PAI-1 genetic polymorphisms influence septic patients' outcomes by regulating neutrophil activity / 中华医学杂志(英文版)

BACKGROUND@#Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathophysiology of sepsis, but the exact mechanism remains debatable. In this study, we investigated the associations among the serum levels of PAI-1, the incidence of 4G/5G promoter PAI-1 gene polymorphisms, immunological indicators, and clinical outcomes in septic patients.@*METHODS@#A total of 181 patients aged 18-80 years with sepsis between November 2016 and August 2018 in the intensive care unit in the Xinhua Hospital were recruited in this retrospective study, with 28-day mortality as the primary outcome. The initial serum level of PAI-1 and the presence of rs1799768 single nucleotide polymorphisms (SNPs) were examined. Univariate logistic regression and multivariate analyses were performed to determine the factors associated with different genotypes of PAI-1, serum level of PAI-1, and 28-day mortality.@*RESULTS@#The logistic analysis suggested that a high serum level of PAI-1 was associated with the rs1799768 SNP of PAI-1 (4G/4G and 4G/5G) (Odds ratio [OR]: 2.49; 95% confidence interval [CI]: 1.09, 5.68). Furthermore, a high serum level of PAI-1 strongly influenced 28-day mortality (OR 3.36; 95% CI 1.51, 7.49). The expression and activation of neutrophils (OR 0.96; 95% CI 0.93, 0.99), as well as the changes in the expression patterns of cytokines and chemokine-associated neutrophils (OR: 1.00; 95% CI: 1.00, 1.00), were both regulated by the genotype of PAI-1.@*CONCLUSIONS@#Genetic polymorphisms of PAI-1 can influence the serum levels of PAI-1, which might contribute to mortality by affecting neutrophil activity. Thus, patients with severe sepsis might clinically benefit from enhanced neutrophil clearance and the resolution of inflammation via the regulation of PAI-1 expression and activity.

Construction and evaluation of the functional polygenic risk score for gastric cancer in a prospective cohort of the European population / 中华医学杂志(英文版)

BACKGROUND@#A polygenic risk score (PRS) derived from 112 single-nucleotide polymorphisms (SNPs) for gastric cancer has been reported in Chinese populations (PRS-112). However, its performance in other populations is unknown. A functional PRS (fPRS) using functional SNPs (fSNPs) may improve the generalizability of the PRS across populations with distinct ethnicities.@*METHODS@#We performed functional annotations on SNPs in strong linkage disequilibrium (LD) with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation. Subsequently, we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort. Finally, the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer.@*RESULTS@#During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases, we found no significant association between the PRS-112 and gastric cancer risk in the European population (hazard ratio [HR] = 1.00 [95% confidence interval (CI) 0.93-1.09], P = 0.846). We identified 125 fSNPs, including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs, and used them to construct the fPRS-125. Our result showed that the fPRS-125 was significantly associated with gastric cancer risk (HR = 1.11 [95% CI, 1.03-1.20], P = 0.009). Compared to participants with a low fPRS-125 (bottom quintile), those with a high fPRS-125 (top quintile) had a higher risk of incident gastric cancer (HR = 1.43 [95% CI, 1.12-1.84], P = 0.005). Moreover, we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer (HR = 4.99 [95% CI, 1.55-16.10], P = 0.007) compared to those with both a favorable lifestyle and a low genetic risk.@*CONCLUSION@#These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.

Obesidade genética não sindrômica: histórico, fisiopatologia e principais genes / Non-syndromic genetic obesity: history, pathophysiology and key genes

A obesidade é definida pelo excesso de gordura corporal acumulada no tecido adiposo quando o indivíduo atinge valores de IMC igual ou superior a 30 Kg/m2. Constitui um dos principais fatores de risco para várias doenças não transmissíveis (DNTs) como por exemplo, diabetes mellitus tipo 2 (DM2), doenças cardiovasculares, hipertensão arterial, acidente vascular cerebral e até mesmo o câncer. Embora a obesidade esteja diretamente relacionada com o consumo calórico excessivo em relação ao gasto energético diário, sua etiologia pode estar associada aos baixos níveis de atividade física, às alterações neuroendócrinas e aos fatores genéticos. Considerando o componente genético, esta pode ser classificada como sindrômicas e estar associada às alterações cromossômicas estruturais ou numéricas, ou como não sindrômica, quando relacionada, principalmente, com os polimorfismos de nucleotídeos simples (SNPs) em alelos que atuam como herança monogênica, ou ainda com a interação vários genes (poligênica multifatorial). Apesar de existirem muitas etiologias diferentes, normalmente a obesidade é tratada a partir da mesma abordagem, desconsiderando a fisiologia que a desencadeou. Dessa forma, o objetivo do presente trabalho foi abordar a obesidade genética não sindrômica por meio a) da descrição breve de perspectiva histórica sobre seu entendimento; b) da exposição dos principais mecanismos moleculares envolvidos com o controle de peso; c) da compilação dos principais genes e SNPs relacionados; d) da definição dos principais genes; e e) da abordagem das principais perspectivas de intervenção.

