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1.
Nat Commun ; 12(1): 3770, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145282

RESUMO

Circulating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance of MSK-ACCESS, we report results from 681 prospective blood samples that underwent clinical analysis to guide patient management. Somatic alterations are detected in 73% of the samples, 56% of which have clinically actionable alterations. The utilization of matched normal sequencing allows retention of somatic alterations while removing over 10,000 germline and clonal hematopoiesis variants. Our experience illustrates the importance of analyzing matched normal samples when interpreting cfDNA results and highlights the importance of cfDNA as a genomic profiling source for cancer patients.


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Marcadores Genéticos/genética , Neoplasias/genética , Análise Mutacional de DNA/métodos , Frequência do Gene/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação/genética , Neoplasias/sangue , Neoplasias/patologia
2.
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
3.
Front Immunol ; 12: 658570, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1221947

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.


Assuntos
COVID-19/patologia , Frequência do Gene/genética , Antígeno HLA-A11/genética , Antígeno HLA-B52/genética , Antígenos HLA-C/genética , Fatores Etários , COVID-19/imunologia , Estudos de Casos e Controles , Comorbidade , Feminino , Estudos de Associação Genética , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Insuficiência Respiratória/genética , Insuficiência Respiratória/virologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Fatores Sexuais
4.
Nat Genet ; 53(6): 779-786, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33972781

RESUMO

Long-read sequencing (LRS) promises to improve the characterization of structural variants (SVs). We generated LRS data from 3,622 Icelanders and identified a median of 22,636 SVs per individual (a median of 13,353 insertions and 9,474 deletions). We discovered a set of 133,886 reliably genotyped SV alleles and imputed them into 166,281 individuals to explore their effects on diseases and other traits. We discovered an association of a rare deletion in PCSK9 with lower low-density lipoprotein (LDL) cholesterol levels, compared to the population average. We also discovered an association of a multiallelic SV in ACAN with height; we found 11 alleles that differed in the number of a 57-bp-motif repeat and observed a linear relationship between the number of repeats carried and height. These results show that SVs can be accurately characterized at the population scale using LRS data in a genome-wide non-targeted approach and demonstrate how SVs impact phenotypes.


Assuntos
Doença/genética , Variação Estrutural do Genoma , Sequenciamento de Nucleotídeos em Larga Escala , Característica Quantitativa Herdável , Alelos , LDL-Colesterol/metabolismo , Cromossomos Humanos/genética , Feminino , Frequência do Gene/genética , Humanos , Islândia , Modelos Lineares , Masculino , Pró-Proteína Convertase 9/genética , Recombinação Genética/genética , Deleção de Sequência/genética
5.
Front Immunol ; 12: 658570, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968060

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.


Assuntos
COVID-19/patologia , Frequência do Gene/genética , Antígeno HLA-A11/genética , Antígeno HLA-B52/genética , Antígenos HLA-C/genética , Fatores Etários , COVID-19/imunologia , Estudos de Casos e Controles , Comorbidade , Feminino , Estudos de Associação Genética , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Insuficiência Respiratória/genética , Insuficiência Respiratória/virologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Fatores Sexuais
6.
Biomed Res Int ; 2021: 6634253, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937403

RESUMO

Emerging evidence suggests that the long noncoding RNA (lncRNA) growth arrest special 5 (GAS5) plays crucial roles in the pathogenesis of ischemic stroke (IS). The current research is aimed at assessing the correlation between two functional GAS5 variants (rs145204276 and rs55829688) and susceptibility to IS in a Han Chinese population. This study genotyped the two GAS5 variants in 1086 IS patients as well as 1045 age-matched healthy controls by using an improved multitemperature ligase detection reaction (iMLDR-TM) genotyping technology. We observed a considerable change in the frequencies of the rs145204276 allele and genotype among the IS patients and healthy control group. The del-T haplotype was substantially more prevalent in the IS cases compared to the control individuals. When study participants were stratified according to environmental factors, we found that the rs145204276 del allele was correlated with a higher risk of IS in male, smokers, hypertensive, and those ≥65 years old. Additional stratification conforming to IS subtypes exhibited that individuals carrying the rs145204276 del allele conferred a higher risk of expanding a larger artery atherosclerosis stroke subset. Moreover, there was a significant association between the rs145204276 del allele and elevated expression of GAS5 in IS patients. In contrast, the frequency of the allele related to rs55829688 was not statistically correlated with IS in all analysis. Our study supports a model wherein the rs145204276 variant in the GAS5 lncRNA is associated with IS risk, thus representing a potentially viable biomarker for IS prevention and treatment.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Variação Genética , AVC Isquêmico/genética , RNA Longo não Codificante/genética , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/metabolismo , Fatores de Risco
7.
Biomed Res Int ; 2021: 5532864, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33880367

