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1.
Anticancer Res ; 41(9): 4387-4393, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475058

RESUMO

BACKGROUND/AIM: Breast cancer incidence is highest among women worldwide, and practical markers for personalized therapeutic strategies are few. Interleukin-12 (IL-12) is a cytokine that is reported to be significantly lower in healthy controls than breast cancer cases, however, its genotypic contribution to carcinogenesis has never been revealed in breast cancer. We examined whether IL-12A rs568408 and rs2243115 genotypes contribute to elevated breast cancer risk and summarized related literature among other cancers. MATERIALS AND METHODS: IL-12A genotypic profiles were determined among 1,232 breast cancer cases and 1,232 healthy controls via polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The variant genotypes of IL-12A rs568408 and rs2243115 were not found to be significantly associated with elevated breast cancer risk (both p>0.05). CONCLUSION: IL-12A rs568408 and rs2243115 genotypes may not serve as good predictors of breast cancer risk.


Assuntos
Neoplasias da Mama/genética , Estudos de Associação Genética/métodos , Subunidade p35 da Interleucina-12/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição
2.
Phys Rev Lett ; 127(9): 098103, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34506164

RESUMO

The genotype-phenotype mapping of proteins is a fundamental question in structural biology. In this Letter, with the analysis of a large dataset of proteins from hundreds of protein families, we quantitatively demonstrate the correlations between the noise-induced protein dynamics and mutation-induced variations of native structures, indicating the dynamics-evolution correspondence of proteins. Based on the investigations of the linear responses of native proteins, the origin of such a correspondence is elucidated. It is essential that the noise- and mutation-induced deformations of the proteins are restricted on a common low-dimensional subspace, as confirmed from the data. These results suggest an evolutionary mechanism of the proteins gaining both dynamical flexibility and evolutionary structural variability.


Assuntos
Modelos Químicos , Proteínas/química , Proteínas/genética , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/genética , Evolução Molecular , Estudos de Associação Genética , Mutação , Conformação Proteica
3.
BMC Gastroenterol ; 21(1): 339, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470610

RESUMO

AIM: To discover the novel ATP7B mutations in 103 southern Chinese patients with Wilson disease (WD), and to determine the spectrum and frequency of mutations in the ATP7B gene and genotype-phenotype correlation in a large-scale sample of Chinese WD patients. METHODS: One hundred three WD patients from 101 unrelated families in southern China were enrolled in this study. Genomic DNA was extracted from the peripheral blood. Direct sequencing of all 21 exons within ATP7B was performed. Subsequently, an extensive study of the overall spectrum and frequency of ATP7B mutations and genotype-phenotype correlation was performed in all Chinese patients eligible from the literature, combined with the current southern group. RESULTS: In 103 patients with WD, we identified 48 different mutations (42 missense mutations, 4 nonsense mutations and 2 frameshifts). Of these, 3 mutations had not been previously reported: c.1510_1511insA, c.2233C>A (p.Leu745Met) and c.3824T>C (p.Leu1275Ser). The c.2333G>T (p.Arg778 Leu) at exon 8, was the most common mutation with an allelic frequency of 18.8%, followed by c.2975C>T (p.Pro992Leu) at exon 13, with an allelic frequency of 13.4%. In the comprehensive study, 233 distinct mutations were identified, including 154 missense mutations, 23 nonsense mutations and 56 frameshifts. Eighty-five variants were identified as novel mutations. The c.2333G>T (p.Arg778 Leu) and c.2975C>T (p.Pro992Leu) were the most common mutations, with allelic frequencies of 28.6% and 13.0%, respectively. Exons 8, 12, 13, 16 and 18 were recognised as hotspot exons. Phenotype-genotype correlation analysis suggested that c.2333G>T (p.Arg778 Leu) was significantly associated with lower levels of serum ceruloplasmin (P = 0.034). c.2975C>T (p.Pro992Leu) was correlated with earlier age of disease onset (P = 0.002). Additionally, we found that the c.3809A>G (p.Asn1270Ser) mutation significantly indicated younger onset age (P = 0.012), and the c.3884C>T (p.Ala1295Val) mutation at exon 18 was significantly associated with hepatic presentation (P = 0.048). Moreover, the patients with mixed presentation displayed the initial WD features at an older onset age than the groups with either liver disease or neurological presentation (P = 0.039, P = 0.015, respectively). No significant difference was observed in the presence of KF rings among the three groups with different clinical manifestations. CONCLUSION: In this study, we identified three novel mutations in 103 WD patients from the southern part of China, which could enrich the previously established mutational spectrum of the ATP7B gene. Moreover, we tapped into a large-scale study of a Chinese WD cohort to characterise the overall phenotypic and genotypic spectra and assess the association between genotype and phenotype, which enhances the current knowledge about the population genetics of WD in China.