Obesity is defined as excess body fat accumulated in the adipose tissue when the individual reaches BMI values equal to or greater than 30 kg/m2. It is one of the main risk factors for several non-communicable diseases (NCDs), such as Type 2 Diabetes mellitus (T2D), cardiovascular diseases, high blood pressure, stroke and even cancer. Although obesity is directly related to excessive calorie intake in relation to daily energy expenditure, its etiology may be associated with low levels of physical activity, neuroendocrine changes, and genetic factors. Considering the genetic component, it can be classified as syndromic and be associated with chromosomal or numerical changes, or as non-syndromic and being related mainly to single nucleotide polymorphisms (SNPs) in alleles that act as monogenic inheritance, or with an interaction of several genes (multifactorial polygenic). Although there are many different etiologies, obesity is usually treated using the same approach, disregarding the physiology that triggered it. Thus, the aim of this study was to address non-syndromic genetic obesity through a) a brief description of a historical perspective on its understanding; b) the exposure of the main molecular mechanisms involved in weight control, c) the compilation of the key genes and related SNPs, d) the definition of the key genes and e) the approach of the main intervention representations.

Association of IL-1ß +3954 G>A and IL-6 -174 G/C polymorphisms in congenital toxoplasmosis / Asociación de polimorfismos de IL-1ß +3954 G>A e IL-6-174 G/C en la toxoplasmosis congénita

Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii, that has the capacity to infect all warm-blooded animals worldwide. The purpose of this investigation was to determine the distribution of genotypes and alleles in miscarriages woman as a result of Toxoplasma gondii infection associated with interleukin-1β and interleukin-6 polymorphisms. A total of 125 miscarriage women suspected of toxoplasma infection and 50 healthy pregnant without previous miscarriage as control were enrolled in this study. The cases were screened for anti-toxoplasma IgM and IgG by ELISA test. Among the 125 miscarriage women, only 50 were positive to anti-Toxoplasma gondii IgG and IgM antibodies. The present study focused on assay the genotypes at IL-6 -174 G/C and IL-1β +3954 G>A to establish the associations between genetic polymorphisms and infection with Toxoplasma gondii. Results showed that the altered IL-1β GA, AA genotypes were high significant elevated in miscarriage women with toxoplasmosis (P=0.03), OR = 10 and 95 percent confidence intervals (1.32-81.48); (P=0.0007), OR = 0.07 and 95 percent confidence interval (0.01-0.32). The genotype GC at IL-6 (G/C) appears to be highly correlated with infection (P=0.01); OR = 3.18 and 95 percent confidence interval, (1.22- 8.30). In terms of allelic heterogeneity, C alleles were significantly more common in infected than uninfected cases for IL-6, while A allele is common in IL-1β single nucleotide polymorphisms (P =0.050). Furthermore, this study demonstrates that there is a strong and highly significant association between two forms of single nucleotide polymorphisms and the increased risk for toxoplasmosis. Genotypes of these polymorphism should be considered when evaluating genetic effects on toxoplasmosis incidence. However, to improve the prediction of this disease predisposition, a further study based on a larger cohort of patients is warranted(AU)

La toxoplasmosis es causada por la infección con el parásito protozoario Toxoplasma gondii, que tiene la capacidad de infectar a todos los animales de sangre caliente en todo el mundo. El propósito de esta investigación fue determinar la distribución de genotipos y alelos en mujeres con abortos espontáneos como resultado de la infección por Toxoplasma gondii asociada con polimorfismos de interleucina 1β e interleucina 6. Se inscribieron en este estudio un total de 125 mujeres con aborto espontáneo sospechosas de infección por toxoplasma y 50 embarazadas sanas, sin aborto espontáneo previo, como control. Los casos se examinaron para detectar IgM e IgG anti-toxoplasma mediante la prueba ELISA. Entre las 125 mujeres que sufrieron un aborto espontáneo, solo 50 fueron positivas a anticuerpos IgG e IgM anti-Toxoplasma gondii. El presente estudio se centró en analizar los genotipos de IL-6-174 G/C e IL-1β +3954 G>A para establecer las asociaciones entre polimorfismos genéticos e infección por Toxoplasma gondii. Los resultados mostraron que los genotipos alterados de IL-1β GA, AA fueron significativamente elevados en mujeres con aborto espontáneo con toxoplasmosis (P = 0,03), OR = 10 e intervalos de confianza del 95 por ciento (1,32-81,48); (P = 0,0007), OR = 0,07 e intervalo de confianza del 95 por ciento (0,01-0,32). El genotipo GC de IL-6 (G/C) parece estar altamente correlacionado con la infección (P = 0.01); OR = 3,18 e intervalo de confianza del 95%, (1,22- 8,30). En términos de heterogeneidad alélica, los alelos C fueron significativamente más comunes en los casos infectados que en los no infectados para la IL-6, mientras que el alelo A es común en los polimorfismos de nucleótido simple de IL-1β (P = 0.050). Además, este estudio demuestra que existe una asociación fuerte y altamente significativa entre dos formas de polimorfismos nucleótido simple y el mayor riesgo de toxoplasmosis. Se deben considerar los genotipos de estos polimorfismos al evaluar los efectos genéticos sobre la incidencia de la toxoplasmosis. Sin embargo, para mejorar la predicción de esta predisposición a la enfermedad, se justifica un estudio adicional basado en una cohorte más grande de pacientes(AU)

Association between interleukin-10 polymorphisms and CD4+CD25+FOXP3+ T cells in asthmatic children