RESUMO

Bovine tuberculosis (bTB) is a widespread zoonotic infection targeting the livestock sector, especially in developing countries, and posing a risk to humans and animal populations. Its recent prevalence in river buffaloes has been estimated as higher as 33.7%. In emergent countries like Pakistan, there is likeliness of human-livestock interfaces extensively and lacking of effective preventive measures that illustrate the risk of spreading the infection at a remarkable rate. The river buffalo (Bubalus bubalis) is an upkeep host of Mycobacterium bovis and is responsible for disease transmission among buffaloes and other livestock species. In this study, potential molecular biomarkers in the Interferon-gamma gene (IFNg) were identified after genomic screening of river buffaloes. Unique genomic loci in river buffalo proved the novelty of the genomic structure of this phenomenal animal but also highlighted its significance in natural immunity against the Mycobacterium. A total of eight single nucleotide polymorphisms were identified in the coding region of IFNg. The SNPs in the exonic region were all transitions, i.e., the conversion of purines to purines. These SNPs were analyzed for Hardy Weinberg Equilibrium, chi2 test, gene diversity, and protein structural conformation. Pathway analysis in tuberculosis revealed that IFNg inhibits the antigen-presenting cells (APC) through JAK and STAT pathways. Network analysis of IFNg proteins in both species showed strong associations among the immunity-related proteins (interleukins, tissue necrosis factors) and receptors of interferons. The identified polymorphic sites might be novel-potentiated markers for the selection of animals with superior immune response against bTB and can be exploited as promising genomic sites for breeding the resistant animal herds to combat Mycobacterium infection in a long run.


Assuntos
Búfalos/genética , Búfalos/imunologia , Interferon gama/genética , Tuberculose Bovina/genética , Tuberculose Bovina/imunologia , Animais , Bovinos , Frequência do Gene/genética , Redes Reguladoras de Genes , Genoma , Haplótipos/genética , Heterozigoto , Interferon gama/química , Razão de Chances , Estrutura Secundária de Proteína
8.
J Med Virol ; 93(7): 4430-4437, 2021 07.
Artigo em Inglês | MEDLINE | ID: covidwho-1263109

RESUMO

Regional variations are found in the incidence and severity of the COVID-19 infection. Human leukocyte antigen (HLA) polymorphism is one of the genetic factors that might have an impact on the outcome of the disease. This study explored the association between the HLA genotype and the severity of COVID-19 among patients from South Asia. Blood samples from 95 Asians (Bangladeshis, Indians, and Pakistanis) with COVID-19 were collected. The patients were divided according to the severity of their infection: mild (N = 64), severe (N = 31), and fatal (N = 20). DNA was extracted from all samples, and HLA genotyping was performed for both class I (A, B, and C) and class II (DRB1, DQA1, and DQB1) using the PCR-rSSO (polymerase chain reaction-reverse sequence-specific oligonucleotide) molecular method. The frequency of HLA-B*51 was significantly higher among patients in the fatal group than among those in the mild infection group (15% vs. 4.7%, p = 0.027). Additionally, the frequency of HLA-B*35 was significantly higher in the mild infection group than in the fatal group (21.1% vs. 7.5%, p = 0.050 [a borderline p-value]). In terms of HLA class II, DRB1*13 was significantly observed in the fatal group than in the mild infection group (17.5% vs. 11.3%, p = 0.049). However, the p-value for all alleles became insignificant after a statistical correction for the p-values (pc = 0.216, pc = 0.4, and pc = 0.49, respectively). Compared with all published data, this study highlights that the association between the HLA system and the COVID-19 outcome might be ethnic-dependent. Genetic variation between populations must be examined on a wider scale to assess infection prognosis and vaccine effectiveness.


