorfismo A/G del gen VAMP-8 y el riesgo de infarto agudo de miocardio. Resultados Se incluyeron un total de 35 controles y 97 pacientes con infarto agudo de miocardio de nuestro Hospital durante el periodo del estudio. Nuestros resultados encontraron que el polimorfismo A/G del gen VAMP-8 no estaba relacionado con el riesgo de infarto agudo de miocardio. Por otra parte, tampoco pudimos establecer una relación entre el polimorfismo A/G del gen VAMP-8 y tanto tabaquismo como hipertensión en pacientes con infarto agudo de miocardio. Asimismo, en el contexto de infarto agudo de miocardio prematuro, tampoco se confirmó la correlación. Conclusión: En nuestra población, no existe una relación entre el polimorfismo A/G del gen VAMP-8 y el riesgo de infarto agudo de miocardio.

Glutathione S-transferase, catalase, and mitochondrial superoxide dismutase gene polymorphisms modulate redox potential in systemic lupus erythematosus patients from Manaus, Amazonas, Brazil.

OBJECTIVE: To investigate the frequency of glutathione S-transferase (GST), catalase, and SOD2 genetic polymorphisms and their correlation with SLE. METHODS: A total of 290 females (patients = 151; controls= 139) were recruited. Multiplex PCR was performed for genotyping GSTM1 and GSTT1 genes, whereas real-time qPCR was used for determination of SNPs: CAT C262T, SOD2 C47T, GSTP1 A313G and GSTP1 IVS6 -C16T. RESULTS: Thiol levels are decreased in SLE patients (p<0.001), while MDA levels were significantly higher (p<0.001) and those carrying the polymorphisms had higher rates of oxidative stress. Patients with double null deletion GSTT1null/GSTM1null had a frequency almost five times higher than the controls (p<0.001, OR 4.81, CI 1.98-12.11). SLE patients had a lower wild-type frequency of SOD2CC allele compared to controls (12.4% vs 27.3%). Statistical significances were observed on the association between the GSTT1null and GSTM1null with SOD2mut (p<0.001, OR 0.15, CI 0.05-0.47), with GSTP1 A303G (p=0.012, OR 0.19, CI 0.05-0.69), and with GSTP1 IVS6 (p=0.008, OR 0.14, CI 0.03-0.63). The same was observed between SOD2 C47T with GSTP1 A303G (p=0.09, OR 0.27, CI 0.09-0.74) and GSTP1 IVS6 (p=0.036, OR 0.41, CI 0.18-0.92). CONCLUSIONS: The deletion GSTT1null/GSTM1null may contribute to the increased of the oxidative stress in SLE patients. Isolated GSTP1 and CAT polymorphisms do not seem to influence the increased oxidative stress, neither SLE clinical manifestations. SOD2 47CT/TT allele may have greater oxidative stress due to structural change in the protein and decreased H2O2 production. The combination of polymorphic genes may be involved in the pathogenesis of the disease. Key points • Major question of our paper: Many studies have shown that the antioxidant status levels are decreased in patients with SLE, especially in severe stages of disease. We believe that this paper will be of interest to the readership of your journal had the involvement of polymorphisms and mutations in several genes that contribute to the genetic etiology of SLE, suggesting that these may influence the mechanisms of disease. • Our results. Thiol level was significantly (p<.001) lower and MDA level significantly increased (p<.001) among SLE patients. Those carrying the polymorphisms had higher rates of oxidative stress. SLE Patients had a frequency almost five times higher of double null deletion GSTT1null/GSTM1null than the controls. SLE Patients had a lower wild type frequency of SOD2CC allele compared to controls (12.4% vs 27.3%). We believed the deletion GSTT1null/GSTM1null may contribute to the increased of the oxidative stress in SLE patients while carriers of the mutant SOD2 47CT/TT allele may have greater oxidative stress due to structural change in the protein and decreased H2O2 production. The combination of polymorphic genes may be involved in the pathogenesis of the disease. • Implications of our results: Evidence for the involvement of genetic factors in severe clinical to lupus is compelling. This manuscript shows genetic insights in pathogenic pathways that may lead to severe clinical implications to LES. Therefore, it is necessary to understand their impact on overall disease pathogenesis and prognosis in these patients. We understand from general consensus about environmental factors can modify disease, however, maybe just in individuals who have a permissive genetic background. Even that no single gene predisposes some individuals to LES, we believe the genetic factors described in this manuscript are important elements in susceptibility to severe clinical to LES.

PTPN22 gene functional polymorphism (rs2476601) in older adults with frailty syndrome.