Abstract Objective: The aim of this study was to evaluate the association between possible functional interleukin-10 (IL-10) polymorphisms, IL-10 expression and regulatory T cells (Tregs) frequency, and/or asthma severity in a sample of children and adolescents. Methods: This is a nested case-control genetic association study. The study sample consisted of children and adolescents aged 8-14 from public schools. Four polymorphisms of the IL-10 gene (rs1518111, rs3024490, rs3024496, rs3024491) were genotyped in asthmatic subjects and controls using real-time PCR. Tregs cells and IL-10 were analyzed in peripheral blood mononuclear cells by flow cytometry. The severity of asthma was defined according to the Global Initiative for Asthma (GINA) guideline. Results: One hundred twenty-three asthmatic subjects and fifty-eight controls participated in the study. The single nucleotide polymorphism (SNP) rs3024491 (T allele) showed association with asthma severity, presenting a higher frequency in patients in the moderate asthma group. The T allele of variant rs3024491 also showed an association with reduced IL-10 levels (p = 0.01) and with increased Tregs frequency (p = 0.01). The other variants did not present consistent associations. Conclusions: Our results suggest that moderate asthma is associated with a higher frequency of the T allele in the SNP rs3024491. In addition, the variant rs3024491 (TT) was associated with a reduction in IL-10 production and an increased percentage of Tregs cells, suggesting possible mechanisms that influence asthma severity.

Polymorphism (-499C/G) in DDAH2 promoter may act as a protective factor for metabolic syndrome: A case-control study in Azar-Cohort population

ABSTRACT Objective: Globally developing metabolic syndrome (MetS) prevalence as a major health problem can be related to multiple factors of genetic and environmental. Dimethylaminohydrolase 2 (DDAH2) is the main enzyme implicated in the cardiovascular system, which regulates the nitric oxide pathway. This study investigated the association of DDAH2 polymorphism −499C/G (rs805305) with the risk of MetS among the Azar-Cohort population. Subjects and methods: The occurrence of SNP rs805305 in the DDAH2 gene was tested using the PCR-RFLP method in 332 MetS cases and 294 healthy controls. Afterward, the association of the allele and genotypes with the risk of MetS and its components were examined. Results: The G allele and GC genotype were significantly associated with a reduced risk of MetS (P ≤ 0.001). Also, the dominant genetic model (GG+GC) significantly decreased the risk of MetS (P = 0.001), however, in sex subtypes MetS risk was significantly reduced in males before and in females after adjustment for age (P ≤ 0.02). Conclusion: The −499C/G polymorphism of DDAH2 may play a protective role and reduce MetS risk among the Azar-Cohort population.

Development of tetra-primer ARMS-PCR protocol to genotype the prolactin receptor SNP 39136666 and assessment of this SNP in Brazilian locally adapted cattle breeds / [Desenvolvimento de protocolo de tetra-primer ARMS- PCR para genotipagem do SNP 39136666 do receptor da prolactina e avaliação desse SNP em raças bovinas brasileiras localmente adaptadas]

As raças taurinas de origem ibérica Limonero e Carora (Bos primigenius taurus) possuem o fenótipo de pelo curto, liso e com baixa densidade folicular, o que confere a esses animais maior tolerância térmica e melhor produtividade em regiões quentes. Diferentes mutações associadas a esse fenótipo foram descritas no gene do receptor de prolactina PRLR, localizado no cromossomo bovino BTA20. Uma mutação recentemente encontrada é a substituição do nucleotídeo C por T, SNP 39136666 (p. R497*), no exon 11, que gera um códon de parada e, consequentemente, uma menor isoforma desse receptor. Neste trabalho, desenvolveu-se um protocolo rápido e de baixo custo para detecção desse SNP, utilizando-se a técnica de tetra-primer ARMS-PCR. Assim, foi possível detectar essa mutação nas raças brasileiras de origem ibérica localmente adaptadas: Caracu, Crioulo Lageano, Mocho Nacional e Pantaneiro. O alelo T foi mais frequente na raça Caracu (80%), enquanto o alelo C foi mais frequente na raça Crioulo Lageano (84%). Essa simples metodologia pode ser usada para genotipar esse SNP e ajudar na aplicação dessas informações moleculares em programas de melhoramento focados na tolerância térmica em bovinos taurinos e seus mestiços.(AU)

Development of Kompetitive Allele Specific PCR markers for identification of persimmon varieties using genotyping-by-sequencing

BACKGROUND: Persimmon (Diospyros kaki Thunb.) is the most widely cultivated species of the genus Diospyros. In this study, genetic diversity and variations in persimmon genotypes were investigated using single nucleotide polymorphism (SNP) markers identified by genotyping-by-sequencing (GBS) analysis. RESULTS: Ninety-five persimmon accessions grown in the Pear Research Institute, National Institute Horticultural and Herbal Science, were sequenced using the Illumina Hiseq2500 platform and polymorphic SNPs were detected to develop molecular markers. These reliable SNPs were analyzed using the Kompetitive Allele Specific PCR (KASP) assay to discriminate among persimmon genotypes. GBS generated a total of 447,495,724 trimmed reads, of which 89.7% were raw reads. After demultiplexing and sequence quality trimming, 108,876,644 clean reads were mapped to the reference transcriptome. An average of 1,146,070 genotype reads were mapped. Filtering of raw SNPs in each sample led to selection of a total of 1,725,401 high-quality SNPs. The number of homozygous and heterozygous SNPs ranged from 1,933 to 6,834 and from 846 to 5,927, respectively. CONCLUSIONS: Of the 49 SNPs selected for development of an identification system for persimmons, 15 SNPs were used in the KASP assay to analyze 32 persimmon accessions. These KASP markers discriminated among all accessions.