Assuntos
COVID-19/patologia , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Bangladesh , COVID-19/genética , Frequência do Gene/genética , Estudos de Associação Genética , Genótipo , Humanos , Índia , Paquistão , Polimorfismo de Nucleotídeo Único/genética , SARS-CoV-2 , Índice de Gravidade de Doença
9.
Clin Exp Hypertens ; 43(5): 443-449, 2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-33877007

RESUMO

OBJECTIVE: To investigate the correlation between transient receptor potential channel 1 (TRPC1) gene polymorphism and microalbuminuria in patients with primary hypertension. Methods: A total of 468 patients with primary hypertension were admitted to the Department of Hypertension of the First Affiliated Hospital of Xinjiang Medical University from April 2015 to November 2017. According to microalbuminuria, the patients were divided into two groups: high urinary albumin group (EH+mALB group, n = 71) and normal urinary microalbuminuria group (EH group, n = 397). The Sequenom detection technology was used for genotyping the single nucleotide polymorphism (SNP) sites of the TRPC1 gene, such as rs1382688, rs3821647, rs7638459, rs953239, and rs7621642. RESULTS: (1) No significant differences were detected in gender, smoking history, drinking history, family history, course of hypertension, fasting blood glucose, urea, creatinine, triglyceride, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, glycosylated hemoglobin, vitamin D, homocysteine, and cystatin C between the two groups (P > .05). However, age, body mass index (BMI), 24-h mean systolic and diastolic blood pressure, and 24-h average pulse pressure were statistically significant (P < .05). (2) No significant difference was detected in the distribution frequency of the polymorphisms of the TRPC1 gene between the two groups (P > .05), while the genotype, allele, and recessive model of rs7638459 differed significantly difference (P < .05). (3) Logistic regression analysis showed that BMI and rs7638459 CC genotype were the risk factors of increased microalbuminuria in patients with primary hypertension. CONCLUSION: TRPC1 gene polymorphism is associated with increased microalbuminuria in patients with primary hypertension. The CC genotype of rs7638459 may increase the risk of microalbuminuria in patients with essential hypertension, while BMI and rs7638459 CC genotype may be the risk factors of increased microalbuminuria in patients with primary hypertension.


Assuntos
Albuminúria/complicações , Albuminúria/genética , Hipertensão Essencial/complicações , Hipertensão Essencial/genética , Polimorfismo de Nucleotídeo Único/genética , Canais de Cátion TRPC/genética , Albuminúria/urina , Hipertensão Essencial/fisiopatologia , Hipertensão Essencial/urina , Feminino , Frequência do Gene/genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
10.
J Med Virol ; 93(7): 4430-4437, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33830530

RESUMO

Regional variations are found in the incidence and severity of the COVID-19 infection. Human leukocyte antigen (HLA) polymorphism is one of the genetic factors that might have an impact on the outcome of the disease. This study explored the association between the HLA genotype and the severity of COVID-19 among patients from South Asia. Blood samples from 95 Asians (Bangladeshis, Indians, and Pakistanis) with COVID-19 were collected. The patients were divided according to the severity of their infection: mild (N = 64), severe (N = 31), and fatal (N = 20). DNA was extracted from all samples, and HLA genotyping was performed for both class I (A, B, and C) and class II (DRB1, DQA1, and DQB1) using the PCR-rSSO (polymerase chain reaction-reverse sequence-specific oligonucleotide) molecular method. The frequency of HLA-B*51 was significantly higher among patients in the fatal group than among those in the mild infection group (15% vs. 4.7%, p = 0.027). Additionally, the frequency of HLA-B*35 was significantly higher in the mild infection group than in the fatal group (21.1% vs. 7.5%, p = 0.050 [a borderline p-value]). In terms of HLA class II, DRB1*13 was significantly observed in the fatal group than in the mild infection group (17.5% vs. 11.3%, p = 0.049). However, the p-value for all alleles became insignificant after a statistical correction for the p-values (pc = 0.216, pc = 0.4, and pc = 0.49, respectively). Compared with all published data, this study highlights that the association between the HLA system and the COVID-19 outcome might be ethnic-dependent. Genetic variation between populations must be examined on a wider scale to assess infection prognosis and vaccine effectiveness.


