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1.
Anticancer Res ; 41(7): 3309-3315, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230126

RESUMO

BACKGROUND/AIM: Matrix metalloproteinase 9 (MMP9) is highly expressed in gastric cancer but the role of MMP9 is unclear. This study aimed at revealing the association of MMP9 promoter rs3918242 genotypes with gastric cancer risk. MATERIALS AND METHODS: MMP9 rs3918242 genotypes of 121 patients with gastric cancer and 363 healthy individuals were examined by polymerase chain reaction-restriction fragment length polymorphism methodology using serum samples. RESULTS: MMP9 rs3918242 TT genotype carriers had an elevated gastric cancer risk compared to wild-type CC carriers (odds ratio=3.92, 95% confidence interval=1.28-11.99; p=0.0103). Patients with CT/TT genotypes were at higher risk of metastasis (p=0.0178) than those with CC. No correlation was found between MMP9 rs3918242 genotype and gastric cancer risk with smoking or alcohol behavior, nor Helicobacter pylori infection. No correlation was observed for MMP9 rs3918242 genotypic distributions with age, gender, or body mass index. CONCLUSION: Carrying a T allele for MMP9 rs3918242 may be predictive for higher gastric cancer risk, and as a predictor for higher risk of metastasis.


Assuntos
Predisposição Genética para Doença/genética , Metaloproteinase 9 da Matriz/genética , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Estudos de Casos e Controles , Feminino , Genótipo , Infecções por Helicobacter/genética , Helicobacter pylori/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição/genética , Fatores de Risco
2.
Sci Rep ; 11(1): 14015, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234248

RESUMO

Venous thromboembolism is the third common cardiovascular disease and is composed of two entities, deep vein thrombosis (DVT) and its potential fatal form, pulmonary embolism (PE). While PE is observed in ~ 40% of patients with documented DVT, there is limited biomarkers that can help identifying patients at high PE risk. To fill this need, we implemented a two hidden-layers artificial neural networks (ANN) on 376 antibodies and 19 biological traits measured in the plasma of 1388 DVT patients, with or without PE, of the MARTHA study. We used the LIME algorithm to obtain a linear approximate of the resulting ANN prediction model. As MARTHA patients were typed for genotyping DNA arrays, a genome wide association study (GWAS) was conducted on the LIME estimate. Detected single nucleotide polymorphisms (SNPs) were tested for association with PE risk in MARTHA. Main findings were replicated in the EOVT study composed of 143 PE patients and 196 DVT only patients. The derived ANN model for PE achieved an accuracy of 0.89 and 0.79 in our training and testing sets, respectively. A GWAS on the LIME approximate identified a strong statistical association peak (rs1424597: p = 5.3 × 10-7) at the PLXNA4 locus. Homozygote carriers for the rs1424597-A allele were then more frequently observed in PE than in DVT patients from the MARTHA (2% vs. 0.4%, p = 0.005) and the EOVT (3% vs. 0%, p = 0.013) studies. In a sample of 112 COVID-19 patients known to have endotheliopathy leading to acute lung injury and an increased risk of PE, decreased PLXNA4 levels were associated (p = 0.025) with worsened respiratory function. Using an original integrated proteomics and genetics strategy, we identified PLXNA4 as a new susceptibility gene for PE whose exact role now needs to be further elucidated.


Assuntos
Predisposição Genética para Doença/genética , Redes Neurais de Computação , Proteômica , Embolia Pulmonar/sangue , Embolia Pulmonar/genética , Receptores de Superfície Celular/sangue , Receptores de Superfície Celular/genética , Adulto , COVID-19/complicações , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Embolia Pulmonar/complicações , Embolia Pulmonar/metabolismo
3.
Nutrients ; 13(6)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198753