Association between single-nucleotide polymorphisms in miRNA and breast cancer risk: an updated review

Breast cancer (BC), a heterogeneous, aggressive illness with high mortality, is essentially a genomic disease. While the high-penetrance genes BRCA1 and BRCA2 play important roles in tumorigenesis, moderate- and low-penetrance genes are also involved. Single-nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes have recently been identified as BC risk factors. miRNA genes are currently classified as low-penetrance. SNPs are the most common variations in the human genome. While the role of miRNA SNPs in BC susceptibility has been studied extensively, results have been inconsistent. This review analyzes the results of association studies between miRNA SNPs and BC risk from countries around the world. We conclude that: (a) By continent, the largest proportion of studies to date were conducted in Asia (65.0 %) and the smallest proportion in Africa (1.8 %); (b) Association studies have been completed for 67 different SNPs; (c) 146a, 196a2, 499, 27a, and 423 are the most-studied miRNAs; (d) The SNPs rs2910164 (miRNA-146a), rs11614913 (miRNA-196a2), rs3746444 (miRNA-499) and rs6505162 (miRNA-423) were the most widely associated with increased BC risk; (e) The majority of studies had small samples, which may affect the precision and power of the results; and (f) The effect of an SNP on BC risk depends on the ethnicity of the population. This review also discusses potential explanations for controversial findings.

Effects of FTO and PPARγ variants on intrauterine growth restriction in a Brazilian birth cohort

Intrauterine growth restriction (IUGR) is related to a higher risk of neonatal mortality, minor cognitive deficit, metabolic syndrome, and cardiovascular disease in adulthood. In previous studies, genetic variants in the FTO (fat mass and obesity-associated) and PPARγ (peroxisome proliferator-activated receptor-gamma) genes have been associated with metabolic disease, body mass index, and obesity among other outcomes. We studied the association of selected FTO (rs1421085, rs55682395, rs17817449, rs8043757, rs9926289, and rs9939609) and PPARγ (rs10865710, rs17036263, rs35206526, rs1801282, rs28763894, rs41516544, rs62243567, rs3856806, and rs1805151) single-nucleotide polymorphisms (SNPs) with IUGR, through a case-control study in a cohort of live births that occurred from June 1978 to May 1979 in a Brazilian city. We selected 280 IUGR cases and 256 controls for analysis. Logistic regression was used to jointly analyze the SNPs as well as factors such as maternal smoking, age, and schooling. We found that the PPARγ rs41516544 increased the risk of IUGR for male offspring (OR 27.83, 95%CI 3.65-212.32) as well as for female offspring (OR=8.94, 95%CI: 1.96-40.88). The FTO rs9939609 TA genotype resulted in a reduced susceptibility to IUGR for male offspring only (OR=0.47, 95%CI: 0.26-0.86). In conclusion, we demonstrated that PPARγ SNP had a positive effect and FTO SNP had a negative effect on IUGR occurrence, and these effects were gender-specific.

Identification of a predominant genotype of Mycobacterium tuberculosis in Brazilian indigenous population

After nearly a century of vaccination and six decades of drug therapy, tuberculosis (TB) kills more people annually than any other infectious disease. Substantial challenges to disease eradication remain among vulnerable and underserved populations. The Guarani-Kaiowá people are an indigenous population in Paraguay and the Brazilian state of Mato Grosso do Sul. This community, marginalized in Brazilian society, experiences severe poverty. Like other South American indigenous populations, their TB prevalence is high, but the disease has remained largely unstudied in their communities. Herein, Mycobacterium tuberculosis isolates from local clinics were whole genome sequenced, and a population genetic framework was generated. Phylogenetics show M. tuberculosis isolates in the Guarani-Kaiowá people cluster away from selected reference strains, suggesting divergence. Most cluster in a single group, further characterized as M. tuberculosis sublineage 4.3.3. Closer analysis of SNPs showed numerous variants across the genome, including in drug resistance-associated genes, and with many unique changes fixed in each group. We report that local M. tuberculosis strains have acquired unique polymorphisms in the Guarani-Kaiowá people, and drug resistance characterization is urgently needed to inform public health to ensure proper care and avoid further evolution and spread of drug-resistant TB

Genome-wide long non-coding RNA association study on Han Chinese women identifies lncHSAT164 as a novel susceptibility gene for breast cancer / 中华医学杂志(英文版)

