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1.
BMC Med Genet ; 20(1): 93, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31146700

RESUMO

BACKGROUND: CHARGE syndrome is characterized by coloboma, heart defects, choanal atresia, growth retardation, genitourinary malformation and ear abnormalities. The chromodomain helicase DNA-binding protein 7 (CHD7) gene is the major cause of CHARGE syndrome and is inherited in an autosomal dominant manner. Currently, the phenotype spectrum of CHARGE syndrome in neonatal population remain elusive. We aimed to investigate the phenotype spectrum of neonatal patients suspected to have CHARGE syndrome with pathogenic or likely pathogenic variants in the CHD7 gene. METHODS: We pooled next-generation sequencing data from the Neonatal Birth Defects Cohort (NBDC, ClinicalTrials.gov Identifier: NCT02551081) in Children's Hospital of Fudan University. The pathogenicity of novel variants was analyzed by bioinformatic and genetic analyses. Clinical information collection, Sanger sequencing and follow-up interviews were performed when possible. Cranial MRI of these patients was performed, the volumes of different regions of the brain were analyzed. RESULTS: A total of 12 unrelated patients in our cohort were found with CHD7 variants. Eight patients received a firm clinical diagnosis of CHARGE syndrome (Bergmann criteria, Blake criteria, Verloes criteria and Hale criteria). Three patients did not match any diagnostic criteria, and no patients matched the Verloes criteria. Phenotype spectrum analysis found that feeding difficulty was the dominant feature among this neonatal cohort. Six novel variants in the CHD7 gene (Glu2408*, Lys651*, c.5607 + 1G > T, Leu373Val, Lys2005Asnfs*37 and Gln1991*) were identified, expanding the variant database of the CHD7 gene. Cranial MRI analysis revealed significant volume loss in cingulate gyrus, occipital lobe, and cerebellum and volume gain in the left medial and inferior temporal gyri anterior white matter parts. CONCLUSIONS: Based on a relatively unbiased neonatal cohort, we concluded that CHARGE syndrome and CHD7 gene variants should be suspected in newborns who have feeding difficulty, and one or more malformations. TRIAL REGISTRATION: Neonatal Birth Defects Cohort (NBDC, ClinicalTrials.gov identifier: NCT02551081 ).


Assuntos
Síndrome CHARGE/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Predisposição Genética para Doença/genética , Mutação , Grupo com Ancestrais do Continente Asiático/genética , Síndrome CHARGE/diagnóstico , Síndrome CHARGE/etnologia , China , Estudos de Coortes , Transtornos da Alimentação e da Ingestão de Alimentos/diagnóstico , Transtornos da Alimentação e da Ingestão de Alimentos/etnologia , Feminino , Predisposição Genética para Doença/etnologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Recém-Nascido , Masculino , Triagem Neonatal/métodos , Fenótipo , Curva ROC
2.
BMC Med Genet ; 20(1): 99, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170924

RESUMO

BACKGROUND: Metabolic syndrome (MetS), defined as a cluster of metabolic risk factors including dyslipidemia, insulin-resistance, and elevated blood pressure, has been known as partly heritable. MetS effects the lives of many people worldwide, yet females have been reported to be more vulnerable to this cluster of risks. METHODS: To elucidate genetic variants underlying MetS specifically in females, we performed a genome-wide association study (GWAS) for MetS as well as its component traits in a total of 9932 Korean female subjects (including 2276 MetS cases and 1692 controls). To facilitate the prediction of MetS in females, we calculated a genetic risk score (GRS) combining 14 SNPs detected in our GWA analyses specific for MetS. RESULTS: GWA analyses identified 14 moderate signals (Pmeta < 5X10- 5) specific to females for MetS. In addition, two genome-wide significant female-specific associations (Pmeta < 5X10- 8) were detected for rs455489 in DSCAM for fasting plasma glucose (FPG) and for rs7115583 in SIK3 for high-density lipoprotein cholesterol (HDLC). Logistic regression analyses (adjusted for area and age) between the GRS and MetS in females indicated that the GRS was associated with increased prevalence of MetS in females (P = 5.28 × 10- 14), but not in males (P = 3.27 × 10- 1). Furthermore, in the MetS prediction models using GRS, the area under the curve (AUC) of the receiver operating characteristics (ROC) curve was higher in females (AUC = 0.85) than in males (AUC = 0.57). CONCLUSION: This study highlights new female-specific genetic variants associated with MetS and its component traits and suggests that the GRS of MetS variants is a likely useful predictor of MetS in females.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/etnologia , Pessoa de Meia-Idade , Fenótipo , República da Coreia , Fatores de Risco , Fatores Sexuais
3.
BMC Med Genet ; 20(1): 102, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174489