RESUMO

Recent cohort studies indicate a potential role of the antioxidant α-tocopherol in reducing bone loss and risk of fractures, especially hip fractures. We performed a Mendelian randomization investigation of the associations of circulating α-tocopherol with estimated bone mineral density (eBMD) using heel ultrasound and fractures, identified from hospital records or by self-reports and excluding minor fractures. Circulating α-tocopherol was instrumented by three genetic variants associated with α-tocopherol levels at p < 5 × 10-8 in a genome-wide association meta-analysis of 7781 participants of European ancestry. Summary-level data for the genetic associations with eBMD in 426,824 individuals and with fracture (53,184 cases and 373,611 non-cases) were acquired from the UK Biobank. Two of the three genetic variants were strongly associated with eBMD. In inverse-variance weighted analysis, a genetically predicted one-standard-deviation increase of circulating α-tocopherol was associated with 0.07 (95% confidence interval, 0.05 to 0.09) g/cm2 increase in BMD, which corresponds to a >10% higher BMD. Genetically predicted circulating α-tocopherol was not associated with odds of any fracture (odds ratio 0.97, 95% confidence interval, 0.91 to 1.05). In conclusion, our results strongly strengthen a causal link between increased circulating α-tocopherol and greater BMD. Both an intervention study in those with a low dietary intake of α-tocopherol is warranted and a Mendelian randomization study with fragility fractures as an outcome.


Assuntos
Densidade Óssea/genética , Fraturas Ósseas/sangue , Fraturas Ósseas/genética , Predisposição Genética para Doença/genética , alfa-Tocoferol/sangue , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Calcanhar/diagnóstico por imagem , Humanos , Masculino , Análise da Randomização Mendeliana , Metanálise como Assunto , Razão de Chances , Polimorfismo de Nucleotídeo Único , Ultrassonografia
4.
Nutrients ; 13(6)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207686

RESUMO

Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of CCNL1 contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of MAST3, whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of SLC5A11. Finally, we noted that rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of POMC, ADCY3 and DNAJC27. In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.


Assuntos
Metilação de DNA/genética , Epigenoma/genética , Predisposição Genética para Doença/genética , Obesidade/genética , Adenilil Ciclases/genética , Índice de Massa Corporal , Ciclinas/genética , Epigenômica/métodos , Estudo de Associação Genômica Ampla , Proteínas de Choque Térmico HSP40/genética , Humanos , Análise da Randomização Mendeliana , Proteínas Associadas aos Microtúbulos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Pró-Opiomelanocortina/genética , Proteínas Serina-Treonina Quinases/genética , Locos de Características Quantitativas , Fatores de Risco , Proteínas de Transporte de Sódio-Glucose/genética , Proteínas rab de Ligação ao GTP/genética
5.
Nat Commun ; 12(1): 3505, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108472

RESUMO

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.


Assuntos
Diabetes Mellitus Tipo 2/genética , Dislipidemias/genética , Predisposição Genética para Doença/genética , Adulto , Variação Biológica da População , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Exoma/genética , Genótipo , Humanos , Herança Multifatorial , Penetrância , Medição de Risco
6.
Stud Health Technol Inform ; 280: 3-8, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34190051

RESUMO

The most common developmental disorder of the spine is scoliosis, a rotated, lateral deformity in the shape of the spinal column. Scoliosis may be part of the clinical spectrum that is observed in many developmental disorders, but typically presents as an isolated symptom in otherwise healthy adolescent children. Adolescent idiopathic scoliosis (AIS) has defied pathogenic understanding in part due to its genetic complexity, and to the lack of well-defined animal models. The disease is also remarkable in its sexual dimorphism, where girls are at more than five times greater risk of progressive deformity than boys. Breakthroughs have come from recent genome wide association studies (GWAS) and next generation sequencing (NGS) of human AIS cohorts. Post-hoc gene set and pathway-level analyses of genetic datasets have highlighted a role for cartilage biogenesis and the development of the intervertebral disc (IVD) in disease susceptibility. Moreover, next generation sequencing in AIS families, as well as modeling in vertebrate systems, has revealed that rare deficiencies in proteins of the cartilaginous extracellular matrix (ECM) collectively contribute to AIS. Thus, as in a jigsaw puzzle, the pieces coming together from multiple biologic studies suggest that deficiencies in the structural integrity and homeostasis of spinal cartilages are culprits in AIS susceptibility. Here, we update progress in understanding the genetic, biochemical, and cellular determinants of AIS. We also suggest a molecular model in which interaction of the hormonal environment with genetic susceptibility may increase risk of this common disorder of childhood.


