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1.
mBio ; 12(4): e0180321, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34372699

RESUMO

Azole resistance in pathogenic Aspergillus fumigatus has become a global public health issue threatening the use of medical azoles. The environmentally occurring resistance mutations, TR34/L98H (TR34) and TR46/Y121F/T289A (TR46), are widespread across multiple continents and emerging in the United States. We used whole-genome single nucleotide polymorphism (SNP) analysis on 179 nationally represented clinical and environmental A. fumigatus genomes from the United States along with 18 non-U.S. genomes to evaluate the genetic diversity and foundation of the emergence of azole resistance in the United States. We demonstrated the presence of clades of A. fumigatus isolates: clade A (17%) comprised a global collection of clinical and environmental azole-resistant strains, including all strains with the TR34/L98H allele from India, The Netherlands, the United Kingdom, and the United States, and clade B (83%) consisted of isolates without this marker mainly from the United States. The TR34/L98H polymorphism was shared among azole-resistant A. fumigatus strains from India, The Netherlands, the United Kingdom, and the United States, suggesting the common origin of this resistance mechanism. Six percent of azole-resistant A. fumigatus isolates from the United States with the TR34 resistance marker had a mixture of clade A and clade B alleles, suggestive of recombination. Additionally, the presence of equal proportions of both mating types further suggests the ongoing presence of recombination. This study demonstrates the genetic background for the emergence of azole resistance in the United States, supporting a single introduction and subsequent propagation, possibly through recombination of environmentally driven resistance mutations. IMPORTANCE Aspergillus fumigatus is one of the most common causes of invasive mold infections in patients with immune deficiencies and has also been reported in patients with severe influenza and severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2). Triazole drugs are the first line of therapy for this infection; however, their efficacy has been compromised by the emergence of azole resistance in A. fumigatus, which was proposed to be selected for by exposure to azole fungicides in the environment [P. E. Verweij, E. Snelders, G. H. J. Kema, E. Mellado, et al., Lancet Infect Dis 9:789-795, 2009, https://doi.org/10.1016/S1473-3099(09)70265-8]. Isolates with environmentally driven resistance mutations, TR34/L98H (TR34) and TR46/Y121F/T289A (TR46), have been reported worldwide. Here, we used genomic analysis of a large sample of resistant and susceptible A. fumigatus isolates to demonstrate a single introduction of TR34 in the United States and suggest its ability to spread into the susceptible population is through recombination between resistant and susceptible isolates.


Assuntos
Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/genética , Farmacorresistência Fúngica/genética , Triazóis/farmacologia , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/isolamento & purificação , Sistema Enzimático do Citocromo P-450/genética , Proteínas Fúngicas/genética , Genoma Fúngico/genética , Humanos , Testes de Sensibilidade Microbiana , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos , Sequenciamento Completo do Genoma
2.
Biol Res ; 54(1): 26, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454612

RESUMO

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.


Assuntos
Neoplasias da Mama , MicroRNAs , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , MicroRNAs/genética , Nucleotídeos , Polimorfismo de Nucleotídeo Único/genética
3.
Nutrients ; 13(7)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34371977

RESUMO

The effectiveness of weight loss treatment displays dramatic inter-individual variabilities, even with well-controlled energy intake/expenditure. This study aimed to determine the association between daily rhythms of cardiac autonomic control and weight loss efficiency and to explore the potential relevance to weight loss resistance in humans carrying the genetic variant C at CLOCK 3111T/C. A total of 39 overweight/obese Caucasian women (20 CLOCK 3111C carriers and 19 non-carriers) completed a behaviour-dietary obesity treatment of ~20 weeks, during which body weight was assessed weekly. Ambulatory electrocardiographic data were continuously collected for up to 3.5 days and used to quantify the daily rhythm of fractal cardiac dynamics (FCD), a non-linear measure of autonomic function. FCD showed a 24 h rhythm (p < 0.001). Independent of energy intake and physical activity level, faster weight loss was observed in individuals with the phase (peak) of the rhythm between ~2-8 p.m. and with a larger amplitude. Interestingly, the phase effect was significant only in C carriers (p = 0.008), while the amplitude effect was only significant in TT carriers (p < 0.0001). The daily rhythm of FCD and CLOCK 3111T/C genotype is linked to weight loss response interactively, suggesting complex interactions between the genetics of the circadian clock, the daily rhythm of autonomic control, and energy balance control.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Proteínas CLOCK/genética , Ritmo Circadiano/genética , Coração/inervação , Sobrepeso/terapia , Perda de Peso/genética , Adulto , Estudos de Casos e Controles , Ritmo Circadiano/fisiologia , Eletrocardiografia Ambulatorial , Ingestão de Energia , Exercício Físico , Feminino , Fractais , Genótipo , Coração/fisiopatologia , Humanos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/fisiopatologia , Obesidade/terapia , Sobrepeso/genética , Sobrepeso/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética
4.
J Transl Med ; 19(1): 350, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34399781