RESUMO

BACKGROUND: Multiple factors are implicated in the etiology and pathogenesis of Abdominal Aortic Aneurysms (AAA). Available literature of genetic studies has previously suggested the possible roles of autoimmunity, genetic predisposition and ethnic susceptibility. Due to the association with autoimmune diseases and proven application in population genetics, we aimed to investigate alleles of the Class II Human Leukocyte Antigens (HLA-DRB1) in the Mexican Mestizo population with aortic aneurysms and determine possible associations with susceptibility. METHODS: We performed a case Control Study; the HLA molecular typing was completed for DRB1 loci by LabType Sequence-Specific Oligonucleotide (SSO) SSO-OneLambda kit (Applied Biosystems; Thermo Fisher Scientific. Inc.) in the studied individuals. Allele frequencies (af) were determined, associations were assessed by chi square or fisher exact tests at significance level (< 0.05), and Odds Ratios (OR) were calculated using the STATA software version 14. RESULTS: The genetic polymorphism of HLA-DRB1 of fifty one patients (70% males with a mean age of 71 years) with atherosclerotic or also known as degenerative AAA were compared with 99 unrelated patients (60% males, mean age 65 years) without the disease [Control group (CG)] from the same ethnic group. We examined a total of 102 Class II HLA-DRB1 alleles of AAA patients and 198 from CG. When comparing af, we observed the HLA-DRB1*01 af of 0.139 in the AAA compared to 0.05 in the CG [p = 0.015, OR 3, 95% confidence interval (CI) 1.29-7.08], the HLA-DRB1*16 af were 0.109 in the AAA and 0.025 in CG (p = 0.006, OR 4.7, 95% CI 1.59-13.98). CONCLUSIONS: Our study confirmed increased frequencies of the alleles HLA-DRB1*01 and HLA-DRB1*16 and their association to the development of AAA in Mexican Mestizo patients. The utility of genetic testing may assist in identifying individuals at genetic risk for the development of this disease in different ethnic groups, who might benefit from earlier ultrasound screening and closer imaging surveillance.


Assuntos
Aneurisma da Aorta Abdominal/genética , Grupos Étnicos/genética , Predisposição Genética para Doença/genética , Cadeias HLA-DRB1/genética , Polimorfismo Genético , Idoso , Alelos , Aneurisma da Aorta Abdominal/diagnóstico , Aneurisma da Aorta Abdominal/etnologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Humanos , Masculino , México , Pessoa de Meia-Idade
4.
BMC Med Genet ; 20(1): 105, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185933

RESUMO

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is an autosomal dominant genetic disorder that is characterized by specific abnormalities of the anterior segment of the eye. Heterozygous mutations in two developmental transcription factor genes PITX2 and FOXC1 have been identified within ARS patients, accounting for 40 to 70% of cases. Our purpose is to describe clinical and genetic findings in a Chinese family with ARS. METHODS: An ARS family with three affected members was recruited. The patients underwent a series of complete ophthalmologic examinations, general physical examination and dental radiography. DNA samples of proband II-1 were used for targeted exome sequencing of the FOXC1 and PITX2 genes. Sanger sequencing was used to validate the variation in PITX2. Quantitative real-time PCR was carried out to detect the expression of PITX2 in patients and normal controls. RESULTS: All affected members showed iris atrophy, corectopia, shallow anterior chamber, complete or partial angle closure, and advanced glaucoma. In addition, they revealed systemic anomalies, including microdontia, hypodontia, and redundant periumbilical skin. A novel heterozygous frameshift variation, c.515delA, in PITX2 was found in the proband, which might lead to a truncated PITX2 protein (p.Gln172ArgfsX36). Sanger sequencing validated that the variation completely cosegregated with the ARS phenotype among this family, but was absent in 100 unrelated controls. Quantitative real-time PCR analysis revealed that the mRNA expression of PITX2 was significantly decreased in patients compared with that in unrelated normal controls. CONCLUSIONS: PITX2 c.515delA (p.Gln172ArgfsX36) was the genetic etiology of our pedigree. The mutation led to decreased PITX2 gene expression and a truncated mRNA transcript.