Assuntos
Escoliose , Adolescente , Criança , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Escoliose/genética , Coluna Vertebral
7.
J Clin Neurosci ; 89: 243-248, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34119275

RESUMO

The sortilin-related receptor 1 (SORL1) gene has been the subject of many studies focusing on frequent polymorphisms, which is associated with increased risk for Alzheimer's Disease (AD). By whole-exome sequencing (WES), we identified two pathogenic missense mutations c.579C > G (p.F193L) and c.1397A > G (p.N466S) in SORL1. The two mutations were located in the same protein domain, and the two unrelated probands both had an onset of memory problems at less than 65 years of age, but their clinical manifestations and cranial imaging are different. The protein structure and function affected by these mutations were predicted using bioinformatics analysis, which suggested they were pathogenic. 3D protein structural analysis revealed that these amino acid substitutions might result in instability of protein structure and adverse intramolecular interactions. These findings suggest that both F193L and N466S should be thought as potential causative mutations in early-onset Alzheimer's disease (EOAD) patients. Further functional studies are warranted to evaluate their roles in the pathogenesis of AD.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Mutação/genética , Adulto , Sequência de Aminoácidos , Feminino , Predisposição Genética para Doença/genética , Humanos , Proteínas Relacionadas a Receptor de LDL/química , Masculino , Proteínas de Membrana Transportadoras/química , Pessoa de Meia-Idade , Linhagem , Estrutura Secundária de Proteína , Fatores de Risco , Sequenciamento Completo do Exoma/métodos
8.
Medicine (Baltimore) ; 100(24): e25937, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34128842

RESUMO

ABSTRACT: The aim of this study was to investigate the correlation between single-nucleotide polymorphisms (SNPs) in the 3 primer of untranslated region (3'UTR) of the Pentraxin 3 (PTX3) gene and the risk of essential hypertension (EHT).PTX3 genotypes, rs2614, rs111451363, and rs73158510 locus, were found in 260 patients with EHT and 260 healthy controls. Quantitative real-time polymerase chain reaction was used to detect plasma hsa-miR-4766-5p levels. Enzyme-linked immunosorbent assay was used to detect plasma PTX3 levels. The dual-luciferase reporter assay was used to identify the binding site of hsa-miR-4766-5p to the PTX3.PTX3 rs2614 locus T allele was a high risk factor for EHT (odds ratio [OR] = 2.76, 95% confidence interval [CI]: 1.86-4.09, P < .01). Sex and diabetes history affected the correlation between PTX3 gene rs2614 locus SNP and EHT risk. The CCG haplotype was a protective factor for EHT (OR = 0.40, 95% CI: 0.28-0.57, P < .01), whereas the TCG haplotype was a risk factor for EHT (OR = 2.35, 95% CI: 1.51-3.66, P < .01). The plasma PTX3 level of patients with EHT was significantly higher than that of the control group, and the difference was statistically significant (P < .01). The area under the curve for EHT diagnosis in plasma PTX3 levels was 0.62 (95% CI: 0.57-0.66, P < .01). The plasma hsa-miR-4766-5p level in patients with EHT was significantly lower than that in the control group (P < .01). The area under the curve for the diagnosis of EHT according to the plasma hsa-miR-4766-5p level was 0.88 (95% CI: 0.85-0.91, P < .01). Plasma PTX3 levels were significantly negatively correlated with hsa-miR-4766-5p levels in patients with EHT and the control group (r = -0.87, -0.85, P < .01, P < .01). The PTX3 gene rs2614 locus C allele was the target gene of hsa-miR-4766-5p.The PTX3 rs2614 locus SNP is significantly associated with EHT risk.