Assuntos
Proteínas de Transporte de Cátions , ATPases Transportadoras de Cobre , Degeneração Hepatolenticular , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Proteínas de Transporte de Cátions/genética , China , ATPases Transportadoras de Cobre/genética , Análise Mutacional de DNA , Estudos de Associação Genética , Genótipo , Degeneração Hepatolenticular/genética , Humanos , Mutação
4.
Anim Sci J ; 92(1): e13611, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34431165

RESUMO

Covariance components were estimated for growth traits (BW, birth weight; WW, weaning weight; YW, yearling weight), visual scores (BQ, breed quality; CS, conformation; MS, muscling; NS, navel; PS, finishing precocity), hip height (HH), and carcass traits (BF, backfat thickness; LMA, longissimus muscle area) measured at yearling. Genetic gains were obtained and validation models on direct and maternal effects for BW and WW were fitted. Genetic correlations of growth traits with CS, PS, MS, and HH ranged from 0.20 ± 0.01 to 0.94 ± 0.01 and were positive and low with NS (0.11 ± 0.01 to 0.20 ± 0.01) and favorable with BQ (0.14 ± 0.02 to 0.37 ± 0.02). Null to moderate genetic correlations were obtained between growth and carcass traits. Genetic gains were positive and significant, except for BW. An increase of 0.76 and 0.72 kg is expected for BW and WW, respectively, per unit increase in estimated breeding value (EBV) for direct effect and an additional 0.74 and 1.43, respectively, kg per unit increase in EBV for the maternal effect. Monitoring genetic gains for HH and NS is relevant to maintain an adequate body size and a navel morphological correction, if necessary. Simultaneous selection for growth, morphological, and carcass traits in line with improve maternal performance is a feasible strategy to increase herd productivity.


Assuntos
Peso ao Nascer/genética , Constituição Corporal/genética , Estatura/genética , Bovinos/crescimento & desenvolvimento , Bovinos/genética , Estudos de Associação Genética/veterinária , Característica Quantitativa Herdável , Animais , Cruzamento , Feminino , Humanos , Masculino , Herança Materna/genética , Fenótipo
5.
Nat Commun ; 12(1): 4842, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376650

RESUMO

Nearby genes are often expressed as a group. Yet, the prevalence, molecular mechanisms and genetic control of local gene co-expression are far from being understood. Here, by leveraging gene expression measurements across 49 human tissues and hundreds of individuals, we find that local gene co-expression occurs in 13% to 53% of genes per tissue. By integrating various molecular assays (e.g. ChIP-seq and Hi-C), we estimate the ability of several mechanisms, such as enhancer-gene interactions, in distinguishing gene pairs that are co-expressed from those that are not. Notably, we identify 32,636 expression quantitative trait loci (eQTLs) which associate with co-expressed gene pairs and often overlap enhancer regions. Due to affecting several genes, these eQTLs are more often associated with multiple human traits than other eQTLs. Our study paves the way to comprehend trait pleiotropy and functional interpretation of QTL and GWAS findings. All local gene co-expression identified here is available through a public database ( https://glcoex.unil.ch/ ).


Assuntos
Regulação da Expressão Gênica , Pleiotropia Genética/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Sítios de Ligação/genética , Ontologia Genética , Estudos de Associação Genética/métodos , Humanos , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/metabolismo
6.
BMC Gastroenterol ; 21(1): 310, 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344313