Assuntos
Segmento Anterior do Olho/anormalidades , Anormalidades do Olho/genética , Oftalmopatias Hereditárias/genética , Mutação da Fase de Leitura , Predisposição Genética para Doença/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma/métodos , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático , China , Anormalidades do Olho/etnologia , Oftalmopatias Hereditárias/etnologia , Saúde da Família , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Masculino , Linhagem , Adulto Jovem
5.
BMC Med Genet ; 20(1): 106, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196117

RESUMO

BACKGROUND: Oculocutaneous albinism (OCA) is a human autosomal-recessive hypopigmentation disorder with hypopigmentation in the skin, hair, and eyes. OCA1 and OCA2 are caused by mutations of the TYR and OCA2 genes, respectively, which are responsible for most oculocutaneous albinism. However, the incidence of oculocutaneous albinism patients in Guangxi remains unclear. METHODS: To evaluate the molecular basis of oculocutaneous albinism in thirty-six patients in Guangxi, China. Peripheral venous blood samples were collected from these unrelated patients. The TYR and OCA2 genes of all individuals were analyzed by direct DNA sequencing and the sequences compared with are reference database and bioinformatics analysis. RESULTS: Among the 36 OCA patients, 8(22.2%) were found mutations on TYR gene, 28 (77.8%) on OCA2. And we identified Twenty-seven different TYR and OCA2 mutations in these patients, including one novel TYR framshift mutation c.561_562insTTATTATGTGTCAAATTATCCCCCA, three novel OCA2 mutations: one nonsense mutation c.2195C > G(p.S732X), one deletation mutation(c.1139-1141delTGG), one missense mutations c.2495A > C(p.H832P). The population screening and the bioinformatic analysis to determined the effects of the mutations, which revealed these four novel mutations were pathogenic. CONCLUSIONS: This study expands the mutation spectrum of oculocutaneous albinism. Four novel mutational alleles c.1139-1141delTGG, c.1832 T > C and c.2195C > G and of the OCA2 gene and c.561_562insTTATTATGTGTCAAATTATCCCCCA of TYR were associated with OCA. The genotype-phenotype correlations suggest that molecular diagnosis is more accurate and important in OCA.


Assuntos
Albinismo Oculocutâneo/genética , Análise Mutacional de DNA/métodos , Predisposição Genética para Doença/genética , Mutação , Adolescente , Adulto , Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Criança , Pré-Escolar , China , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/etnologia , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana Transportadoras/genética , Monofenol Mono-Oxigenase/genética
6.
Gene ; 707: 1-8, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31054364

RESUMO

BACKGROUND: Genome-wide association studies have captured a large proportion of genetic variation related to type 1 diabetes mellitus (T1D). However, most of these studies are performed in populations of European ancestry and therefore the disease risk estimations can be inaccurate when extrapolated to other world populations. METHODS: We conducted a case-control study in 1866 individuals from the three major populations of the Republic of Bashkortostan (Russians, Tatars, and Bashkirs) in Russian Federation, using single-locus and multilocus approach to identify genetic predictors of T1D. RESULTS: We found that LTA rs909253 and TNF rs1800629 polymorphisms were associated with T1D in the group of Tatars. Meta-analysis of the association study results in the three ethnic groups has confirmed the association between the T1D risk and LTA rs909253 genetic variant. LTA rs909253 and TNF rs1800629 loci were also featured in combinations most significantly associated with T1D. CONCLUSION: Our findings suggest that LTA rs909253 and TNF rs1800629 polymorphisms are associated with the risk of T1D both independently and in combination with polymorphic markers in other inflammatory genes, and the analysis of multi-allelic combinations provides valuable insight in the study of polygenic traits.