Assuntos
Regiões 3' não Traduzidas/genética , Proteína C-Reativa/genética , Hipertensão Essencial/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Componente Amiloide P Sérico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Área Sob a Curva , Sítios de Ligação , Estudos de Casos e Controles , Feminino , Genótipo , Haplótipos , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Fatores de Risco
9.
Medicine (Baltimore) ; 100(24): e26186, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34128850

RESUMO

BACKGROUND: Caveolin-1 (CAV1) is an essential structural component of caveolae, regulates cellular processes through complex cellular signaling pathways, and influences tumorigenicity. However, the role of the CAV1 (rs7804372) polymorphism in digestive cancers remains inconclusive. The meta-analysis was performed to evaluate the effect of CAV1 polymorphism on digestive cancer susceptibility and to provide a basis for precise treatment. METHODS: The databases of PubMed, EMBASE, Google Scholar and CNKI were used to retrieve the published studies on CAV1 (rs7804372) polymorphism and susceptibility to digestive cancers up to June 2020. Two researchers conducted study screening, data extraction, and methodological quality evaluation separately according to inclusion and exclusion criteria. Review Manager 5.3 software was used to conduct the meta-analysis. RESULTS: Six case-control studies were enrolled, including 2477 patients with digestive cancers and 2477 healthy controls. The pooled results showed that the CAV1 rs7804372 (T29107A) polymorphism increased the risk of digestive cancer occurrence in the allele (T vs. A: odds ratio (OR) 1.33, 95% confidence interval (CI): 1.15-1.53, P < .01), homozygous (TT vs. AA: OR 1.72, 95% CI: 1.31-2.26, P < .01), heterozygous (TA vs. AA: OR 1.47, 95% CI: 1.21-1.78, P < .01), dominant (TT vs. TA + AA: OR 1.32, 95% CI: 1.18-1.48, P < .01), and recessive comparing models (TT + TA vs. AA: OR 1.61, 95% CI: 1.26-2.07, P < .01). CONCLUSION: Our results indicate that the CAV1 (rs7804372) polymorphism may modify the occurrence of digestive cancers, and the presence of T allele or TT genotype of the CAV1 (rs7804372) may increase the risk of digestive cancers.


Assuntos
Caveolina 1/metabolismo , Neoplasias do Sistema Digestório/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Alelos , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Razão de Chances , Projetos de Pesquisa , Fatores de Risco , Revisões Sistemáticas como Assunto
10.
J Laparoendosc Adv Surg Tech A ; 31(7): 729-737, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34097461

RESUMO

Background: Patients with hereditary diffuse gastric cancer (HDGC) and germline mutations in the E-cadherin gene, CDH1, have a very high cumulative lifetime risk of developing diffuse gastric cancer. In these patients, it is formally recommended to perform a prophylactic total gastrectomy (PTG). Materials and Methods: We analyzed the course of patients with HDGC who have undergone PTG in our institution. Pedigree analysis, preoperative screening results, operative course, postoperative data, and complete stomach pathologic examination were performed in all patients. Results: Seven patients with confirmed CDH1 mutation underwent PTG, five were women, and average age was 27 years (range 17-42). Signet ring cell carcinoma was found in 1 patient in the preoperative surveillance endoscopic biopsies. Laparoscopic PTG was performed in all patients. There were two complications, an intestinal obstruction that required reintervention and an asymptomatic esophagojejunal anastomosis leak that resolved with conservative treatment. In all gastrectomy specimens, intramucosal signet ring cell carcinoma foci limited to the lamina propria were found (range 1-31), 83.5% were in the body-fundus region. The mean follow-up was 28.5 months (range 8-72). The mean weight loss was 9% (range 2-18). Postoperative symptoms associated with Dumping syndrome were the most frequent. All the patients reported of being very satisfied with the procedure and of having a better quality of life than expected before the procedure. Conclusion: Laparoscopic PTG is an excellent resource to prevent the development of advanced diffuse gastric cancer (DGC) in patients with HDGC with CDH1 mutation. The procedure was well tolerated with a high satisfaction rate and very good functional results. It should be considered in these patients due to the high risk of developing advanced DGC and the lack of effective and reliable surveillance studies.