BACKGROUND@#Single-nucleotide polymorphisms (SNPs)-associated genes and long non-coding RNAs (lncRNAs) can contribute to human disease. To comprehensively investigate the contribution of lncRNAs to breast cancer, we performed the first genome-wide lncRNA association study on Han Chinese women.@*METHODS@#We designed an lncRNA array containing >800,000 SNPs, which was incorporated into a 96-array plate by Affymetrix (CapitalBio Technology, China). Subsequently, we performed a two-stage genome-wide lncRNA association study on Han Chinese women covering 11,942 individuals (5634 breast cancer patients and 6308 healthy controls). Additionally, in vitro gain or loss of function strategies were performed to clarify the function of a novel SNP-associated gene.@*RESULTS@#We identified a novel breast cancer-associated susceptibility SNP, rs11066150 (Pmeta = 2.34 × 10-8), and a previously reported SNP, rs9397435 (Pmeta = 4.32 × 10-38), in Han Chinese women. rs11066150 is located in NONHSAT164009.1 (lncHSAT164), which is highly expressed in breast cancer tissues and cell lines. lncHSAT164 overexpression promoted colony formation, whereas lncHSAT164 knockdown promoted cell apoptosis and reduced colony formation by regulating the cell cycle.@*CONCLUSIONS@#Based on our lncRNA array, we identified a novel breast cancer-associated lncRNA and found that lncHSAT164 may contribute to breast cancer by regulating the cell cycle. These findings suggest a potential therapeutic target in breast cancer.

Presença da mutação do gene BRCA1 em cadelas com tumores mamários malignos / Presence of BRCA1 gene mutation in bitches with malignant mammary tumors

Mammary tumors (MTs) in bitches are similar to breast cancers in women. Thus, they can be used as a model for human breast cancer and findings can be extrapolated for use in human medicine. BRCA1 is a tumor suppressor gene. When the gene has a mutation, it cannot repair damaged DNA, which causes genetic instability and tumorigenesis. Therefore, we aimed to study the frequency of single nucleotide polymorphisms (SNPs) in the BRCA1 gene that are associated with distinct histological types of malignant MT in bitches. The study population consisted of 91 bitches, including a control group of 6 animals with healthy mammary glands and 85 animals with MTs. All animals underwent a presurgery evaluation consisting of a questionnaire administered to the person responsible for the animal, a physical examination, collection of peripheral blood for hematological and serum biochemistry evaluations, an electrocardiogram, and a preanesthesia evaluation. In addition, distant metastasis was studied via chest radiography and abdominal ultrasound. After evaluations were complete, the animals that could undergo surgery were administered general anesthesia and underwent a mastectomy or mammary gland sample collection. Histopathological examination and molecular analysis were performed to identify mutations in the BRCA1 gene. Histopathological examinations found 10 different types of malignant tumors in 36 sick animals. Tumor samples plus samples from the 6 control animals were subjected to DNA extraction, polymerase chain reaction (PCR) analysis, and genetic sequencing. The tumor with the highest incidence (33.33%) was a complex carcinoma, followed by carcinoma in mixed tumor (13.88), tubular carcinoma (13.88) and carcinosarcoma (13.88). Molecular analysis revealed 3 different SNP points in 5 samples (4006G>A, 3619A>G, and 3761C>T). The allelic variant 4006G>A (1/36) resulted in the alteration of the amino acid valine by isoleucine (V1336 I). The mutation 3619A>G (2/36) inserted the amino acid alanine instead of threonine (T1207 A). The mutation 3761C>T (2/36) led to the alteration of the amino acid serine by phenylalanine (S1254 F), a mutation for which there are no published reports. The histological types that showed BRCA1 mutations were complex carcinoma (1/5), carcinoma in mixed tumor (1/5), papillary carcinoma (1/5) and tubular carcinoma (2/5). Software analysis identified the new SNP (nucleotide 3761) in BRCA1 and 2 point mutations in nucleotides 4006 and 3619 and responsible for genetic instability. The development of breast cancer is caused by many endogenous and exogenous factors. The results of our study show that these factors have a greater presence in female, mixed breed, uncastrated, and older dogs, confirming the data in the veterinary literature. In the present study, we found different histological types of malignant breast tumors with mutations in the BRCA1 gene, as other authors have reported. However, we also found the mutation 3761C>T, which, to the best of our knowledge, has not been reported in the literature. This shows the need for studies in veterinary medicine that assess mutations in the BRCA1 gene and the most common histological types. In conclusion, SNPs in the BRCA1 gene cause genetic instability, resulting in additional mutations that lead to the development of breast tumors. They are point mutations that affect transcription, resulting in truncated proteins. These proteins may have a loss of function, leading to carcinogenesis.(AU)

Polymorphism in GRHL2 gene may contribute to noise-induced hearing loss susceptibility: a meta-analysis / Polimorfismo no gene GRHL2 pode contribuir para a suscetibilidade à perda auditivainduzida por ruído: uma metanálise

Abstract Instruction: Noise-induced hearing loss is a leading occupational disease caused by gene-environment interaction. The Grainy Like 2, GRHL2, is a candidate gene. In this regard, many studies have evaluated the association between GRHL2 and noise-induced hearing loss, although the results are ambiguous and conflicting. Objective: The purpose of this study was to identify a precise estimation of the association between rs3735715 polymorphism in GRHL2 gene and susceptibility of noise-induced hearing loss. Methods: A comprehensive search was performed to collect data up to July 8, 2018. Finally, 4 eligible articles were included in this meta-analysis comprising 2410 subjects. The pooled odds ratios with 95% confidence intervals were used to evaluate the strength of the association. Results: Significant association was found in the overall population in the dominant model (GA/AA vs. GG, odds ratio = 0.707, 95% confidence interval = 0.594-0.841) and allele model (G allele vs. A allele, odds ratio = 1.189, 95% confidence interval = 1.062-1.333). When stratified by source of the subjects, we also found association between rs3735715 and noise-induced hearing loss risk in the dominant model (GA/AA vs. GG, odds ratio = 0.634, 95% confidence interval = 0.514-0.783) and allele model (G allele vs. A allele, odds ratio = 1.206, 95% confidence interval = 1.054-1.379). Conclusion: Rs3735715 polymorphism in GRHL2 gene may influence the susceptibility of noise-induced hearing loss. Additional large, well-designed and functional studies are needed to confirm this association in different populations.