RESUMO

BACKGROUND: The roles of FTO gene and the level of serum 25-OH-vitamin D in obesity are frequently reported. This study aimed to investigate the interactions of serum 25-OH-vitamin D level, FTO and IRX3 genes expression, and FTO genotype in obese and overweight boys. METHODS: This study was carried out on the 120 male adolescents with overweight in Tehran, Iran. Blood samples were collected from the participants in order to evaluate the serum level of 25-OH-vitamin D, the expression level of FTO and IRX3 genes, and FTO genotype for rs9930506 at baseline and after 18 weeks of the study. RESULTS: In general, no significant association was found between serum 25-OH-vitamin D level and IRX3 and FTO genes expression. The results of linear regression on the relationship between 25-OH-vitamin D serum level and FTO and IRX3 genes expression based on FTO genotypes for rs9930506 indicated that in AA/AG genotype carriers, serum 25-OH-vitamin D level was positively associated with FTO gene expression (B = 0.07, p = 0.02) and inversely associated with IRX3 gene expression (B = - 0.07, p = 0.03). In GG carriers, serum 25-OH-vitamin D level was not associated with expression of IRX3 and FTO genes. CONCLUSION: There are significant interactions between 25-OH-vitamin D and the expression of FTO and IRX3 genes in the subset of obese patients with specific genotypes for FTO rs9930506. There was no association between serum 25-OH-vitamin D levels and the expression of FTO and IRX genes in individuals with a homozygous genotype for the risk allele of the FTO gene polymorphism.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato , Polimorfismo de Nucleotídeo Único , Adolescente , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Expressão Gênica , Genótipo , Proteínas de Homeodomínio/genética , Humanos , Irã (Geográfico) , Masculino , Obesidade/genética , Sobrepeso , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Vitamina D
5.
Clin Pharmacol Ther ; 110(3): 723-732, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34231218

RESUMO

We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (ß-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the ß-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10-8 ). rs139945292 was validated through BP response to ß-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10-4 , Beta = 3.09, diastolic BP response P = 5 × 10-3 , Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the ß-blocker treated patients' subgroup (P = 2.35 × 10-4 , odds ratio = 1.57, 95% confidence interval = 1.23-1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in ß-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in ß-blocker treated patients. Further investigation into this region is warranted.


Assuntos
Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/genética , Sistema Cardiovascular/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Hipertensão/tratamento farmacológico , Afro-Americanos/genética , Idoso , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos/métodos , Polimorfismo de Nucleotídeo Único/genética
6.
J Transl Med ; 19(1): 315, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34289870

RESUMO

BACKGROUND: Sarcopenia is a loss of muscle mass and strength causing disability, morbidity, and mortality in older adults, which is characterized by alterations of the neuromuscular junctions (NMJs). SNAP-25 is essential for the maintenance of NMJ integrity, and the expression of this protein was shown to be modulated by the SNAP-25 rs363050 polymorphism and by a number of miRNAs. METHODS: We analysed these parameters in a cohort of sarcopenic patients undergoing structured rehabilitation. The rs363050 genotype frequency distribution was analyzed in 177 sarcopenic patients and 181 healthy controls (HC). The concentration of seven miRNAs (miR-451a, miR-425-5p, miR155-5p, miR-421-3p, miR-495-3p, miR-744-5p and miR-93-5p), identified by mouse brain miRNome analysis to be differentially expressed in wild type compared to SNAP-25± heterozygous mice, was analyzed as well by droplet digital PCR (ddPCR) in a subgroup of severe sarcopenic patients undergoing rehabilitation. RESULTS: The SNAP-25 rs363050 AA genotype was significantly more common in sarcopenic patients compared to HC (pc = 0.01); miR-451a was significantly up-regulated in these patients before rehabilitation. Rehabilitation modified miRNAs expression, as miR-155-5p, miR-421-3p, miR-451a, miR-425-5p, miR-744-5p and miR-93-5p expression was significantly up-regulated (p < 0.01), whereas that of miR-495-3p was significantly down-regulated (p < 0.001) by rehabilitation. Notably, rehabilitation-associated improvement of the muscle-skeletal SPPB score was significantly associated with the reduction of miR-451a expression. CONCLUSION: These results support the hypothesis of a role for SNAP-25 in sarcopenia and suggest SNAP-25-associated miRNAs as circulatory biomarkers of rehabilitative outcome for sarcopenia.