Assuntos
Antígenos CD/genética , Caderinas/genética , Gastrectomia/métodos , Laparoscopia/métodos , Procedimentos Cirúrgicos Profiláticos/métodos , Neoplasias Gástricas/prevenção & controle , Adolescente , Adulto , Feminino , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Humanos , Masculino , Linhagem , Estudos Retrospectivos , Neoplasias Gástricas/genética , Resultado do Tratamento , Adulto Jovem
11.
Nutrients ; 13(5)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065344

RESUMO

There appears to be a sex-specific association between obesity and colorectal neoplasia in patients with Lynch Syndrome (LS). We meta-analyzed studies reporting on obesity and colorectal cancer (CRC) risk in LS patients to test whether obese subjects were at increased risk of cancer compared to those of normal weight. We explored also a possible sex-specific relationship between adiposity and CRC risk among patients with LS. The summary relative risk (SRR) and 95% confidence intervals (CI) were calculated through random effect models. We investigated the causes of between-study heterogeneity and assessed the presence of publication bias. We were able to retrieve suitable data from four independent studies. We found a twofold risk of CRC in obese men compared to nonobese men (SRR = 2.09; 95%CI: 1.23-3.55, I2 = 33%), and no indication of publication bias (p = 0.13). No significantly increased risk due to obesity was found for women. A 49% increased CRC risk for obesity was found for subjects with an MLH1 mutation (SRR = 1.49; 95%CI: 1.11-1.99, I2 = 0%). These results confirm the different effects of sex on obesity and CRC risk and also support the public measures to reduce overweight in people with LS, particularly for men.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Obesidade/genética , Fatores Sexuais , Adulto , Feminino , Humanos , Masculino , Proteína 1 Homóloga a MutL/genética , Mutação , Risco
12.
Nat Commun ; 12(1): 3750, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145229

RESUMO

Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-P = 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (P = 0.00135), including the SRCAP gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.


Assuntos
Adenosina Trifosfatases/genética , Transtorno Bipolar/genética , Exoma/genética , Predisposição Genética para Doença/genética , Adulto , Éxons/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Exoma
13.
Nat Commun ; 12(1): 3761, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145262

RESUMO

Pernicious anemia is a rare condition characterized by vitamin B12 deficiency anemia due to lack of intrinsic factor, often caused by autoimmune gastritis. Patients with pernicious anemia have a higher incidence of other autoimmune disorders, such as type 1 diabetes, vitiligo, and autoimmune thyroid issues. Therefore, the disease has a clear autoimmune basis, although the genetic susceptibility factors have thus far remained poorly studied. We conduct a genome-wide association study meta-analysis in 2166 cases and 659,516 European controls from population-based biobanks and identify genome-wide significant signals in or near the PTPN22 (rs6679677, p = 1.91 × 10-24, OR = 1.63), PNPT1 (rs12616502, p = 3.14 × 10-8, OR = 1.70), HLA-DQB1 (rs28414666, p = 1.40 × 10-16, OR = 1.38), IL2RA (rs2476491, p = 1.90 × 10-8, OR = 1.22) and AIRE (rs74203920, p = 2.33 × 10-9, OR = 1.83) genes, thus providing robust associations between pernicious anemia and genetic risk factors.