Resumo Introdução: Perda auditiva induzida por ruído é uma das principais doenças ocupacionais causadas pela interação gene-ambiente. O Grainy Like 2, ou GRHL2 é um gene que tem sido considerado como candidato. Nesse sentido, muitos estudos avaliaram a associação entre o GRHL2 e perda auditiva induzida por ruído, embora os resultados sejam ambíguos e conflitantes. Objetivo: Identificar uma estimativa precisa da associação entre o polimorfismo rs3735715 no gene GRHL2 e a suscetibilidade à perda auditiva induzida por ruído. Método: Uma pesquisa abrangente foi feita para coletar dados até 8 de julho de 2018. No fim, quatro artigos elegíveis foram incluídos nesta metanálise, abrangeram 2.410 indivíduos. As odds ratios agrupadas com intervalos de confiança de 95% foram usadas para avaliar a força da associação. Resultados: Uma associação significante foi encontrada na população geral no modelo de dominância (GA/AA vs. GG, odds ratio = 0,707, intervalo de confiança 95% = 0,594-0,841) e modelo de alelo (alelo G vs. alelo A; odds ratio = 1,189, intervalo de confiança 95% = 1,062 a 1,333). Quando estratificados pelo local de trabalho dos indivíduos, também encontramos associação entre rs3735715 e risco de perda auditiva induzida por ruído no modelo de dominância (GA/AA vs. GG, odds ratio = 0,634, intervalo de confiança 95% = 0,514 ± 0,783) e modelo de alelo (alelo G vs. alelo A; odds ratio = 1,206, intervalo de confiança 95% = 1,054- 1,379). Conclusão: O polimorfismo Rs3735715 no gene GRHL2 pode influenciar a suscetibilidade à perda auditiva induzida por ruído. Estudos adicionais, amplos, bem desenhados e funcionais são necessários para confirmar essa associação em diferentes populações.

Evaluation of Polymorphisms in IL8 and IL16 Genes in Patients with Acute Coronary Syndrome

Abstract Background: Acute coronary syndrome (ACS) is a cardiovascular disease caused by obstruction of coronary arteries by atheromatous plaque. Susceptibility to this disease may be related to genetic variations, such as single nucleotide polymorphisms (SNPs). Objective: In this study, we evaluated the relationship between SNPs in IL8 (rs4073; -251 A/T) and IL16 (rs11556218; T/G) genes and SCA in a Brazilian population. Materials and Methods: A sample of 200 patients with ACS and 50 non-ACS patients hospitalized at the Real Hospital Português, Recife - PE, Brazil, and 220 blood donors (donors) was used. Genotyping was carried out by polymerase chain reaction, and DNA sequencing. Statistical analyzes were performed using the Williams G, Chi-square and Kruskal Wallis tests, using the BioEstat 5.0 program, and the data with a value of p < 0.05 were considered significant. Results: In the IL8 gene, the AT genotype was the most frequent (p > 0.05) in all three groups. In the IL16 gene, genotypic distributions were different between patients with ACS and the donor group (p = 0.002), with the most frequent G allele in the second group (p = 0.0052). The IL-16 cytokine was higher in donors than in patients with ACS (p = 0.04) and the G (TG + GG) allele had higher values of this cytokine (p = 0.01). Conclusions: The results demonstrate the important role of the rs11556218 SNP in IL16 gene in SCA, evidencing that the G allele may be associated with a decreased risk of the disease.

The rs11755527 polymorphism in the BACH2 gene and type 1 diabetes mellitus: case control study in a Brazilian population

ABSTRACT Objective Type 1 diabetes mellitus (T1DM) is an autoimmune disorder caused by a complex interaction between environmental and genetic risk factors. BTB domain and CNC homolog 2 (BACH2) gene encodes a transcription factor that acts on the differentiation and formation of B and T lymphocytes. BACH2 is also involved in the suppression of apoptosis and inflammation in pancreatic beta-cells, indicating a role for it in the development of T1DM. Therefore, the aim of this study was to evaluate the association of the BACH2 rs11755527 single nucleotide polymorphism (SNP) with T1DM. Subjects and methods This case-control study comprised 475 patients with T1DM and 598 nondiabetic individuals. The BACH2 rs11755527 (C/G) SNP was genotyped using real-time PCR with TaqMan MGB probes. Results Genotype distributions of rs11755527 SNP were in accordance with frequencies predicted by the Hardy-Weinberg equilibrium in case and control groups and were similar between groups (P = 0.729). The minor allele frequency was 43.6% in cases and 42.5% in controls (P = 0.604). Moreover, the G allele frequency did not differ between groups when considering different inheritance models and adjusting for age, gender, body mass index, and HLA DR/DQ genotypes of high-risk for T1DM. Although, well-known high-risk T1DM HLA DR/DQ genotypes were associated with T1DM in our population [OR= 7.42 (95% CI 3.34 - 17.0)], this association was not influenced by the rs11755527 SNP. Conclusion The BACH2 rs11755527 SNP seems not to be associated with T1DM in a Brazilian population.