Assuntos
MicroRNAs , Sarcopenia , Idoso , Animais , Biomarcadores , Perfilação da Expressão Gênica , Humanos , Camundongos , MicroRNAs/genética , Músculos , Polimorfismo de Nucleotídeo Único/genética , Sarcopenia/genética , Proteína 25 Associada a Sinaptossoma
7.
J Int Med Res ; 49(7): 3000605211019263, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34275374

RESUMO

OBJECTIVE: To investigate the relationship between angiotensin (AGT) rs2493132 gene polymorphism and the risk of developing non-alcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD) in the Chinese Han population. METHODS: Polymerase chain reaction was performed to determine AGT genotypes. Anthropometric and clinical data were investigated and statistically analyzed in the clinical laboratory department of Qingdao Municipal Hospital. RESULTS: The AGT rs2493132 CT + TT genotype was an important risk factor for CAD in patients with NAFLD and NAFLD + CAD in healthy controls. The AGT rs2493132 T allele increased the risk of NAFLD + CAD in healthy controls. The AGT rs2493132 CT + TT genotype and T allele also significantly increased the risk of CAD in patients with NAFLD after adjustments for age, sex, and body mass index. In addition, AGT rs2493132 T allele carriers showed higher total cholesterol (TC) and low-density lipoprotein (LDL) levels compared with non-carriers. CONCLUSIONS: The AGT rs2493132 CT + TT genotype and T allele significantly increased the risk of developing CAD in patients with NAFLD in the Chinese Han population. The AGT rs2493132 T allele was associated with increased serum TC and LDL levels.


Assuntos
Doença da Artéria Coronariana , Hepatopatia Gordurosa não Alcoólica , Angiotensinogênio , Angiotensinas , Grupo com Ancestrais do Continente Asiático/genética , China , Doença da Artéria Coronariana/genética , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
8.
J Genet ; 1002021.
Artigo em Inglês | MEDLINE | ID: mdl-34282737

RESUMO

Eucalyptus breeding programme mainly aims at increasing productivity associated with wood property traits which are suitable for different end uses. The principal challenge in this endeavor is to combine productivity with industrially relevant wood traits. In the present study, 23 hybrid clones derived from a biparental mapping population of Eucalyptus camaldulensis × E. tereticornis was assessed for six wood property traits across two sites in Tamil Nadu, India. The mean of most of the traits evaluated was consistently higher in Muthupettai, indicating significant site effect. Combined and location-wise analysis indicated additive genetic control of assessed traits. The stability of acoustic velocity in study sites, negligible G × E interaction and significant correlation with dynamic modulus of elasticity (DMoE) implies its use in selecting trees/logs for solid wood properties. Combined analysis of locations revealed low to moderate heritability (0.294-0.439) for all the traits with H2 being highest for cellulose per cent (0.439) followed by acoustic velocity (0.416). Genetic advance was calculated and was the highest for diameter (10.47%) followed by DMoE (9.19%). The two major chemical constituents of wood, namely total lignin and cellulose per cent showed 7.13% and 7.53% advancement in the hybrids. The out-performance of several hybrid clones when compared to the parents for different wood traits reiterates the use of Eucalyptus hybrids in plantation programmes to improve quality of raw material suitable for industrial application.