Assuntos
Diabetes Mellitus Tipo 1/genética , Linfotoxina-alfa/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Bashkiria/etnologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/etnologia , Feminino , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
J Immunol Res ; 2019: 4730507, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31093510

RESUMO

Background: Kawasaki disease (KD) is a systemic form of self-limited vasculitis in children less than five years old, and the main complication is coronary artery injury. However, the etiology of KD remains unclear. The IL-1B polymorphisms rs16944 GG and rs1143627 AA and their diplotype GA/GA have been associated with significantly increased risk of intravenous immunoglobulin (IVIG) resistance in a Taiwanese population, but the relationship between rs16944 A/G and rs1143627 G/A and coronary artery lesions (CALs) in patients with KD has not been investigated. The present study is aimed at investigating whether the rs16944 A/G and rs1143627 G/A polymorphisms in IL-1B were associated with KD susceptibility and CALs in a southern Chinese population. Methods and Results: We recruited 719 patients with KD and 1401 healthy children. Multiplex PCR was used to assess the genotypes of single nucleotide polymorphisms (SNPs), including two SNPs of IL-1B, rs16944 A/G and rs1143627 G/A. According to the results, no significant association was observed between the IL-1B (rs16944 and rs1143627) polymorphisms and KD risk in the patients compared with the healthy controls in our southern Chinese population. However, in further stratified analysis, we found that children younger than 12 months with the rs16944 GG and rs1143627 AA genotypes of IL-1B had a higher risk of CALs than those with the AA/AG genotypes of rs16944 and GG/AG genotypes of rs1143627 (OR = 2.28, 95% CI = 1.32-3.95, P = 0.0032, adjusted OR = 2.33, 95% CI = 1.34-4.04, P = 0.0027). Conclusions: Our results indicated that there was no association between the rs16944 A/G and rs1143627 G/A gene polymorphisms and KD susceptibility. However, the rs16944 GG and rs1143627 AA genotypes of IL-1B may significantly impact the risk of CAL formation in children younger than 12 months, which may contribute to the pathogenesis of KD. These findings need further validation in multicenter studies with larger sample sizes.


Assuntos
Vasos Coronários/patologia , Predisposição Genética para Doença/etnologia , Interleucina-1beta/genética , Síndrome de Linfonodos Mucocutâneos/genética , Adolescente , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Feminino , Genótipo , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/etnologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco
8.
BMC Med Genet ; 20(1): 87, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31117968

RESUMO

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the sodium taurocholate co-transporting polypeptide (NTCP) have been showed to be associated with natural history of hepatitis B virus (HBV) infection. However, it is unclear whether the SNPs are related to the clinical outcome of HBV infection in Thai individuals. METHODS: The rs2296651 and rs4646287 polymorphisms of NTCP were determined by allelic discrimination using commercial TaqMan probes in blood samples of 1021 Thai individuals. These subjects included 610 patients with chronic HBV infection [CHB, 305 with hepatocellular carcinoma (HCC) and 305 without HCC], 206 subjects with spontaneous HBV clearance and 205 healthy controls who were age and gender-matched. RESULTS: The frequencies of rs2296651 A minor allele in the CHB group, the HBV clearance group and healthy controls were 7.8, 7.3 and 13.9%, respectively. For rs4646287, the frequencies of T minor allele of the corresponding groups were 10.4, 8.0 and 9.5%, respectively. Compared with healthy controls, the frequencies of rs2296651 GA + AA genotypes were significantly lower in the CHB group (P < 0.001) and in the HBV clearance group (P = 0.001). There was no difference in their distribution between the HBV clearance and CHB groups. Among the CHB group, the distribution of GA + AA genotypes in patients with HCC were significantly lower than in patients without HCC (P = 0.014). The frequencies of HBeAg positivity in patients harboring GG and GA + AA genotypes were 39.8 and 23.5%, respectively (P = 0.004). Among patients with HCC, the mean HBV DNA of the corresponding genotypes were 4.9 ± 1.3 vs. 2.7 ± 1.0 log10 IU/mL, respectively (P < 0.001). There was no difference in genotype and allele frequencies of rs4646287 polymorphism among all studied groups. CONCLUSIONS: Our results showed that rs2296651 polymorphism was associated with a decreased risk of susceptibility to HBV infection and the development of HCC. These data suggest that the NTCP polymorphism might have an influence on natural history of HBV infection in Thai individuals. This abstract was partly presented at the American Association for the Study of Liver Diseases (AASLD) Meeting 2018, November 9-13, 2018, in San Francisco, CA, USA and was published in Hepatology 2018; 68:1237A-1238A.


Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença/genética , Hepatite B Crônica/genética , Neoplasias Hepáticas/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Polimorfismo de Nucleotídeo Único , Simportadores/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/etnologia , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Hepatite B Crônica/complicações , Hepatite B Crônica/etnologia , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/etnologia , Masculino , Pessoa de Meia-Idade , Tailândia
9.
Hum Genet ; 138(6): 601-611, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968251

RESUMO

Facial shape differences are one of the most significant phenotypes in humans. It is affected largely by skull shape. However, research into the genetic basis of the craniofacial morphology has rarely been reported. The present study aimed to identify genetic variants influencing craniofacial morphology in northern Han Chinese through whole-exome sequencing (WES). Phenotypic data of the volunteers' faces and skulls were obtained through three-dimensional CT scan of the skull. A total of 48 phenotypes (35 facial and 13 cranial phenotypes) were used for the bioinformatics analysis. Four genetic loci were identified affecting the craniofacial shapes. The four candidate genes are RGPD3, IGSF3, SLC28A3, and USP40. Four single-nucleotide polymorphism (SNP) site mutations in RGPD3, IGSF3, and USP40 were significantly associated with the skull shape (p < 1×10-6), and three SNP site mutations in RGPD3, IGSF3, and SLC28A3 were significantly associated with the facial shape (p < 1×10-6). The rs62152530 site mutation in the RGPD3 gene may be closely associated with the nasal length, ear length, and alar width. The rs647711 site mutation in the IGSF3 gene may be closely associated with the nasal length, mandibular width, and width between the mental foramina. The rs10868138 site mutation in the SLC28A3 gene may be associated with the nasal length, alar width, width between tragus, and width between the mental foramina. The rs1048603 and rs838543 site mutations in the USP40 gene may be closely associated with the pyriform aperture width. Our findings provide useful genetic information for the determination of face morphology.


Assuntos
Ossos Faciais/metabolismo , Loci Gênicos/genética , Polimorfismo de Nucleotídeo Único , Crânio/metabolismo , Sequenciamento Completo do Exoma/métodos , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , China , Anormalidades Craniofaciais/etnologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Ossos Faciais/anatomia & histologia , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Crânio/anatomia & histologia
10.
Niger J Clin Pract ; 22(2): 149-153, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30729935

RESUMO

The association between interleukin-10 (IL-10) promoter region (1082 A/G (rs1800896), 819 C/T (rs1800871)) polymorphisms, and acute pancreatitis (AP) is inconclusive in Chinese Han population. In this study, six eligible studies extracted from the databases of PubMed, Web of Science, and Cochrane Library were evaluated. The results revealed a significant association between 1082 A/G (rs1800896) polymorphism and AP risk in all these five models (AG/AA: OR = 1.19, 95% Cl = 1.02-1.40, P = 0.03; GG/AA: OR = 1.80, 95% Cl = 1.38-2.23, P = 0.01; AG+GG/AA: OR = 1.29, 95% Cl = 1.11-1.50, P = 0.01; GG/AG+AA: OR = 1.62, 95% Cl = 1.27-2.08, P = 0.01; G/A: OR = 1.29, 95% Cl = 1.15-1.45, P = 0.01). In contrast, no statistically significant association was found in all these five models for 819 C/T (rs1800871) polymorphism. In summary, IL-10 polymorphism 1082 A/G (rs1800896) could increase the risk of AP in Chinese Han population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Interleucina-10/genética , Pancreatite/genética , Doença Aguda , Grupo com Ancestrais do Continente Asiático/etnologia , Estudos de Casos e Controles , Predisposição Genética para Doença/etnologia , Humanos , Pancreatite/etnologia , Polimorfismo Genético/genética
11.
BJOG ; 126(6): 784-794, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30767407