Association of il-8 -251t>a (rs4073) polymorphism with susceptibility to gastric cancer: a systematic review and meta-analysis based on 33 case-control studies / Associação de polimorfismo IL-8 -251T> A (rs4073) com suscetibilidade ao câncer gástrico: uma revisão sistemática e meta-análise com base em 33 estudos caso controle

ABSTRACT BACKGROUND: The role of -251A>T polymorphism in the anti-inflammatory cytokine interleukin-8 (IL-8) gene in gastric cancer was intensively evaluated, but the results of these studies were inconsistent. OBJECTIVE: Therefore, we performed a meta-analysis to provide a comprehensive data on the association of IL-8 -251T>A polymorphism with gastric cancer. METHODS: All eligible studies were identified in PubMed, Web of Science, EMBASE, Wanfang and CNKI databases before September 01, 2019. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were derived from a fixed effect or random effect model. RESULTS: A total of 33 case-control studies with 6,192 cases and 9,567 controls were selected. Overall, pooled data showed that IL-8 -251T>A polymorphism was significantly associated with an increased risk of gastric cancer under all five genetic models, i.e., allele (A vs T: OR=1.189, 95% CI 1.027-1.378, P=0.021), homozygote (AA vs TT: OR=1.307, 95% CI 1.111-1.536, P=0.001), heterozygote (AT vs TT: OR=1.188, 95% CI 1.061-1.330, P=0.003), dominant (AA+AT vs TT: OR=1.337, 95% CI 1.115-1.602, P=0.002) and recessive (AA vs AT+TT: OR=1.241, 95% CI 1.045-1.474, P=0.014). The stratified analysis by ethnicity revealed an increased risk of gastric cancer in Asians and mixed populations, but not in Caucasians. Moreover, stratified by country found a significant association in Chinese, Korean and Brazilian, but not among Japanese. CONCLUSION: This meta-analysis suggests that the IL-8 -251T>A polymorphism is associated with an increased risk of gastric cancer, especially by ethnicity (Asian and mixed populations) and country (Chinese, Korean and Brazilian).

RESUMO CONTEXTO: O papel do polimorfismo -251A>T no gene anti-inflamatório citocina interleucina-8 (IL-8) no câncer gástrico foi intensamente avaliado, mas os resultados desses estudos foram inconsistentes. OBJETIVO: Portanto, realizamos uma meta-análise para fornecer dados abrangentes sobre a associação de IL-8 -251T>A polimorfismo com câncer gástrico. MÉTODOS: Todos os estudos elegíveis foram identificados nos bancos de dados PubMed, Web of Science, EMBASE, Wanfang e CNKI antes de 01 de setembro de 2019. As relações de probabilidades agrupadas (ORs) com intervalos de confiança de 95% (IC) foram derivadas de um modelo de efeito fixo ou efeito aleatório. RESULTADOS: Foram selecionados 33 estudos de controle de caso com 6.192 casos e 9.567 controles. No geral, dados agrupados mostraram que o polimorfismo IL-8 -251T>A foi significativamente associado a um risco aumentado de câncer gástrico em todos os cinco modelos genéticos, isto é, alelo (A vs T: OR=1,189; 95% CI 1,027-1,378; P=0,021), homozigoto (AA vs TT: OR=1,307; 95% CI 1,111-1,536; P=0,001), heterozigoto (AT vs TT: OR=1,188; 95% CI 1,061-1,330; P=0,003), dominante (AA+AT vs TT: OR=1,337; 95% CI 1,115-1,602; P=0,002) e recessivo (AA vs AT+TT: OR=1,241; 95% CI 1,045-1,474; P=0,014). A análise estratificada por etnia revelou um risco aumentado de câncer gástrico em asiáticos e populações mistas, mas não em caucasianos. Além disso, estratificado por país. Encontrou-se uma associação significativa em chineses, coreanos e brasileiros, mas não entre os japoneses. CONCLUSÃO: Esta meta-análise sugere que o polimorfismo IL-8 -251T>A está associado a um risco aumentado de câncer gástrico, especialmente por etnia (populações asiáticas e mistas) e por país (chinês, coreano e brasileiro).