Assuntos
Eucalyptus/química , Hibridização Genética , Locos de Características Quantitativas/genética , Madeira/genética , Eucalyptus/genética , Índia , Fenótipo , Melhoramento Vegetal , Polimorfismo de Nucleotídeo Único/genética , Madeira/química
9.
J Genet ; 1002021.
Artigo em Inglês | MEDLINE | ID: mdl-34282739

RESUMO

The preproinsulin gene encodes a precursor protein of insulin, which is the most important hormone for lowering blood glucose levels and promoting the synthesis of glycogen, fat and protein. To explore the correlation between polymorphisms in the preproinsulin gene and growth traits in grass carp, the preproinsulin gene sequence, measuring a total of 5708 bp, was identified in the grass carp genome. The sequence includes a promoter, two introns and three exons, and encodes a 108-aa protein. A total of three SNPs were identified, including SNP1 (g.-2661C>G) in the promoter and SNP2 (g.1305G>C) and SNP3 (g.1682G>A) in intron 2. The correlation between SNPs and growth traits in grass carp was analysed by a general linear model (GLM). The results indicated that no genotype in each single SNP, SNP1 with SNP2, or SNP1 with SNP3 was related to rapid growth and low fatness, respectively. While eight genotypes of SNP1, SNP2 and SNP3 were combined into six types of effective diplotypes, the H5 diplotype was significantly superior to the other diplotypes (P<0.05) concerning body weight, body length, body height and body width, and its fatness was lower than those of the other diplotypes, except for H6 diplotype. This result indicated that the H5 diplotype of the preproinsulin gene in grass carp may be a candidate molecular marker for selecting fast-growing and low-fatness grass carp.


Assuntos
Carpas/genética , Insulina/genética , Regiões Promotoras Genéticas/genética , Precursores de Proteínas/genética , Animais , Sequência de Bases , Éxons/genética , Genótipo , Íntrons/genética , Polimorfismo de Nucleotídeo Único/genética
10.
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
11.
J Int Med Res ; 49(7): 3000605211029504, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34266338

RESUMO

OBJECTIVE: Schizophrenia is a complex mental disorder with high heritability. The hypothalamic-pituitary-adrenal (HPA) axis, which is the stress system of the neuroendocrine system, is considered to impact psychotic disorders. We hypothesized that polymorphisms of HPA axis genes might be involved in the development of schizophrenia. METHODS: A case-control study comprising 234 patients with schizophrenia and 399 matched healthy controls was conducted to investigate the association between the human melanocortin 2 receptor (MC2R) gene and schizophrenia risk. Seven tag single nucleotide polymorphisms (SNPs) (rs16941303, rs16941314, rs2186944, rs28926188, rs7230126, rs948322, and rs948331) of MC2R were genotyped by direct sequencing. RESULTS: No significant associations were observed between any of the alleles, genotypes, or haplotypes examined within the MC2R gene and the risk of schizophrenia in the total group or in subgroups stratified by smoking or alcoholism. However, a subgroup analysis stratified by sex revealed that under the additive model, the C allele of the MC2R rs948331 SNP significantly decreased the risk of schizophrenia in females (odds ratio=0.18). CONCLUSION: The C allele of the MC2R rs948331 locus may be a protective factor, reducing the risk of schizophrenia in the female Han Chinese population.


Assuntos
Grupo com Ancestrais do Continente Asiático , Receptor Tipo 2 de Melanocortina , Esquizofrenia , Regiões 3' não Traduzidas , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 2 de Melanocortina/genética , Receptor Tipo 2 de Melanocortina/metabolismo , Esquizofrenia/genética
12.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298916

RESUMO

This review aims at better understanding the genetics of endometriosis. Endometriosis is a frequent feminine disease, affecting up to 10% of women, and characterized by pain and infertility. In the most accepted hypothesis, endometriosis is caused by the implantation of uterine tissue at ectopic abdominal places, originating from retrograde menses. Despite the obvious genetic complexity of the disease, analysis of sibs has allowed heritability estimation of endometriosis at ~50%. From 2010, large Genome Wide Association Studies (GWAS), aimed at identifying the genes and loci underlying this genetic determinism. Some of these loci were confirmed in other populations and replication studies, some new loci were also found through meta-analyses using pooled samples. For two loci on chromosomes 1 (near CCD42) and chromosome 9 (near CDKN2A), functional explanations of the SNP (Single Nucleotide Polymorphism) effects have been more thoroughly studied. While a handful of chromosome regions and genes have clearly been identified and statistically demonstrated as at-risk for the disease, only a small part of the heritability is explained (missing heritability). Some attempts of exome sequencing started to identify additional genes from families or populations, but are still scarce. The solution may reside inside a combined effort: increasing the size of the GWAS designs, better categorize the clinical forms of the disease before analyzing genome-wide polymorphisms, and generalizing exome sequencing ventures. We try here to provide a vision of what we have and what we should obtain to completely elucidate the genetics of this complex disease.