The frailty syndrome is a common clinical marker of vulnerability in older adults conducive to an overall decline in inflammatory stress responsiveness; yet little is known about the genetic risk factors for frailty in elderly. Our aim was to investigate the association between the rs2476601 polymorphism in PTPN22 gene and susceptibility to frailty in Mexican older adults. Data included 630 subjects 70 and older from The Coyoacán cohort, classified as frail, pre-frail, and non-frail following Fried's criteria. Sociodemographic and clinical characteristics were compared between groups at baseline and after a multivariate analysis. The rs2476601 polymorphism was genotyped by TaqMan genotyping assay using real-time PCR and genotype frequencies were determined for each frailty phenotype in all participants and subsets by age range. Genetic association was examined using stratified and interaction analyses adjusting for age, sex and variables selected in the multivariate analysis. Disability for day-life activities, depression and cognitive impairment were associated with the risk of pre-frailty and frailty at baseline and after adjustment. Carrying the T allele increased significantly the risk of frailty in patients 76 and older (OR 5.64, 95% CI 4.112-7.165) and decreased the risk of pre-frailty under no clinical signs of depression (OR 0.53; 95% CI 0.17-1.71). The PTPN22 polymorphism, rs2476601, could be a genetic risk factor for frailty as subject to quality of life. This is the first study analyzing such relationship in Mexican older adults. Confirming these findings requires additional association studies on wider age ranges in populations of older adults with frailty syndrome.

Polymorphism of the bradykinin type 2 receptor gene modulates blood pressure profile and microvascular function in prepubescent children.

Previous reports reveal that +9/-9 polymorphism of the bradykinin B2 receptor (BDKRB2) is suggestive of cardiometabolic diseases. The aim of this study was to examine the impact of BDKRB2 + 9/-9 polymorphism genotypes on the blood pressure parameters and microvascular function in prepubescent children. We screened for BDKRB2 + 9/-9 polymorphism in the DNA of 145 children (86 boys and 59 girls), and its association with body composition, blood pressure levels, biochemical parameters, and endothelial function was determined. No significant association of the BDKRB2 genotypes with gender (P=0.377), race (P=0.949) or family history of cardiovascular disease (CVD) (P=0.858) was observed. Moreover, we did not identify any interaction between BDKRB2 genotypes with a phenotype of obesity (P=0.144). Children carrying the +9/+9 genotype exhibited a significant linear trend with higher levels of systolic blood pressure and pulse pressure (P<0.001). Moreover, the presence of +9 allele resulted in a decrease of reactive hyperemia index, showing a decreasing linear trend from -9/-9 to +9/+9, wherein this parameter of endothelial function was the lowest in the +9/+9 children, intermediate in the +9/-9 children, and the highest in the -9/-9 children (P<0.001). There was a significant inverse correlation between reactive hyperemia index and systolic blood pressure (r= - 0.348, P< 0.001) and pulse pressure (r= - 0.399, P< 0.001). Our findings indicate that the +9/+9 BDKRB2 genotype was associated with high blood pressure and microvascular dysfunction in prepubescent Brazilian children.

Association of -94 ATTG insertion/deletion NFkB1 and c.*126G>A NFkBIA genetic polymorphisms with oxidative and nitrosative stress biomarkers in Brazilian subjects with Parkinson's Disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder, resulting dopaminergic neuronal cell death in the substantia nigra. The disease is characterized by major motor impairment, being bradykinesia, rest tremor, rigidity and loss of postural reflexes the most common, while autonomic dysfunctions, sleep disturbances and psychiatric disorders are some of the wide range of non-motor symptoms. Several processes have been identified to be associated with disease development, such as mitochondrial dysfunction, oxidative/nitrosative stress and neuroinflammation. NF-κB is an important transcription factor that regulates several inflammatory elements and pathways, and polymorphisms on NFKB1 and NFKBIA genes can potentially influence redox balance towards a pro-oxidative frame, modulating disease progression. Evaluation of these polymorphisms in the redox status of PD subjects could provide new insights on the pathogenesis of this disorder. The study aimed to test associations of -94 in./del ATTG NFKB1 (rs28362491) and c.*126G > A NFKBIA (rs696) polymorphisms with PD development, and to test the influence of both polymorphisms on oxidative/nitrosative stress (OS/NS) parameters. A total of 110 Brazilian individuals were enrolled, being 55 subjects recruited from University Hospital of Londrina as the PD group, and 55 subjects matched for age, sex and ethnicity composed the healthy control (HC) group. NFkB1 and NFkBIA polymorphisms were genotyped by PCR-RFLP. Lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), sulfhydryl groups (SH), total radical trapping antioxidant parameter (TRAP) and paraoxonase-1 activity (PON-1) were assessed. Despite no association of polymorphisms on disease development was observed, in PD subjects the NFKB1 del/del genotype was associated with higher levels of LOOH, while NFkBIA GA and AA genotypes were associated with higher NOx levels, suggesting that NFkB plays a role in PD susceptbility. In conclusion, the prospect of genetic polymorphisms of elements involved in inflammation and OS/NS might be a new approach to unravel PD etiology.