Assuntos
Anemia Perniciosa/genética , Doenças Autoimunes/genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Exorribonucleases/genética , Feminino , Gastrite/patologia , Variação Genética/genética , Estudo de Associação Genômica Ampla , Cadeias beta de HLA-DQ/genética , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Masculino , Pessoa de Meia-Idade , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Fatores de Risco , Fatores de Transcrição/genética
14.
Braz J Biol ; 83: e244123, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34161457

RESUMO

Toll-like receptor 9 (TLR9) is an important component of the innate immune system and have been associated with several autoimmune diseases, such as Systemic Lupus Erythematosus (SLE). The aim of this study was to investigate polymorphisms in TLR9 gene in a Brazilian SLE patients group and their association with clinical manifestation, particularly Jaccoud's arthropathy (JA). We analyzed DNA samples from 204 SLE patients, having a subgroup of them presenting JA (n=24). A control group (n=133) from the same city was also included. TLR9 single nucleotide polymorphisms (SNPs) (-1237 C>T and +2848 G>A) were identified by sequencing analysis. The TLR9 gene genotype frequency was similar both in SLE patients and the control group. In the whole SLE population, an association between the homozygosis of allele C at position -1237 with psychosis and anemia (p < 0.01) was found. Likewise, the homozygosis of allele G at position +2848 was associated with a discoid rash (p < 0.05). There was no association between JA and TLR9 polymorphisms. These data show that TLR9 polymorphisms do not seem to be a predisposing factor for SLE in the Brazilian population, and that SNPs are not associated with JA.


Assuntos
Lúpus Eritematoso Sistêmico , Receptor Toll-Like 9 , Brasil , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Humanos , Lúpus Eritematoso Sistêmico/genética , Projetos Piloto , Receptor Toll-Like 9/genética
15.
Radiologe ; 61(7): 658-666, 2021 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-34170362

RESUMO

CLINICAL ISSUE: Tumor predisposition syndromes (TPS) are a heterogeneous group of genetic cancers. About 10% of the approximately 2200 malignancies in the childhood in Germany develop due to an inherited disposition, whereby TPS may be underdiagnosed. The focus of this review is set on imaging of Li-Fraumeni syndrome, neurofibromatoses, tuberous sclerosis, overgrowth, and neuroendocrine syndromes. STANDARD RADIOLOGICAL METHODS: In order to detect tumors at an early stage, screening at specific time intervals for each TPS are required. Ultrasonography and magnetic resonance imaging (MRI), especially whole-body MRI, are particularly important imaging modalities. METHODOLOGICAL INNOVATIONS: Innovative MRI techniques can increase image quality and patient comfort. MRI acquisition time can be significantly reduced through optimized acceleration factors, motion robust radial sequences and joint acquisition and readout of multiple slices during excitation. Thus, shorter MRI examinations can be performed in younger children without anesthesia. PRACTICAL RECOMMENDATION: Regular screening with ultrasound and MRI can reduce the morbidity and mortality of the patients affected with TPS.


Assuntos
Síndrome de Li-Fraumeni , Criança , Predisposição Genética para Doença/genética , Alemanha , Humanos , Imageamento por Ressonância Magnética , Programas de Rastreamento , Imagem Corporal Total
16.
Syst Rev ; 10(1): 174, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108050