Association of leptin and leptin receptor polymorphisms with coronary artery disease in a North Chinese Han population

Abstract INTRODUCTION: Leptin (LEP) is a peptide hormone that acts via leptin receptor (LEPR) binding. Genetic evidence from different human populations has implicated LEP/LEPR in the pathogenesis of coronary artery disease (CAD), and suggests that certain LEP/LEPR gene polymorphisms may increase the risk of CAD. The aim of this study was to assess two single nucleotide polymorphisms (SNPs) in LEP genes (rs2167270 and rs7799039) and two in LEPR genes (rs6588147, rs1137100) for association with CAD. METHODS: We enrolled 271 North Chinese Han CAD patients, and 113 healthy age- and sex-matched controls. Genomic DNA was extracted from whole blood, and the four SNPs were assessed using a MassArray system. RESULTS: The G allele frequency at rs2167270 was significantly higher among CAD cases than among controls. The AG genotype at rs7799039 was associated with a significantly decreased risk of CAD unlike the AA genotype used as the reference. The A allele was significantly associated with the CAD patient group. Interestingly, statistically significant differences in genotype and allele frequency at LEP rs2167270 and rs7799039 existed among females but not among males. CONCLUSIONS: The current study detected a significant association between genetic variations at LEP rs7799039 and rs2167270 and the risk of CAD in a north Chinese population, and revealed that LEP rs2167270 and rs7799039 gene polymorphisms might act as predisposing factors for CAD.

Interaction between NOS3 and HMOX1 on antihypertensive drug responsiveness in preeclampsia / Interação entre os genes NOS3 e HMOX1 na resposta à terapia antihipertensiva em pré-eclâmpsia

Abstract Objective We examined the interaction of polymorphisms in the genes heme oxygenase- 1 (HMOX1) and nitric oxide synthase (NOS3) in patients with preeclampsia (PE) as well as the responsiveness to methyldopa and to total antihypertensive therapy. Methods The genes HMOX1 (rs2071746, A/T) and NOS3 (rs1799983, G/T) were genotyped using TaqMan allele discrimination assays (Applied Biosystems, Foster City, CA, USA ), and the levels of enzyme heme oxygenase-1 (HO-1) were measured using enzyme-linked immunosorbent assay (ELISA). Results We found interactions between genotypes of the HMOX-1 and NOS3 genes and responsiveness tomethyldopa and that PE genotyped as AT presents lower levels of protein HO-1 compared with AA. Conclusion We found interactions between the HMOX-1 and NOS3 genes and responsiveness to methyldopa and that the HMOX1 polymorphism affects the levels of enzyme HO-1 in responsiveness to methyldopa and to total antihypertensive therapy. These data suggest impact of the combination of these two polymorphisms on antihypertensive responsiveness in PE.

Resumo Objetivo Examinamos a interação dos polimorfismos nos genes heme oxigenase-1 (HMOX1) eóxido nítrico sintase (NOS3) empacientes compré-eclâmpsia (PE)bem como as capacidades de resposta à metildopa e à terapia anti-hipertensiva. Métodos Os polimorfismos nos genes HMOX1 (rs2071746, A/T) e NOS3 (rs1799983, G/T) foram genotipados usando TaqMan allele discrimination assays (Applied Biosystems, Foster City, CA, EUA), e os níveis da enzima heme oxigenase-1 (HO-1) foram medidos por enzyme-linked immunosorbent assay (ELISA). Resultados Foram encontradas interações entre os genótipos da HMOX-1 e NOS3 e responsividade à metildopa, e que pacientes genotipados como AT apresentam níveis mais baixos de proteína HO-1 em comparação com o genótipo AA. Conclusão Foram encontradas interações entre os genes HMOX-1 e NOS3 e responsividade à metildopa e que o polimorfismo localizado no gene HMOX1 afeta os níveis de enzima HO-1 na resposta à metildopa e à terapia anti-hipertensiva. Esses dados sugerem o impacto da combinação desses dois polimorfismos na resposta antihipertensiva na PE.

High levels of chemerin associated with variants in the NOS3 and APOB genes in rural populations of Ouro Preto, Minas Gerais, Brazil

Chemerin is an adipokine that has been associated with components of metabolic syndrome. It has been described to affect adipocyte metabolism and inflammatory responses in adipose tissue, as well as the systemic metabolism of lipids and glucose. Few epidemiological studies have evaluated classical and genetics cardiovascular risk factors (CVRFs) in the mixed adult rural population in Brazil. Therefore, the present study explored possible associations between CVRFs and chemerin. This cross-sectional study included 508 adults from the rural localities of Lavras Novas, Chapada, and Santo Antônio do Salto in Ouro Preto, Minas Gerais, Southeast Brazil. Demographic, behavioral, clinical, biochemical, anthropometric variables, and 12 single nucleotide polymorphisms (SNPs) linked with metabolic syndrome phenotypes were evaluated for associations with chemerin level. There was a significant association of high triglyceride levels [odds ratio (OR)=1.91, 95%CI: 1.23−2.98], insulin resistance (OR=1.82, 95%CI: 1.03−3.22), age (OR=1.64, 95%CI: 1.08−2.49), and sex (OR=1.99, 95%CI: 1.35−2.95) with high levels of chemerin. High chemerin levels were significantly associated with the genetic polymorphisms rs693 in the APOB gene (OR=1.50, 95%CI: 1.03−2.19) and rs1799983 in the NOS3 gene (OR=1.46, 95%CI: 1.01−2.12) for the AA and GT+TT genotypes, respectively. In the concomitant presence of genotypes AA of rs693 and GT+TT of rs1799983, the chance of presenting high levels of chemerin showed a 2.21-fold increase (95%CI: 1.25−3.88) compared to the reference genotype. The development of classical CVRFs in this population may be influenced by chemerin and by two risk genotypes characteristic of variants in well-studied genes for hypertension and dyslipidemia.