Assuntos
Endometriose/genética , Exoma/genética , Animais , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Exoma/métodos
13.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298919

RESUMO

This study was conducted to investigate doubled haploid (DH) lines produced between high GSL (HGSL) Brassica rapa ssp. trilocularis (yellow sarson) and low GSL (LGSL) B. rapa ssp. chinensis (pak choi) parents. In total, 161 DH lines were generated. GSL content of HGSL DH lines ranged from 44.12 to 57.04 µmol·g-1·dry weight (dw), which is within the level of high GSL B. rapa ssp. trilocularis (47.46 to 59.56 µmol g-1 dw). We resequenced five of the HGSL DH lines and three of the LGSL DH lines. Recombination blocks were formed between the parental and DH lines with 108,328 single-nucleotide polymorphisms in all chromosomes. In the measured GSL, gluconapin occurred as the major substrate in HGSL DH lines. Among the HGSL DH lines, BrYSP_DH005 had glucoraphanin levels approximately 12-fold higher than those of the HGSL mother plant. The hydrolysis capacity of GSL was analyzed in HGSL DH lines with a Korean pak choi cultivar as a control. Bioactive compounds, such as 3-butenyl isothiocyanate, 4-pentenyl isothiocyanate, 2-phenethyl isothiocyanate, and sulforaphane, were present in the HGSL DH lines at 3-fold to 6.3-fold higher levels compared to the commercial cultivar. The selected HGSL DH lines, resequencing data, and SNP identification were utilized for genome-assisted selection to develop elite GSL-enriched cultivars and the industrial production of potential anti-cancerous metabolites such as gluconapin and glucoraphanin.


Assuntos
Brassica rapa/genética , Glucosinolatos/genética , Brassica rapa/efeitos dos fármacos , Genótipo , Glucosinolatos/farmacologia , Haploidia , Isotiocianatos/farmacologia , Oximas/farmacologia , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Sulfóxidos/farmacologia
14.
Epidemiol Infect ; 149: e162, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34210368

RESUMO

Clinical and genetic risk factors for severe coronavirus disease 2019 (COVID-19) are often considered independently and without knowledge of the magnitudes of their effects on risk. Using severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) positive participants from the UK Biobank, we developed and validated a clinical and genetic model to predict risk of severe COVID-19. We used multivariable logistic regression on a 70% training dataset and used the remaining 30% for validation. We also validated a previously published prototype model. In the validation dataset, our new model was associated with severe COVID-19 (odds ratio per quintile of risk = 1.77, 95% confidence interval (CI) 1.64-1.90) and had acceptable discrimination (area under the receiver operating characteristic curve = 0.732, 95% CI 0.708-0.756). We assessed calibration using logistic regression of the log odds of the risk score, and the new model showed no evidence of over- or under-estimation of risk (α = -0.08; 95% CI -0.21-0.05) and no evidence or over-or under-dispersion of risk (ß = 0.90, 95% CI 0.80-1.00). Accurate prediction of individual risk is possible and will be important in regions where vaccines are not widely available or where people refuse or are disqualified from vaccination, especially given uncertainty about the extent of infection transmission among vaccinated people and the emergence of SARS-CoV-2 variants of concern.


Assuntos
COVID-19 , Modelos Genéticos , Medição de Risco/métodos , Idoso , Idoso de 80 Anos ou mais , COVID-19/epidemiologia , COVID-19/genética , COVID-19/fisiopatologia , Comorbidade , Feminino , Humanos , Masculino , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único/genética , Curva ROC , Reprodutibilidade dos Testes , SARS-CoV-2 , Índice de Gravidade de Doença
15.
Nat Commun ; 12(1): 4249, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253716

RESUMO

5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark that regulates gene expression. Charting the landscape of 5hmC in human tissues is fundamental to understanding its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues. We found that 5hmC preferentially decorates gene bodies and outperforms gene body 5mC in reflecting gene expression. Approximately one-third of 5hmC peaks are tissue-specific differentially-hydroxymethylated regions (tsDhMRs), which are deposited in regions that potentially regulate the expression of nearby tissue-specific functional genes. In addition, tsDhMRs are enriched with tissue-specific transcription factors and may rewire tissue-specific gene expression networks. Moreover, tsDhMRs are associated with single-nucleotide polymorphisms identified by genome-wide association studies and are linked to tissue-specific phenotypes and diseases. Collectively, our results show the tissue-specific 5hmC landscape of the human genome and demonstrate that 5hmC serves as a fundamental regulatory element affecting tissue-specific gene expression programs and functions.