RESUMO

BACKGROUND: Genetic variations within the regulatory region of the gene encoding NOD-like receptor pyrin domain containing 3 (NLRP3) have been associated with Crohn's Disease (CD). NLRP3 is part of the NLRP3-inflammasome that mediates the maturation of IL-1ß and IL-18. Carrying the major allele of the single nucleotide polymorphisms (SNPs) rs10733113, rs4353135 and rs55646866 is associated with an increased risk for CD. We here studied the impact of these polymorphisms on clinical characteristics in patients of the Swiss IBD Cohort Study (SIBDCS). METHODS: We included 981 Crohn's disease (CD) patients and 690 ulcerative colitis (UC) patients of the SIBDCS. We analyzed whether three CD-associated NLRP3 polymorphisms have an impact on the clinical disease course in these patients. RESULTS: In CD patients presence of the major allele (G) of rs10733113 was associated with less surgeries and lower maximal CDAI and a similar trend was observed for rs55646866 and rs4353135. Presence of the major allele of all three SNPs was negatively correlated to maximal CDAI. In UC patients homozygous genotype for the major allele (CC) for rs55646866 was associated with a higher age at diagnosis and a higher MTWAI index. Homozygous genotype for the major allele of all three polymorphisms was associated with a higher number of ambulatory visits and longer hospital stays. CONCLUSIONS: In CD patients presence of the major allele of all three polymorphisms was associated with markers of a less severe disease course, while in UC the homozygous genotype for all major alleles suggested a more severe disease activity.


Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Estudos de Coortes , Colite Ulcerativa/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas NLR , Polimorfismo de Nucleotídeo Único , Domínio Pirina , Suíça
7.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360893

RESUMO

Flowering is a morphogenetic process in which angiosperms shift from vegetative growth to reproductive growth. Flowering time has a strong influence on fruit growth, which is closely related to productivity. Therefore, research on crop flowering time is particularly important. To better understand the flowering period of the tomato, we performed transcriptome sequencing of early flower buds and flowers during the extension period in the later-flowering "Moneymaker" material and the earlier-flowering "20965" homozygous inbred line, and we analyzed the obtained data. At least 43.92 million clean reads were obtained from 12 datasets, and the similarity with the tomato internal reference genome was 92.86-94.57%. Based on gene expression and background annotations, 49 candidate genes related to flowering time and flower development were initially screened, among which the greatest number belong to the photoperiod pathway. According to the expression pattern of candidate genes, the cause of early flowering of "20965" is predicted. The modes of action of the differentially expressed genes were classified, and the results show that they are closely related to hormone regulation and participated in a variety of life activities in crops. The candidate genes we screened and the analysis of their expression patterns provide a basis for future functional verification, helping to explore the molecular mechanism of tomato flowering time more comprehensively.


Assuntos
Produtos Agrícolas/crescimento & desenvolvimento , Produtos Agrícolas/genética , Flores/crescimento & desenvolvimento , Flores/genética , Genes de Plantas , Lycopersicon esculentum/crescimento & desenvolvimento , Lycopersicon esculentum/genética , Transcriptoma , Produtos Agrícolas/metabolismo , Flores/metabolismo , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Estudos de Associação Genética/métodos , Lycopersicon esculentum/metabolismo , Fotoperíodo , Proteínas de Plantas/genética , RNA-Seq/métodos , Transdução de Sinais/genética
8.
Am J Hum Genet ; 108(9): 1692-1709, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34375587

RESUMO

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.


Assuntos
Encéfalo/metabolismo , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Deficiência Intelectual/genética , Mutação , Receptores de Ácido Caínico/genética , Adolescente , Adulto , Alelos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Epilepsia/diagnóstico por imagem , Epilepsia/metabolismo , Epilepsia/patologia , Potenciais Evocados/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética , Heterozigoto , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Ativação do Canal Iônico , Masculino , Modelos Moleculares , Neurônios/metabolismo , Neurônios/patologia , Conformação Proteica , Receptores de Ácido Caínico/química , Receptores de Ácido Caínico/metabolismo
9.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445290

RESUMO

Celery (Apium graveolens L.) is an important leafy vegetable worldwide. The development of F1 hybrids in celery is highly dependent on cytoplasmic male sterility (CMS) because emasculation is difficult. In this study, we first report a celery CMS, which was found in a high-generation inbred line population of the Chinese celery "tanzhixiangqin". Comparative analysis, following sequencing and assembly of the complete mitochondrial genome sequences for this celery CMS line and its maintainer line, revealed that there are 21 unique regions in the celery CMS line and these unique regions contain 15 ORFs. Among these ORFs, only orf768a is a chimeric gene, consisting of 1497 bp sequences of the cox1 gene and 810 bp unidentified sequences located in the unique region, and the predicted protein product of orf768a possesses 11 transmembrane domains. In summary, the results of this study indicate that orf768a is likely to be a strong candidate gene for CMS induction in celery. In addition, orf768a can be a co-segregate marker, which can be used to screen CMS in celery.