Familial Focal Segmental Glomerulosclerosis With Late-Onset Presentation and R229Q/R291W Podocin Mutations.

INTRODUCTION: Pathogenic variants in different genes have been described as involved in the development of familial focal segmental glomerulosclerosis (FSGS). A more precise genotype-phenotype correlation would be helpful to better characterize the clinical and laboratorial manifestations of this disease, as well as response to treatment. We analyzed podocin (NPHS2) gene variants in 50 members of four generations of a family with late-onset presentation of glomerular disease. RESULTS AND DISCUSSION: The NPHS2 gene variants R229Q and/or R291W were detected in several individuals, and the phenotype of FSGS with progressive loss of renal function was observed in all the family members carrying both mutations simultaneously. Patients manifested ongoing proteinuria over the years and progressive loss of renal function, which in three women culminated in renal replacement therapy by the 4th decade of life. In two affected patients with nephrotic syndrome, remission was not reached by the use of corticosteroids and other immunosuppressive drugs. The R229Q variant was pathogenic only when trans-associated with specific mutations, as the R291W variant in this family. CONCLUSION: Coexistence of the two NPHS2 variants R229Q and R291W in compound heterozygosis was a determinant of the FSGS phenotype. The presence of these variants alone in heterozygosis did not cause significant proteinuria.

Association of ERAP2 polymorphisms in Colombian HLA-B27+ or HLA-B15+ patients with SpA and its relationship with clinical presentation: axial or peripheral predominance.

OBJECTIVE: To determine the association between endoplasmic reticulum aminopeptidase (ERAP)1 and ERAP2 single-nucleotide polymorphisms (SNPs) and human leukocyte antigens (HLA)-B27+ or HLA-B15+ patients with spondyloarthritis (SpA). METHODS: 104 patients with SpA according to Assessment of Spondyloarthritis International Society criteria were included in the study. HLA typing was performed by PCR. The polymorphisms were determined by real-time PCR on genomic DNA using customised probes for SNPs rs27044, rs17482078, rs10050860 and rs30187 in ERAP1, and rs2910686, rs2248374 and rs2549782 in ERAP2. RESULTS: 70 of the104 patients with SpA were HLA-B27+ and 34 were HLA-B15+. The distribution of ERAP1 and ERAP2 SNPs between the HLA-B15+ and HLA-B27+ patients with SpA did not reveal differences. Likewise, no differences in the frequencies of ERAP1 SNP haplotypes and alleles HLA-B15 or HLA-B27 were found. Interestingly, however, the frequencies of three particular haplotypes formed by ERAP2 SNPs rs2549782/rs2248374/rs2910686 varied between HLA-B15+ and HLA-B27+ patients: the ERAP2 SNPs haplotype TGT was more common in HLA-B15+ patients with SpA (OR 2.943, 95% CI 1.264 to 6.585; P=0.009), whereas the ERAP2 SNP haplotypes TGC and CAT were more associated with HLA-B27+ patients with SpA: (OR 4.483, 95% CI 1.524 to 13.187; p=0.003) and (OR 9.014, 95% CI 1.181 to 68.807; p=0.009), respectively. CONCLUSION: An association was found between HLA-B15+ patients with SpA and haplotype TGT of ERAP2 SNPs. On the other hand, HLA-B27+ patients with SpA were associated with ERAP2 haplotypes TGC and CAT. These associations could be related to the clinical presentation of the disease, specifically with a peripheral or axial predominance, respectively.