Assuntos
COVID-19/patologia , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Bangladesh , COVID-19/genética , Frequência do Gene/genética , Estudos de Associação Genética , Genótipo , Humanos , Índia , Paquistão , Polimorfismo de Nucleotídeo Único/genética , SARS-CoV-2 , Índice de Gravidade de Doença
11.
Biomed Res Int ; 2021: 3653157, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33829059

RESUMO

PPARGC1A gene plays an important role in the activation of various important hormone receptors and transcriptional factors involved in the regulation of adaptive thermogenesis, gluconeogenesis, fiber-type switching in skeletal muscle, mitochondrial biogenesis, and adipogenesis, regulating the reproduction and proposed as a candidate gene for milk-related traits in cattle. This study identified polymorphisms in the PPARGC1A gene in Italian Mediterranean buffaloes and their associations to milk production and quality traits (lactation length, peak milk yield, fat and protein yield, and percentage). As a result, a total of seven SNPs (g.-78A>G, g.224651G>C, g.286986G>A, g.304050G>A, g.325647G>A, g.325817T>C, and g.325997G>A) were identified by DNA pooled sequencing. Analysis of productivity traits within the genotyped animals revealed that the g.286986G>A located at intron 4 was associated with milk production traits, but the g.325817T>C had no association with milk production. Polymorphisms in g.-78A>G was associated with peak milk yield and milk yield, while g.304050G>A and g.325997 G>A were associated with both milk yield and protein percentage. Our findings suggest that polymorphisms in the buffalo PPARGC1A gene are associated with milk production traits and can be used as a candidate gene for milk traits and marker-assisted selection in the buffalo breeding program.


Assuntos
Búfalos/genética , Estudos de Associação Genética , Leite/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , Animais , Frequência do Gene/genética , Itália
12.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803916

RESUMO

The glycine conjugation pathway in humans is involved in the metabolism of natural substrates and the detoxification of xenobiotics. The interactions between the various substrates in this pathway and their competition for the pathway enzymes are currently unknown. The pathway consists of a mitochondrial xenobiotic/medium-chain fatty acid: coenzyme A (CoA) ligase (ACSM2B) and glycine N-acyltransferase (GLYAT). The catalytic mechanism and substrate specificity of both of these enzymes have not been thoroughly characterised. In this study, the level of evolutionary conservation of GLYAT missense variants and haplotypes were analysed. From these data, haplotype variants were selected (156Asn > Ser, [17Ser > Thr,156Asn > Ser] and [156Asn > Ser,199Arg > Cys]) in order to characterise the kinetic mechanism of the enzyme over a wide range of substrate concentrations. The 156Asn > Ser haplotype has the highest frequency and the highest relative enzyme activity in all populations studied, and hence was used as the reference in this study. Cooperative substrate binding was observed, and the kinetic data were fitted to a two-substrate Hill equation. The coding region of the GLYAT gene was found to be highly conserved and the rare 156Asn > Ser,199Arg > Cys variant negatively affected the relative enzyme activity. Even though the 156Asn > Ser,199Arg > Cys variant had a higher affinity for benzoyl-CoA (s0.5,benz = 61.2 µM), kcat was reduced to 9.8% of the most abundant haplotype 156Asn > Ser (s0.5,benz = 96.6 µM), while the activity of 17Ser > Thr,156Asn > Ser (s0.5,benz = 118 µM) was 73% of 156Asn > Ser. The in vitro kinetic analyses of the effect of the 156Asn > Ser,199Arg > Cys variant on human GLYAT enzyme activity indicated that individuals with this haplotype might have a decreased ability to metabolise benzoate when compared to individuals with the 156Asn > Ser variant. Furthermore, the accumulation of acyl-CoA intermediates can inhibit ACSM2B leading to a reduction in mitochondrial energy production.