Assuntos
Apium/genética , Genoma Mitocondrial , Infertilidade das Plantas/genética , Apium/crescimento & desenvolvimento , Apium/metabolismo , Mapeamento Cromossômico , Herança Extracromossômica/genética , Flores/genética , Flores/crescimento & desenvolvimento , Flores/metabolismo , Genes de Plantas , Estudos de Associação Genética , Fases de Leitura Aberta , Pólen/genética , Análise de Sequência de DNA
10.
BMC Plant Biol ; 21(1): 388, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34416870

RESUMO

BACKGROUND: Soybean is a globally important legume crop that provides a primary source of high-quality vegetable protein and oil. Seed protein content (SPC) is a valuable quality trait controlled by multiple genes in soybean. RESULTS: In this study, we performed quantitative trait loci (QTL) mapping, QTL-seq, and RNA sequencing (RNA-seq) to reveal the genes controlling protein content in the soybean by using the high protein content variety Nanxiadou 25. A total of 50 QTL for SPC distributed on 14 chromosomes except chromosomes 4, 12, 14, 17, 18, and 19 were identified by QTL mapping using 178 recombinant inbred lines (RILs). Among these QTL, the major QTL qSPC_20-1 and qSPC_20-2 on chromosome 20 were repeatedly detected across six tested environments, corresponding to the location of the major QTL detected using whole-genome sequencing-based QTL-seq. 329 candidate DEGs were obtained within the QTL region of qSPC_20-1 and qSPC_20-2 via gene expression profile analysis. Nine of which were associated with SPC, potentially representing candidate genes. Clone sequencing results showed that different single nucleotide polymorphisms (SNPs) and indels between high and low protein genotypes in Glyma.20G088000 and Glyma.16G066600 may be the cause of changes in this trait. CONCLUSIONS: These results provide the basis for research on candidate genes and marker-assisted selection (MAS) in soybean breeding for seed protein content.


Assuntos
Mapeamento Cromossômico , Estudos de Associação Genética , Proteínas de Plantas/análise , Proteínas de Plantas/genética , Sementes/química , Soja/química , Soja/genética , Produtos Agrícolas/química , Produtos Agrícolas/genética , Regulação da Expressão Gênica de Plantas , Marcadores Genéticos , Variação Genética , Genótipo , Locos de Características Quantitativas , Análise de Sequência de RNA
11.
Nutrients ; 13(8)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445060

RESUMO

Milk intake has been associated with risk of neurodegenerative diseases in observational studies. Nevertheless, whether the association is causal remains unknown. We adopted Mendelian randomization design to evaluate the potential causal association between milk intake and common neurodegenerative diseases, including multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Genetic associations for neurodegenerative diseases were obtained from the International Multiple Sclerosis Genetics Consortium (n = 80,094), FinnGen consortium (n = 176,899), AD GWAS (n = 63,926), Web-Based Study of Parkinson's Disease (n = 308,518), PDGene (n = 108,990), and ALS GWAS (n = 80,610). Lactase persistence variant rs4988235 (LCT-13910 C > T) was used as the instrumental variable for milk intake. Genetically predicted higher milk intake was associated with a decreased risk of MS and AD and with an increased risk of PD. For each additional milk intake increasing allele, the odds ratios were 0.94 (95% confidence intervals [CI]: 0.91-0.97; p = 1.51 × 10-4) for MS, 0.97 (0.94-0.99; p = 0.019) for AD and 1.09 (95%CI: 1.06-1.12, p = 9.30 × 10-9) for PD. Genetically predicted milk intake was not associated with ALS (odds ratio: 0.97, 95%CI: 0.94-1.01, p = 0.135). Our results suggest that genetically predicted milk intake is associated with a decreased risk of MS and AD but with an increased risk of PD. Further investigations are needed to clarify the underlying mechanisms.