RESUMO

OBJECTIVE: To evaluate factors affecting unselected population-based BRCA testing in Ashkenazi Jews (AJ). DESIGN: Cohort-study set within recruitment to the GCaPPS trial (ISRCTN73338115). SETTING: North London AJ population. POPULATION OR SAMPLE: Ashkenazi Jews women/men >18 years, recruited through self-referral. METHODS: Ashkenazi Jews women/men underwent pre-test counselling for BRCA testing through recruitment clinics (clusters). Consenting individuals provided blood samples for BRCA testing. Data were collected on socio-demographic/family history/knowledge/psychological well-being along with benefits/risks/cultural influences (18-item questionnaire measuring 'attitude'). Four-item Likert-scales analysed initial 'interest' and 'intention-to-test' pre-counselling. Uni- and multivariable logistic regression models evaluated factors affecting uptake/interest/intention to undergo BRCA testing. Statistical inference was based on cluster robust standard errors and joint Wald tests for significance. Item-Response Theory and graded-response models modelled responses to 18-item questionnaire. MAIN OUTCOME MEASURES: Interest, intention, uptake, attitude towards BRCA testing. RESULTS: A total of 935 individuals (women = 67%/men = 33%; mean age = 53.8 (SD = 15.02) years) underwent pre-test genetic-counselling. During the pre-counselling, 96% expressed interest in and 60% indicated a clear intention to undergo BRCA testing. Subsequently, 88% opted for BRCA testing. BRCA-related knowledge (P = 0.013) and degree-level education (P = 0.01) were positively and negatively (respectively) associated with intention-to-test. Being married/cohabiting had four-fold higher odds for BRCA testing uptake (P = 0.009). Perceived benefits were associated with higher pre-counselling odds for interest in and intention to undergo BRCA testing. Reduced uncertainty/reassurance were the most important factors contributing to decision-making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional impact/inability to prevent cancer/marriage ability/ethnic focus/stigmatisation) were significantly associated with lower odds of uptake of BRCA testing, and discriminated between acceptors and decliners. Male gender/degree-level education (P = 0.001) had weaker correlations, whereas having children showed stronger (P = 0.005) associations with attitudes towards BRCA testing. CONCLUSIONS: BRCA testing in the AJ population has high acceptability. Pre-test counselling increases awareness of disadvantages/limitations of BRCA testing, influencing final cost-benefit perception and decision-making on undergoing testing. TWEETABLE ABSTRACT: BRCA testing in Ashkenazi Jews has high acceptability and uptake. Pre-test counselling facilitates informed decision-making.


Assuntos
Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário , Judeus , Adulto , Atitude Frente a Saúde/etnologia , Características Culturais , Feminino , Aconselhamento Genético/psicologia , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/psicologia , Testes Genéticos/economia , Testes Genéticos/estatística & dados numéricos , Síndrome Hereditária de Câncer de Mama e Ovário/etnologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/psicologia , Humanos , Judeus/genética , Judeus/psicologia , Londres , Masculino , Mutação , Participação do Paciente/estatística & dados numéricos , Fatores Socioeconômicos
12.
PLoS One ; 14(1): e0210076, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30650098

RESUMO

BACKGROUND: Correlation between severity of psoriasis and psoriatic arthritis (PsA) is inconsistent. Also, human leukocyte antigen (HLA)-Cw6 was found to be underrepresented in severe psoriasis who failed conventional systemic therapies, but the effect of HLA polymorphism on PsA severity needs to be confirmed. OBJECTIVES: To describe the severity of psoriasis, demographic features and HLA polymorphism among Chinese patients with active peripheral type PsA who had inadequate response to conventional disease-modifying antirheumatic drugs. METHODS: We included all patients with PsA who had at least 3 tender and swollen peripheral joints despite at least two conventional non-biologic treatments in our clinic. Demographic results were compared with global pivotal studies of biologics for PsA. HLA-Cw and HLA-DRB1 genotyping was also analyzed. RESULTS: We identified 60 patients who met our inclusion criteria. The male to female ratio was 1.31:1. The majority of patients presented with psoriasis first (81.7%). The mean interval between psoriasis and PsA was 7.2 ± 8.1 years (mean ± SD). The baseline number of tender and swollen joints was 14.9 ± 10.7 and 11.3 ±10.2, respectively. In total, 41.7% subjects had more than 3% body surface area involvement of psoriasis. Genotyping of HLA-Cw and HLA-DRB1 was performed in 47 subjects. HLA-Cw*0702 was the most frequent allele (29.8%), followed by HLA-Cw*01 (26.6%). The frequency of HLA-Cw*0602 allele was similar to normal population. The most frequent HLA-DRB1 allele was HLA-DRB1*04 (20.2%), followed by HLA-DRB1*08 (16.0%). No cases carrying HLA-DRB1*13 were detected. CONCLUSIONS: Compared with Western population, our patients had less psoriasis and PsA burden. The frequencies of HLA-Cw*06, HLA-Cw*12, and HLA-DRB1*07 were not increased. In contrast, HLA-Cw*0702 and HLA-DRB1*08 allele frequencies were increased compared with psoriasis patients and normal population in Taiwan. Future studies are still needed to characterize the demographic and genetic features of high need PsA patients.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Predisposição Genética para Doença/genética , Antígenos HLA/genética , Polimorfismo Genético , Adulto , Alelos , Artrite Psoriásica/etnologia , Artrite Psoriásica/genética , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Psoríase/etnologia , Psoríase/genética , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Taiwan
13.
Clin Lab ; 64(11)2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30549993