Assuntos
5-Metilcitosina/análogos & derivados , Genoma Humano , Especificidade de Órgãos/genética , 5-Metilcitosina/metabolismo , Sequência de Bases , Sítios de Ligação/genética , Metilação de DNA/genética , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Fatores de Transcrição/metabolismo
16.
J Contemp Dent Pract ; 22(3): 248-252, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210923

RESUMO

AIM AND OBJECTIVE: This study is conducted to find the association of BMP2 (bone morphogenic protein 2) gene variant rs1005464 and rs15705 with skeletal class I crowding cases. MATERIALS AND METHODS: Blood samples from 60 subjects who visited the Department of Orthodontics and Dentofacial Orthopaedics, D.A.P.M.R.V. Dental College, Bengaluru, were taken after written informed consent. These were divided into two groups: group A with 30 subjects having skeletal class I bases with crowding and group B with 30 subjects having skeletal class I bases without visible crowding or spacing (±2 mm). Around 2 mL of venous blood sample was procured from cases and controls after careful examination. All the samples were then subjected to polymerase chain reaction followed by DNA sequencing and capillary electrophoresis. BMP2 rs1005464 and rs15705 gene variants were assessed and Z-Test was used for statistical analysis. RESULT: GG (p = 0.001) and CC (p = 0.0024) genotype of BMP2 gene variant rs1005464 and rs15705, respectively, are significantly associated with skeletal class I crowding cases. CONCLUSION: This study concludes that BMP2 variants rs1005464 and rs15705 can be used as genetic markers for skeletal class I bases having crowding. CLINICAL SIGNIFICANCE: Predisposing genetic markers BMP2 can be identified prior and this would help in predicting the probability of potential crowding in the future and this would help in early prevention and intervention of crowding.


Assuntos
Má Oclusão , Polimorfismo de Nucleotídeo Único , Proteína Morfogenética Óssea 2/genética , Humanos , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único/genética
17.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203967

RESUMO

A substantial proportion of subjects with autosomal recessive retinitis pigmentosa (arRP) or Usher syndrome type II (USH2) lacks a genetic diagnosis due to incomplete USH2A screening in the early days of genetic testing. These cases lack eligibility for optimal genetic counseling and future therapy. USH2A defects are the most frequent cause of USH2 and are also causative in individuals with arRP. Therefore, USH2A is an important target for genetic screening. The aim of this study was to assess unscreened or incompletely screened and unexplained USH2 and arRP cases for (likely) pathogenic USH2A variants. Molecular inversion probe (MIP)-based sequencing was performed for the USH2A exons and their flanking regions, as well as published deep-intronic variants. This was done to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in 29 unscreened or partially pre-screened USH2 and 11 partially pre-screened arRP subjects. In 29 out of these 40 cases, two (likely) pathogenic variants were successfully identified. Four of the identified SNVs and one CNV were novel. One previously identified synonymous variant was demonstrated to affect pre-mRNA splicing. In conclusion, genetic diagnoses were obtained for a majority of cases, which confirms that MIP-based sequencing is an effective screening tool for USH2A. Seven unexplained cases were selected for future analysis with whole genome sequencing.


Assuntos
Análise Custo-Benefício , Éxons/genética , Proteínas da Matriz Extracelular/genética , Sondas Moleculares/metabolismo , Sítios de Splice de RNA/genética , Retinite Pigmentosa/genética , Análise de Sequência de DNA , Síndromes de Usher/genética , Sequência de Bases , Variações do Número de Cópias de DNA/genética , Deleção de Genes , Humanos , Polimorfismo de Nucleotídeo Único/genética , Retinite Pigmentosa/economia , Síndromes de Usher/economia
18.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299222