Assuntos
Interação Gene-Ambiente , Lactase/genética , Leite , Doenças Neurodegenerativas/genética , Polimorfismo de Nucleotídeo Único , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Esclerose Amiotrófica Lateral , Animais , Estudos de Casos e Controles , Bases de Dados Genéticas , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Análise da Randomização Mendeliana , Leite/efeitos adversos , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/genética , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/epidemiologia , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Medição de Risco , Fatores de Risco
12.
Gene ; 803: 145898, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34391864

RESUMO

Chronic inflammation is a key factor in symptomology and comorbidities of post-traumatic stress disorder (PTSD). Levels of a proinflammatory marker, C-reactive protein (CRP) are increased in individuals with PTSD but it is not clear if this is due to trauma exposure or PTSD. Our study aimed to assess the relationship between serum CRP levels, CRP SNPs, methylation, mRNA expression and PTSD in a homogenous trauma exposed Australian Vietnam veteran cohort. We hypothesized that decreased DNA methylation would be associated with increased gene expression and increased peripheral CRP levels in PTSD patients and that this would be independent of trauma. Participants were 299 Vietnam veterans who had all been exposed to trauma and approximately half were diagnosed with PTSD. We observed higher levels of serum CRP in the PTSD group compared to the non-PTSD group but after controlling for BMI and triglycerides the association did not remain significant. No association was found between CRP SNPs and PTSD or CRP levels. Absent in Melanoma 2 (AIM2) which is a mediator of inflammatory response and a determinant of CRP levels was analysed for DNA methylation and mRNA expression. We observed a trend level association between PTSD and AIM2 methylation after controlling for age, smoking, triglycerides, BMI and cell types. There was no significant interaction between PTSD and CRP levels on AIM2 methylation after controlling for covariates. We observed that as AIM2 methylation levels decreased, AIM2 mRNA expression increased. Elevated CRP levels were associated with AIM2 mRNA in the trauma exposed cohort but there was no significant interaction effect with PTSD. Our results could not confirm that CRP is a marker of PTSD independent of trauma in this group of older veterans. CRP may be a broad marker of disease risk, or a marker of PTSD in younger cohorts than those in this study.


Assuntos
Proteína C-Reativa/genética , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas do Tecido Nervoso/sangue , Proteínas do Tecido Nervoso/genética , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Veteranos/psicologia , Idoso , Austrália , Estudos de Casos e Controles , Epigênese Genética , Estudos de Associação Genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Transtornos de Estresse Pós-Traumáticos/sangue , Transtornos de Estresse Pós-Traumáticos/genética , Regulação para Cima , Guerra do Vietnã
13.
Nutrients ; 13(8)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445011

RESUMO

White blood cell (WBC) counts represent overall immunity. However, a few studies have been conducted to explore the genetic impacts of immunity and their interaction with lifestyles. We aimed to identify genetic variants associated with a low-WBC risk and document interactions between polygenetic risk scores (PRS), lifestyle factors, and nutrient intakes that influence low-WBC risk in a large hospital-based cohort. Single nucleotide polymorphisms (SNPs) were selected by genome-wide association study of participants with a low-WBC count (<4 × 109/L, n = 4176; low-WBC group) or with a normal WBC count (≥4 × 109/L, n = 36,551; control group). The best model for gene-gene interactions was selected by generalized multifactor dimensionality reduction. PRS was generated by summing selected SNP risk alleles of the best genetic model. Adjusted odds ratio (ORs) of the low-WBC group were 1.467 (1.219-1.765) for cancer incidence risk and 0.458 (0.385-0.545) for metabolic syndrome risk. Vitamin D intake, plant-based diet, and regular exercise were positively related to the low-WBC group, but smoking and alcohol intake showed an inverse association. The 7 SNPs included in the best genetic model were PSMD3_rs9898547, LCT_rs80157389, HLA-DRB1_rs532162239 and rs3097649, HLA-C rs2308575, CDKN1A_rs3176337 and THRA_rs7502539. PRS with 7 SNP model were positively associated with the low-WBC risk by 2.123-fold (1.741 to 2.589). PRS interacted with fat intake and regular exercise but not with other nutrient intakes or lifestyles. The proportion with the low WBC in the participants with high-PRS was lower among those with moderate-fat intake and regular exercise than those with low-fat intake and no exercise. In conclusion, adults with high-PRS had a higher risk of a low WBC count, and they needed to be advised to have moderate fat intake (20-25 energy percent) and regular exercise.