Assuntos
Acil Coenzima A/metabolismo , Aciltransferases/genética , Aciltransferases/metabolismo , Glicina/metabolismo , Mutação/genética , Animais , Sequência Conservada/genética , Frequência do Gene/genética , Humanos , Cinética , Filogenia
13.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809601

RESUMO

Recurrent implantation failure (RIF) refers to the occurrence of more than two failed in vitro fertilization-embryo transfers (IVF-ETs) in the same individual. RIF can occur for many reasons, including embryo characteristics, immunological factors, and coagulation factors. Genetics can also contribute to RIF, with some single-nucleotide variants (SNVs) reported to be associated with RIF occurrence. We examined SNVs in a long non-coding RNA, homeobox (HOX) transcript antisense RNA (HOTAIR), which is known to affect cancer development. HOTAIR regulates epigenetic outcomes through histone modifications and chromatin remodeling. We recruited 155 female RIF patients and 330 healthy controls, and genotyped HOTAIR SNVs, including rs4759314, rs920778, rs7958904, and rs1899663, in all participants. Differences in these SNVs were compared between the patient and control groups. We identified significant differences in the occurrence of heterozygous genotypes and the dominant expression model for the rs1899663 and rs7958904 SNVs between RIF patients and control subjects. These HOTAIR variants were associated with serum hemoglobin (Hgb), luteinizing hormone (LH), total cholesterol (T. chol), and blood urea nitrogen (BUN) levels, as assessed by analysis of variance (ANOVA). We analyzed the four HOTAIR SNVs and found significant differences in haplotype patterns between RIF patients and healthy controls. The results of this study showed that HOTAIR is not only associated with the development of cancer but also with pregnancy-associated diseases. This study represents the first report showing that HOTAIR is correlated with RIF.


Assuntos
Fertilização In Vitro , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Humanos , Desequilíbrio de Ligação/genética , Recidiva , Falha de Tratamento
14.
Mol Biol Rep ; 48(3): 2273-2284, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33713253

RESUMO

Genome-wide association studies have revealed that some single nucleotide polymorphisms at 8q24, such as rs6983267, might be effective in susceptibility to various cancers in different populations. Therefore, rs6983267 might be useful as a marker for multiple cancers. In this study, we considered a population, including 478 gastrointestinal cancer cases from the Iranian population, to investigate the association between rs6983267 and susceptibility to gastrointestinal cancers. The samples were genotyped using the TaqMan real-time PCR method while 10% of them were also confirmed by sequencing. Higher frequency of G allele was associated with higher grades of tumors in esophageal cancer and the tumors located in the lower portion of the esophagus (OR 3.56; 95% CI 1.13-11.24; P = 0.03) and cardia (OR 5.24; 95% CI 1.26-21.83; P = 0.02), which both locations are involved in esophageal adenocarcinomas with poor prognosis. The results indicated that in the male subgroup, the rs6983267 GG genotype significantly enhanced the gastric cancer susceptibility (OR 4.76; 95% CI 1.57-14.45; P = 0.01). GG genotype also increased the risk of intestinal-type gastric cancer, located in non-cardia (OR 4.62; 95% CI 1.25-17.04; P = 0.02). Moreover, gastric cancer cases and controls with a family history of gastrointestinal tumors were mostly genotyped with the G allele (OR 3.61; 95% CI = 1.09-12.01; P = 0.04). There were no remarkable associations between rs6983267 and susceptibility to esophageal and colon cancers in the Iranian population. However, different genotypes of rs6983267 had significant correlations with tumor grade, cancer type, and family history of gastrointestinal cancers. Further investigations in a larger population and other ethnicities are required to confirm these results.