Assessment of circulating MCP-1 level and 2518A>G gene polymorphism in systemic lupus erythematosus / Avaliação do nível de MCP-1 circulante e polimorfismo do gene 2518A> G no lúpus eritematoso sistêmico

Lupus nephritis (LN) is a major contributor to morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE). This study aims to investigate the possible role of a functional polymorphism in the regulatory region of the monocyte chemo-attractant protein-1 (MCP-1) gene and MCP-1 blood level in the diagnosis of LN and in correlating the MCP-1 blood levels with disease activity. The study included 56 SLE patients and 56 controls. All the SLE patients suffered from LN. An analysis of MCP-1 gene polymorphism by polymerase chain reaction was performed followed by restriction fragment length polymorphism (PCR-RFLP) analysis and MCP-1 blood level was determined using the ELISA technique. Calculation of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was performed. Serologic tests included the determination of antinuclear antibody (ANA) and anti-double-stranded (ds) DNA antibodies, Complement C3 and C4 levels. A significant increase in the frequency of genotype A/G and a decrease in the frequency of genotype A/A were found among patients with active LN compared to inactive LN. There was a statistically significant difference in the blood level of MCP-1 between LN patients and controls. Also, MCP-1 blood levels were significantly higher in active LN patients than inactive LN. A significant positive linear correlation was detected between MCP-1 blood level and SLEDAI, creatinine, and 24 hours protein in LN patients. These results suggest that an A/G genotype together with the measurement of the blood level of MCP-1 can be a useful tool for detection and follow up of active LN.

A nefrite do lúpus (LN) é um dos principais contribuintes para a morbidade e mortalidade em pacientes com o Lúpus Eritematoso Sistémico (LES). Este estudo tem como objetivo investigar o possível papel de um polimorfismo funcional na região reguladora do gene da proteína quimioatraente de monócitos-1 (MCP-1) e do nível sanguíneo de MCP-1 no diagnóstico de LN e na correlação do sangue de MCP-1 níveis com atividade da doença. O estudo incluiu 56 pacientes com LES e 56 controles. Todos os pacientes com LES sofriam de LN. Uma análise do polimorfismo do gene MCP-1 por reação em cadeia da polimerase foi realizada seguida pela análise do polimorfismo do comprimento do fragmento de restrição (PCR-RFLP) e o nível sanguíneo do MCP-1 foi determinado pela técnica ELISA. O cálculo do índice de atividade da doença sistêmica do lúpus eritematoso (SLEDAI) foi realizado. Os testes sorológicos incluíram a determinação de anticorpos antinucleares (ANA) e anticorpos anti-DNA de fita dupla (ds), níveis de Complemento C3 e C4. Um aumento significativo na frequência do genótipo A/G e uma diminuição na frequência do genótipo A/A foram encontrados entre os pacientes com LN ativo em comparação com o LN inativo. Houve uma diferença estatisticamente significante no nível sanguíneo de MCP-1 entre pacientes com LN e controles. Além disso, os níveis sanguíneos de MCP-1 foram significativamente mais altos em pacientes com LN ativo do que com LN inativo. Uma correlação linear positiva significativa foi detectada entre o nível sanguíneo de MCP-1 e SLEDAI, creatinina e proteína de 24 horas em pacientes com LN. Esses resultados sugerem que um genótipo A/G, juntamente com a medição do nível sanguíneo de MCP-1, pode ser uma ferramenta útil para a detecção e acompanhamento do LN ativo

Ficolin-1 and ficolin-3 polymorphisms and susceptibility to rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease, which compromises the synovial membrane resulting in chronic inflammation. Ficolins are key proteins of the lectin pathway of complement able to recognize pathogen-associated molecular patterns, apoptotic cells, and cellular debris mediating the clearance by phagocytes. High ficolin-1 and ficolin-3 levels have been observed in RA patients, however, the influence of polymorphisms in the FCN1 gene in RA is not completely established, while no study evaluated FCN3 gene polymorphisms in RA to date. We investigated the influence of FCN1 and FCN3 gene polymorphisms in the susceptibility and clinical presentation of RA. A total of 148 patients with RA and up to 160 controls from Southern Brazil were genotyped by sequence-specific PCR (PCR-SSP) for five FCN1 promoter polymorphisms (rs2989727, rs10120023, rs17039495, rs10117466, and rs10858293) and three FCN3 gene variants (rs532781899, rs28362807, and rs4494157). The FCN1 g.-542GG (rs10120023) genotype and g.-542G allele, were associated with increased susceptibility to RA (p = .025, OR = 1.69 [1.07-2.69]; p = .041, OR = 1.47 [1.02-2.12], respectively) and related to decreased FCN1 gene expression in whole blood (p < .00001), according to gene expression databases. In addition, the FCN1 AAGAG haplotype was more prevalent in rheumatoid factor seronegative in comparison to seropositive patients (p = .006, OR = 0.042 [0.002-0.80]). There was no association of FCN3 polymorphisms with the susceptibility or clinical characteristics of RA. Our results indicate that the FCN1 rs10120023 [g.-542G>A] polymorphism in the promoter region might contribute to RA susceptibility, probably by impacting FCN1 gene expression.