Assuntos
Gorduras na Dieta/administração & dosagem , Imunidade/genética , Leucócitos/imunologia , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto , Fatores Etários , Idoso , Fatores de Risco Cardiometabólico , Estudos de Casos e Controles , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/genética , Doenças Transmissíveis/imunologia , Estudos Transversais , Dieta com Restrição de Gorduras , Exercício Físico , Feminino , Estudos de Associação Genética , Humanos , Contagem de Leucócitos , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Síndrome Metabólica/imunologia , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/genética , Neoplasias/imunologia , Recomendações Nutricionais , República da Coreia/epidemiologia , Medição de Risco
14.
Nat Commun ; 12(1): 4680, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344887

RESUMO

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10-10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.


Assuntos
Síndrome de Goldenhar/genética , Haploinsuficiência , Fatores de Processamento de RNA/genética , Adolescente , Adulto , Animais , Criança , Exoma/genética , Feminino , Estudos de Associação Genética , Síndrome de Goldenhar/patologia , Humanos , Lactente , Masculino , Mutação , Crista Neural/crescimento & desenvolvimento , Crista Neural/patologia , Linhagem , Spliceossomos/genética , Xenopus laevis
15.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204499

RESUMO

BACKGROUND: Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by "coved type" ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The SCN5A gene, encoding for the cardiac voltage-gated sodium channel Nav1.5, accounts for ~20-30% of BrS cases and is considered clinically relevant. METHODS: Here, we describe the clinical findings of two Italian families affected by BrS and provide the functional characterization of two novel SCN5A mutations, the missense variant Pro1310Leu and the in-frame insertion Gly1687_Ile1688insGlyArg. RESULTS: Despite being clinically different, both patients have a family history of sudden cardiac death and had history of arrhythmic events. The Pro1310Leu mutation significantly reduced peak sodium current density without affecting channel membrane localization. Changes in the gating properties of expressed Pro1310Leu channel likely account for the loss-of-function phenotype. On the other hand, Gly1687_Ile1688insGlyArg channel, identified in a female patient, yielded a nearly undetectable sodium current. Following mexiletine incubation, the Gly1687_Ile1688insGlyArg channel showed detectable, albeit very small, currents and biophysical properties similar to those of the Nav1.5 wild-type channel. CONCLUSIONS: Overall, our results suggest that the degree of loss-of-function shown by the two Nav1.5 mutant channels correlates with the aggressive clinical phenotype of the two probands. This genotype-phenotype correlation is fundamental to set out appropriate therapeutical intervention.


Assuntos
Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Potenciais de Ação , Idoso , Idoso de 80 Anos ou mais , Alelos , Substituição de Aminoácidos , Eletrocardiografia , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Itália , Masculino , Modelos Biológicos , Modelos Moleculares , Canal de Sódio Disparado por Voltagem NAV1.5/química , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Linhagem , Fenótipo , Conformação Proteica , Transporte Proteico
16.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204582

RESUMO

Autosomal recessive polycystic kidney disease (ARPKD) is a rare disorder and one of the most severe forms of polycystic kidney disease, leading to end-stage renal disease (ESRD) in childhood. PKHD1 is the gene that is responsible for the vast majority of ARPKD. However, some cases have been related to a new gene that was recently identified (DZIP1L gene), as well as several ciliary genes that can mimic a ARPKD-like phenotypic spectrum. In addition, a number of molecular pathways involved in the ARPKD pathogenesis and progression were elucidated using cellular and animal models. However, the function of the ARPKD proteins and the molecular mechanism of the disease currently remain incompletely understood. Here, we review the clinics, treatment, genetics, and molecular basis of ARPKD, highlighting the most recent findings in the field.


Assuntos
Suscetibilidade a Doenças , Rim Policístico Autossômico Recessivo/etiologia , Rim Policístico Autossômico Recessivo/metabolismo , Animais , Biomarcadores , Ensaios Clínicos como Assunto , Terapia Combinada , Diagnóstico Diferencial , Gerenciamento Clínico , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Humanos , Mutação , Fenótipo , Rim Policístico Autossômico Recessivo/patologia , Locos de Características Quantitativas , Receptores de Superfície Celular/química , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Resultado do Tratamento
17.
Transl Psychiatry ; 11(1): 413, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330890

RESUMO

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.