Assuntos
Neoplasias Gastrointestinais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Idoso , Estudos de Casos e Controles , Meio Ambiente , Feminino , Frequência do Gene/genética , Humanos , Irã (Geográfico) , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos
15.
Mol Biol Rep ; 48(3): 2253-2260, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33759053

RESUMO

Pumpkins (Cucurbita spp.) are among most neglected and underutilized crops cultivated for food and medicine. The major constraint to pumpkin production is lack of genetically improved seeds. The current study was aimed at evaluating the genetic diversity of pumpkins from eight counties in western Kenya using five SSR markers. Seeds were extracted from pumpkin fruits, dried and planted on plastic trays for 4 weeks. DNA was isolated from young leaves using CTAB method and amplified. The samples were genotyped using an ABI 3730 genetic analyzer and the allelic data analyzed using Power Marker V 3.25, DARwin V 6.0.12 and GenAIEx V 6.41software. The five SSR loci were polymorphic with a total of 33 alleles and a mean PIC value of 0.534. The gene diversity and observed heterozygosity was 0.796-0.329 and 0.967-0.164, respectively. Most of genetic variations were found within and among individual samples rather than among counties, with samples of some counties having private alleles. Based on the inbreeding coefficient (F), there was outbreeding in pumpkins from Kakamega county (F = - 0.282) and inbreeding in pumpkins from Kisii, Bungoma and Nyamira counties (F = 0.500, 0.409 and 0.286 respectively). The findings of this study suggest that genetic variation and distribution of pumpkins in western Kenya was due to monocropping and intercropping farming systems, trading of pumpkins in markets and exchange of seeds among local farmers rather than geographical and climatic differences.


Assuntos
Cucurbita/genética , Variação Genética , Repetições de Microssatélites/genética , Alelos , Frequência do Gene/genética , Genética Populacional , Quênia , Filogenia , Polimorfismo Genético , Análise de Componente Principal
16.
Mol Biol Rep ; 48(3): 2519-2525, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33778919

RESUMO

Fanconi anemia (FA) occurs due to genomic instability with predisposition to bone marrow failure, phenotypic abnormalities and cancers. Though mutations in 22 genes leading to DNA repair defect have been identified, the cellular factor such as oxidative stress has also shown to be associated with FA. Nitrosative Stress (NS) is biochemically correlated to many oxidative stress related disorders and the NS as a pathological hallmark in FA has been so far overlooked. We carried out the study first time in Indian patients with FA with an objective to understand the role of NS in the pathogenesis of FA. The study was carried out in 70 FA subjects. The FA subjects were diagnosed by chromosomal breakage analysis. Molecular study was carried out by Next Generation Sequencing and Sanger sequencing. The 3-nitrotyrosine [3-NT] levels were estimated through enzyme-linked immuno-sorbent assay (ELISA) and the nitric oxide synthase genes- NOS1 (c.-420-34221G>A (rs1879417), c.-420-10205C>T (rs499776), c.4286+720G>C (rs81631)) and NOS2 (c.1823C>T (p. Ser608Leu) (rs2297518)) polymorphism were studied by direct sequencing. Chromosomal breakage analysis revealed a high frequency of chromosomal breaks (Mean chromosomal breakage-4.13 ± 1.5 breaks/metaphase) in 70 FA patients as compared to the control. Molecular studies revealed FANCA (58.34%), FANCG (18.34%) and FANCL (16.6%) complementation groups. The 3-nitrotyrosine [3-NT] levels showed to be significantly (p < 0.05) elevated in FA subjects when compared to the age match controls. Genotyping of the NOS2 gene c.1823C>T (p. Ser608Leu) (rs2297518), showed statistically significant (P < 0.05) association with FA. Elevated level of 3-NT is one of the cause of NS and NOS2 gene polymorphism associated with FA is an important target in the treatment regimen.