RESUMO

FMS-like tyrosine kinase 3 (FLT3) gene mutations have been found in more than one-third of Acute Myeloid Leukemia (AML) cases. The most common point mutation in FLT3 occurs at the 835th residue (D835A/E/F/G/H/I/N/V/Y), in the activation loop region. The D835 residue is critical in maintaining FLT3 inactive conformation; these mutations might influence the interaction with clinically approved AML inhibitors used to treat the AML. The molecular mechanism of each of these mutations and their interactions with AML inhibitors at the atomic level is still unknown. In this manuscript, we have investigated the structural consequence of native and mutant FLT-3 proteins and their molecular mechanisms at the atomic level, using molecular dynamics simulations (MDS). In addition, we use the molecular docking method to investigate the binding pattern between the FLT-3 protein and AML inhibitors upon mutations. This study apparently elucidates that, due to mutations in the D835, the FLT-3 structure loses its conformation and becomes more flexible compared to the native FLT3 protein. These structural changes are suggested to contribute to the relapse and resistance responses to AML inhibitors. Identifying the effects of FLT3 at the molecular level will aid in developing a personalized therapeutic strategy for treating patients with FLT-3-associated AML.


Assuntos
Leucemia Mieloide Aguda/genética , Tirosina Quinase 3 Semelhante a fms/genética , Simulação por Computador , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Mutação/efeitos dos fármacos , Mutação/genética , Mutação Puntual/efeitos dos fármacos , Mutação Puntual/genética , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Conformação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase 3 Semelhante a fms/metabolismo
19.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299232

RESUMO

The genetic architecture of complex traits is multifactorial. Genome-wide association studies (GWASs) have identified risk loci for complex traits and diseases that are disproportionately located at the non-coding regions of the genome. On the other hand, we have just begun to understand the regulatory roles of the non-coding genome, making it challenging to precisely interpret the functions of non-coding variants associated with complex diseases. Additionally, the epigenome plays an active role in mediating cellular responses to fluctuations of sensory or environmental stimuli. However, it remains unclear how exactly non-coding elements associate with epigenetic modifications to regulate gene expression changes and mediate phenotypic outcomes. Therefore, finer interrogations of the human epigenomic landscape in associating with non-coding variants are warranted. Recently, chromatin-profiling techniques have vastly improved our understanding of the numerous functions mediated by the epigenome and DNA structure. Here, we review various chromatin-profiling techniques, such as assays of chromatin accessibility, nucleosome distribution, histone modifications, and chromatin topology, and discuss their applications in unraveling the brain epigenome and etiology of complex traits at tissue homogenate and single-cell resolution. These techniques have elucidated compositional and structural organizing principles of the chromatin environment. Taken together, we believe that high-resolution epigenomic and DNA structure profiling will be one of the best ways to elucidate how non-coding genetic variations impact complex diseases, ultimately allowing us to pinpoint cell-type targets with therapeutic potential.


Assuntos
Cromatina/genética , Cromatina/metabolismo , Cromatina/fisiologia , Sítios de Ligação/genética , Imunoprecipitação da Cromatina/métodos , Epigênese Genética/genética , Epigenoma/genética , Epigenômica/métodos , Regulação da Expressão Gênica/genética , Genoma , Estudo de Associação Genômica Ampla/métodos , Código das Histonas/genética , Humanos , Herança Multifatorial/genética , Nucleossomos/metabolismo , Nucleossomos/fisiologia , Polimorfismo de Nucleotídeo Único/genética , RNA não Traduzido/genética , RNA não Traduzido/metabolismo
20.
Biomed Pharmacother ; 139: 111557, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243621

RESUMO

Migraine is a neurological ailment that is characterized by severe throbbing unilateral headache and associated with nausea, photophobia, phonophobia and vomiting. A full and clear mechanism of the pathogenesis of migraine, though studied extensively, has not been established yet. The current available information indicates an intracranial network activation that culminates in the sensitization of the trigemino-vascular system, release of inflammatory markers, and initiation of meningeal-like inflammatory reaction that is sensed as headache. Genetic factors might play a significant role in deciding an individual's susceptibility to migraine. Twin studies have revealed that a single gene polymorphism can lead to migraine in individuals with a monogenic migraine disorder. In this review, we describe recent advancements in the genetics, pathophysiology, diagnosis, treatment, management, and prevention of migraine. We also discuss the potential roles of genetic and abnormal factors, including some of the metabolic triggering factors that result in migraine attacks. This review will help to accumulate current knowledge about migraine and understanding of its pathophysiology, and provides up-to-date prevention strategies.


Assuntos
Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/patologia , Animais , Genética , Humanos , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Polimorfismo de Nucleotídeo Único/genética
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