Assuntos
Agressão , Transtornos Mentais , Adolescente , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Lactente , Estudos Retrospectivos
18.
Nat Genet ; 53(7): 1006-1021, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34211179

RESUMO

SPTBN1 encodes ßII-spectrin, the ubiquitously expressed ß-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal ßII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect ßII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of ßII-spectrin in the central nervous system.


Assuntos
Genes Dominantes , Predisposição Genética para Doença , Variação Genética , Transtornos do Neurodesenvolvimento/genética , Espectrina/genética , Animais , Estudos de Associação Genética/métodos , Heterozigoto , Humanos , Camundongos , Transtornos do Neurodesenvolvimento/diagnóstico , Fenótipo , Espectrina/metabolismo
19.
BMC Genomics ; 22(1): 505, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34225652

RESUMO

BACKGROUND: Sunflower is an important oilseed crop domesticated in North America approximately 4000 years ago. During the last century, oil content in sunflower was under strong selection. Further improvement of oil properties achieved by modulating its fatty acid composition is one of the main directions in modern oilseed crop breeding. RESULTS: We searched for the genetic basis of fatty acid content variation by genotyping 601 inbred sunflower lines and assessing their lipid and fatty acid composition. Our genome-wide association analysis based on the genotypes for 15,483 SNPs and the concentrations of 23 fatty acids, including minor fatty acids, revealed significant genetic associations for eleven of them. Identified genomic regions included the loci involved in rare fatty acids variation on chromosomes 3 and 14, explaining up to 34.5% of the total variation of docosanoic acid (22:0) in sunflower oil. CONCLUSIONS: This is the first large scale implementation of high-throughput lipidomic profiling to sunflower germplasm characterization. This study contributes to the genetic characterization of Russian sunflower collections, which made a substantial contribution to the development of sunflower as the oilseed crop worldwide, and provides new insights into the genetic control of oil composition that can be implemented in future studies.


Assuntos
Ácidos Graxos/análise , Helianthus , Óleos Vegetais/análise , Estudos de Associação Genética , Genótipo , Helianthus/genética , América do Norte , Melhoramento Vegetal , Federação Russa
20.
Front Immunol ; 12: 632353, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220799

RESUMO

Background: KIR/HLA-C signaling pathway influences the innate immune response which is the first defense to hepatitis C virus (HCV) infection. The aim of this study was to determine the association between the genetic polymorphisms of KIR/HLA-C genes and the outcomes of HCV infection in a high-risk Chinese population. Methods: In this case-control study, four single nucleotide polymorphisms (SNPs) of KIR/HLA-C genes (KIR2DS4/KIR2DS1/KIR2DL1 rs35440472, HLA-C rs2308557, HLA-C rs1130838, and HLA-C rs2524094) were genotyped by TaqMan assay among drug users and hemodialysis (HD) patients including 1,378 uninfected control cases, 307 subjects with spontaneous viral clearance, and 217 patients with persistent HCV infection. Bioinformatics analysis was used to functionally annotate the SNPs. Results: After logistic regression analysis, the rs35440472-A and rs1130838-A alleles were found to be associated with a significantly elevated risk of HCV infection (OR = 1.562, 95% CI: 1.229-1.987, P < 0.001; OR = 2.134, 95% CI: 1.180-3.858, P = 0.012, respectively), which remained significant after Bonferroni correction (0.05/4). The combined effect of their risk alleles and risk genotypes (rs35440472-AA and rs1130838-AA) were linked to the increased risk of HCV infection in a locus-dosage manner (all P trend < 0.001). Based on the SNPinfo web server, rs35440472 was predicted to be a transcription factor binding site (TFBS) while rs1130838 was predicted to have a splicing (ESE or ESS) function. Conclusion: KIR2DS4/KIR2DS1/KIR2DL1 rs35440472-A and HLA-C rs1130838-A variants are associated with increased susceptibility to HCV infection in a high-risk Chinese population.


Assuntos
Predisposição Genética para Doença/genética , Hepatite C/genética , Receptores KIR/genética , Adulto , Alelos , Estudos de Casos e Controles , China , Feminino , Estudos de Associação Genética , Genótipo , Antígenos HLA-C/genética , Hepacivirus , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
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