Assuntos
Anemia de Fanconi/genética , Estudos de Associação Genética , Óxido Nítrico Sintase Tipo II/genética , Estresse Nitrosativo/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Sequência de Bases , Estudos de Casos e Controles , Criança , Pré-Escolar , Frequência do Gene/genética , Humanos , Óxido Nítrico Sintase Tipo I/genética , Tirosina/análogos & derivados , Tirosina/metabolismo , Adulto Jovem
17.
Am J Phys Anthropol ; 175(2): 406-421, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33772750

RESUMO

OBJECTIVES: In genetic admixture processes, source groups for an admixed population possess distinct patterns of genotype and phenotype at the onset of admixture. Particularly in the context of recent and ongoing admixture, such differences are sometimes taken to serve as markers of ancestry for individuals-that is, phenotypes initially associated with the ancestral background in one source population are assumed to continue to reflect ancestry in that population. Such phenotypes might possess ongoing significance in social categorizations of individuals, owing in part to perceived continuing correlations with ancestry. However, genotypes or phenotypes initially associated with ancestry in one specific source population have been seen to decouple from overall admixture levels, so that they no longer serve as proxies for genetic ancestry. Here, we aim to develop an understanding of the joint dynamics of admixture levels and phenotype distributions in an admixed population. METHODS: We devise a mechanistic model, consisting of an admixture model, a quantitative trait model, and a mating model. We analyze the behavior of the mechanistic model in relation to the model parameters. RESULTS: We find that it is possible for the decoupling of genetic ancestry and phenotype to proceed quickly, and that it occurs faster if the phenotype is driven by fewer loci. Positive assortative mating attenuates the process of dissociation relative to a scenario in which mating is random with respect to genetic admixture and with respect to phenotype. CONCLUSIONS: The mechanistic framework suggests that in an admixed population, a trait that initially differed between source populations might serve as a reliable proxy for ancestry for only a short time, especially if the trait is determined by few loci. It follows that a social categorization based on such a trait is increasingly uninformative about genetic ancestry and about other traits that differed between source populations at the onset of admixture.


Assuntos
Frequência do Gene/genética , Genética Populacional , Antropologia Física , Feminino , Fluxo Gênico/genética , Genoma Humano/genética , Genótipo , Humanos , Masculino , Fenótipo , Pigmentação da Pele/genética
18.
Med Sci Monit ; 27: e930591, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33723203

RESUMO

BACKGROUND Cytochrome P450 (CYP) genes are necessary for the production or metabolism of fetal sex hormones during pregnancy. The second-to-fourth digit ratio (2D: 4D) is formed in the early stage of human fetal development and considered an indicator reflecting prenatal sex steroids levels. We explored the association between 2D: 4D and single-nucleotide polymorphisms (SNPs) of CYP. MATERIAL AND METHODS Correlation analysis between 2D: 4D and 8 SNPs, rs2687133 (CPY3A7), rs7173655 (CYP11A1), rs1004467, rs17115149, and rs2486758 (CYP17A1), and rs4646, rs2255192, rs4275794 (CYP19A1), was performed using data from 426 female and 412 male Chinese university students. SNP genotyping was conducted using PCR. Digit lengths were photographed and measured by image processing software. RESULTS rs2486758 (CYP17A1) correlated with left hand 2D: 4D in men (P=0.026), and rs1004467 (CYP17A1) correlated with right hand 2D: 4D in men (P=0.008) and the whole population (P=0.032). In men, allele G rs1004467 decreased right hand 2D: 4D, while allele C of rs2486758 increased left hand 2D: 4D. In women, left hand 2D: 4D was higher in genotypes with allele A of SNP rs4646 (CYP19A1) under the dominant genetic model; female DR-L was higher in genotypes with allele T of rs17115149 (CYP11A1). SNPs rs2687133 (CYP3A7) and rs1004467 (CYP17A1) were significantly correlated with right hand 2D: 4D (P=0.0107). CONCLUSIONS SNPs rs1004467 and rs2486758 of CYP17A1 are significant in the relationship between 2D: 4D and CYP gene polymorphisms under different conditions. SNP interactions between CYP genes probably impact 2D: 4D. The correlation between 2D: 4D and some sex hormone-related diseases may be due to the effect of CYP variants on the 2 phenotypes.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Dedos/anatomia & histologia , Alelos , Aromatase/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Citocromo P-450 CYP3A/genética , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Nucleotídeos/genética , Polimorfismo de Nucleotídeo Único/genética , Esteroide 17-alfa-Hidroxilase/genética , Estudantes , Universidades , Adulto Jovem
19.
Hum Immunol ; 82(4): 247-254, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: covidwho-1039364