RESUMO

BACKGROUND: Tuberculosis (TB) is still one of the leading causes of death worldwide. Genetic studies have pointed to the relevance of the NOD2 and CD14 polymorphic alleles in association with the risk of diseases caused by Mycobacterium tuberculosis (Mtb) infection. METHODS: A systematic review was performed on PubMed, EMBASE, Scientific Electronic Library Online (SciELO), and Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs) to examine the association between single nucleotide polymorphisms (SNP) and risk of Mtb diseases. Study quality was evaluated using the Newcastle-Ottawa Quality Scale (NOQS), and the linkage disequilibrium was calculated for all SNPs using a webtool (Package LDpop). RESULTS: Thirteen studies matched the selection criteria. Of those, 9 investigated CD14 SNPs, and 6 reported a significant association between the T allele and TT genotypes of the rs2569190 SNP and increased risk of Mtb diseases. The genotype CC was found to be protective against TB disease. Furthermore, in two studies, the CD14 rs2569191 SNP with the G allele was significantly associated with increased risk of Mtb diseases. Four studies reported data uncovering the relationship between NOD2 SNPs and risk of Mtb diseases, with two reporting significant associations of rs1861759 and rs7194886 and higher risk of Mtb diseases in a Chinese Han population. Paradoxically, minor allele carriers (CG or GG) of rs2066842 and rs2066844 NOD2 SNPs were associated with lower risk of Mtb diseases in African Americans. CONCLUSIONS: The CD14 rs2569190 and rs2569191 polymorphisms may influence risk of Mtb diseases depending on the allele. Furthermore, there is significant association between NOD2 SNPs rs1861759 and rs7194886 and augmented risk of Mtb diseases, especially in persons of Chinese ethnicity. The referred polymorphisms of CD14 and NOD2 genes likely play an important role in risk of Mtb diseases and pathology and may be affected by ethnicity. SYSTEMATIC REVIEW REGISTRATION: CRD42020186523.


Assuntos
Mycobacterium tuberculosis , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Predisposição Genética para Doença/genética , Genótipo , Humanos , Mycobacterium tuberculosis/genética , Proteína Adaptadora de Sinalização NOD2/genética
17.
Nat Commun ; 12(1): 2878, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001886

RESUMO

Structural variations of the human brain are heritable and highly polygenic traits, with hundreds of associated genes identified in recent genome-wide association studies (GWAS). Transcriptome-wide association studies (TWAS) can both prioritize these GWAS findings and also identify additional gene-trait associations. Here we perform cross-tissue TWAS analysis of 211 structural neuroimaging and discover 278 associated genes exceeding Bonferroni significance threshold of 1.04 × 10-8. The TWAS-significant genes for brain structures have been linked to a wide range of complex traits in different domains. Through TWAS gene-based polygenic risk scores (PRS) prediction, we find that TWAS PRS gains substantial power in association analysis compared to conventional variant-based GWAS PRS, and up to 6.97% of phenotypic variance (p-value = 7.56 × 10-31) can be explained in independent testing data sets. In conclusion, our study illustrates that TWAS can be a powerful supplement to traditional GWAS in imaging genetics studies for gene discovery-validation, genetic co-architecture analysis, and polygenic risk prediction.


Assuntos
Encéfalo/metabolismo , Perfilação da Expressão Gênica/métodos , Pleiotropia Genética/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Encéfalo/diagnóstico por imagem , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Humanos , Neuroimagem/métodos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética
18.
Med Sci Monit ; 27: e929911, 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33935279

RESUMO

BACKGROUND We performed the present study to better elucidate the correlation of reduced folate carrier-1 (RFC1) A80G (rs1051266) polymorphism with the risk of congenital heart disease (CHD). MATERIAL AND METHODS According to the designed search strategy, a systematic literature search was performed through the PubMed, Cochrane Library, Web of Science, EMBASE, CNKI, VIP, and Wan Fang databases to collect published case-control studies on the correlation between RFC1 A80G polymorphism and CHD. All relevant studies up to October 1, 2019 were identified. The odds ratio (OR) and 95% confidence interval (CI) of the genotype distribution were used as the effect indicators. RESULTS A total of 6 eligible studies was finally included in our meta-analysis, including 724 children with CHD, 760 healthy children, 258 mothers of the children with CHD, and 334 mothers of healthy control children. The meta-analysis revealed that for fetal analysis, only in the heterozygous model (GA vs GG, OR=1.36, 95% CI [1.06, 1.75], P=0.02) was RFC1 A80G polymorphism associated with risk of CHD. In maternal analysis, 3 genetic models of RFC1 A80G polymorphism increased the risk of CHD: the allelic model (A vs G, OR=1.36, 95% CI [1.07, 1.71], P=0.01), the homozygote model (AA vs GG, OR=2.99, 95%CI [1.06, 8.41], P=0.04), and the dominance model (GA+AA vs GG, OR=1.53, 95%CI [1.08, 2.16], P=0.02). CONCLUSIONS The maternal RFC1 A80G polymorphism has a strong correlation with CHD. Compared with the G allele, the A allele increases the risk of CHD by 0.36-fold.