RESUMO

Immunorelevant genes are among the most probable modulators of coronavirus disease 2019 (COVID-19) progression and prognosis. However, in the few months of the pandemic, data generated on host genetics has been scarce. The present study retrieved data sets of HLA-B alleles, KIR genes and functional single nucleotide polymorphisms (SNPs) in cytokines related to COVID-19 cytokine storm from two publicly available databases: Allele Frequency Net Database and Ensembl, and correlated these frequency data with Case Fatality Rate (CFR) and Daily Death Rates (DDR) across countries. Correlations of eight HLA-B alleles and polymorphisms in three cytokine genes (IL6, IL10, and IL12B) were observed and were mainly associated with DDR. Additionally, HLA-B correlations suggest that differences in allele affinities to SARS-CoV-2 peptides are also associated with DDR. These results may provide rationale for future host genetic marker surveys on COVID-19.


Assuntos
COVID-19/patologia , Citocinas/genética , Antígenos HLA-B/genética , Receptores KIR/genética , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/mortalidade , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Frequência do Gene/genética , Marcadores Genéticos/genética , Humanos , Interleucina-10/genética , Subunidade p40 da Interleucina-12/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único/genética
20.
Genet Test Mol Biomarkers ; 25(2): 102-110, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33596137

RESUMO

Objective: To study the association of the expression levels of long noncoding RNA Taurine-upregulated gene 1 (lncRNA TUG1) and TUG1 polymorphisms with knee osteoarthritis (KOA). Materials and Methods: A total of 255 KOA patients and 255 controls from May 2017 to December 2019 were selected for the study. Sanger sequencing was conducted to detect the genotypes of the TUG1 rs5749201, rs7284767, and rs886471 loci in all study subjects. Unconditional logistic regression analysis was used to calculate odds ratios and 95% confidence intervals, and the associations between the TUG1 rs574901, rs7284767 and rs886471 loci and KOA risk were analyzed. Multifactor dimensionality reduction was used to analyze the interactions among alleles at the three TUG1 loci examined. Quantitative real-time polymerase chain reaction was used to evaluate the expression levels of TUG1 lncRNA in plasma. Results: A total of 255 KOA patients and 255 control subjects completed the study. After adjusting for the factors of gender, age, body mass index, smoking history, drinking history, and family history, we found that the carriers of the A allele of the TUG1 rs5749201 locus were 1.36 times more likely to develop KOA than the carriers of the T allele (95% confidence interval [CI] = 1.05-1.75, p = 0.02); the G allele of the rs7284767 locus was a protective factor for KOA (odds ratio [OR] = 0.71, 95% CI = 0.54-0.92, p = 0.01); and the allelic variation at rs886471 G > T led to an increased risk of KOA by 2.34 times (95% CI = 1.53-3.57, p < 0.01). We also found that the GAG haplotype for the three loci was significantly associated with the increased risk of KOA (OR = 2.77, 95% CI = 1.67-4.57, p < 0.01). There was no correlation found between the TUG1 rs886471, rs5749201, and rs7284767 single nucleotide polymorphisms loci and the severity of KOA. The allelic variation at TUG1 rs5749201 T > A, rs886471 T > G were associated with decreased levels of TUG1 lncRNA in the plasma of the subjects, while the allelic variation at rs7284767 A > G was associated with increased levels of TUG1 lncRNA in plasma (p = 0.01, p < 0.01, p < 0.01). Conclusion: Plasma TUG1 lncRNA levels and loci at the TUG1 rs5749201, rs7284767, and rs886471 loci are associated with KOA risk.


Assuntos
Osteoartrite do Joelho/genética , RNA Longo não Codificante/genética , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Osteoartrite do Joelho/metabolismo , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/metabolismo , Fatores de Risco
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