Assuntos
Predisposição Genética para Doença/genética , Cardiopatias Congênitas/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína Carregadora de Folato Reduzido/genética , Alelos , Estudos de Casos e Controles , Genótipo , Humanos , Fatores de Risco
19.
Nat Commun ; 12(1): 2657, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976227

RESUMO

Life history theory predicts that the intensity of selection declines with age, and this trend should impact how genes expressed at different ages evolve. Here we find consistent relationships between a gene's age of expression and patterns of molecular evolution in two mammals (the human Homo sapiens and the mouse Mus musculus) and two insects (the malaria mosquito Anopheles gambiae and the fruit fly Drosophila melanogaster). When expressed later in life, genes fix nonsynonymous mutations more frequently, are more polymorphic for nonsynonymous mutations, and have shorter evolutionary lifespans, relative to those expressed early. The latter pattern is explained by a simple evolutionary model. Further, early-expressed genes tend to be enriched in similar gene ontology terms across species, while late-expressed genes show no such consistency. In humans, late-expressed genes are more likely to be linked to cancer and to segregate for dominant disease-causing mutations. Last, the effective strength of selection (Ne s) decreases and the fraction of beneficial mutations increases with a gene's age of expression. These results are consistent with the diminishing efficacy of purifying selection with age, as proposed by Medawar's classic hypothesis for the evolution of senescence, and provide links between life history theory and molecular evolution.


Assuntos
Envelhecimento/genética , Anopheles/genética , Drosophila melanogaster/genética , Evolução Molecular , Seleção Genética , Algoritmos , Animais , Expressão Gênica , Predisposição Genética para Doença/genética , Humanos , Longevidade/genética , Camundongos , Modelos Genéticos , Mutação , Neoplasias/genética , Especificidade da Espécie
20.
Hum Genomics ; 15(1): 29, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001248

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global health problem that causes millions of deaths worldwide. The clinical manifestation of COVID-19 widely varies from asymptomatic infection to severe pneumonia and systemic inflammatory disease. It is thought that host genetic variability may affect the host's response to the virus infection and thus cause severity of the disease. The SARS-CoV-2 virus requires interaction with its receptor complex in the host cells before infection. The transmembrane protease serine 2 (TMPRSS2) has been identified as one of the key molecules involved in SARS-CoV-2 virus receptor binding and cell invasion. Therefore, in this study, we investigated the correlation between a genetic variant within the human TMPRSS2 gene and COVID-19 severity and viral load. RESULTS: We genotyped 95 patients with COVID-19 hospitalised in Dr Soetomo General Hospital and Indrapura Field Hospital (Surabaya, Indonesia) for the TMPRSS2 p.Val160Met polymorphism. Polymorphism was detected using a TaqMan assay. We then analysed the association between the presence of the genetic variant and disease severity and viral load. We did not observe any correlation between the presence of TMPRSS2 genetic variant and the severity of the disease. However, we identified a significant association between the p.Val160Met polymorphism and the SARS-CoV-2 viral load, as estimated by the Ct value of the diagnostic nucleic acid amplification test. Furthermore, we observed a trend of association between the presence of the C allele and the mortality rate in patients with severe COVID-19. CONCLUSION: Our data indicate a possible association between TMPRSS2 p.Val160Met polymorphism and SARS-CoV-2 infectivity and the outcome of COVID-19.


Assuntos
COVID-19/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , SARS-CoV-2/isolamento & purificação , Serina Endopeptidases/genética , Adulto , Alelos , COVID-19/diagnóstico , COVID-19/virologia , Estudos Transversais , Feminino , Frequência do Gene , Genótipo , Humanos , Indonésia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/fisiologia , Carga Viral/genética
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