RESUMO

Background: MicroRNAs (miRNAs) play important roles in cancer development. miR-605 was reported in several studies and showed potential as a prognostic biomarker. However, the association between miR-605 and the risk of cancer remained controversial in previous studies. Therefore, this meta-analysis was carried out to elaborate the association between polymorphism in miR-605 and cancer susceptibility. Methods: PubMed, Embase, Ovid Medline, and CNKI were searched for eligible studies through up to April 2018. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were derived from a random effects model. Statistical analysis was performed using STATA10.0 software or Review Manager 5.3 software. Results: A total of 8 eligible studies consisting of 2,462 cases and 3,716 controls were included in this meta-analysis. The ORs and 95% CIs in the 4 genetic models were (GA+GG vs. AA: OR = 0.97, 95% CI: 0.97, 1.19; GG vs. GA+AA: OR = 1.09, 95% CI: 0.81, 1.47; GG vs. AA: OR = 1.19, 95% CI: 0.77, 1.82; GA vs. AA: OR = 0.94, 95% CI: 0.77, 1.15). When stratified by cancer type and race, the results showed that polymorphism in miR-605 (rs2043556) is a protective factor for cancer in Asian population. But rs2043556 could increase the susceptibility of head and neck squamous cell carcinoma (NSCC) in the dominant genotype model. The results of subgroup analysis of race (Asian: GA+GG vs. AA: OR = 0.86, 95% CI: 0.75, 1.00; GA vs. AA: OR = 0.82, 95% CI: 0.72, 0.92) and of cancer type (NSCC: GA+GG vs. AA: OR = 1.36, 95% CI: 1.14, 1.61). Conclusions: The current meta-analysis demonstrated that the rs2043556 may decrease susceptibility in Asian populations, especially allelic-G may be a protective factor for cancer in carriers.


Assuntos
Predisposição Genética para Doença/genética , MicroRNAs/genética , Neoplasias/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Associação Genética , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Neoplasias/etnologia , Neoplasias/patologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco
14.
Medicine (Baltimore) ; 97(35): e11859, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30170377

RESUMO

BACKGROUND: Cyclooxygenase-2 (COX-2) is an inducible enzyme that mediates the synthesis of prostaglandin, which plays an important role in the inflammation response. The overexpression of COX-2 in lung cancer has been found in several studies, suggesting that COX-2 contributes to carcinogenesis. There are many previous case-control studies focused on the association between COX-2 polymorphism and lung cancer risk, however, the conclusion remained controversial. OBJECTIVES: We performed this meta-analysis to evaluate the association between COX-2 rs5275 and rs689466 polymorphism and susceptibility to lung cancer. METHODS: A systematic literature research was conducted on PubMed, Embase, Cochrane Library, OVID, Web of Science, and Google Scholar up to November 30, 2017. The quality of studies was assessed by Newcastle-Ottawa scale. We combined odds ratios (ORs) and 95% confidence intervals (CIs) in 5 different genetic models for evaluation under a fixed-effect model or random-effect model. Subgroup analysis was performed according to source of control, ethnicity, pathological types, and smoking status. Sensitivity analysis and publication bias were also conducted. RESULTS: Eventually, 14 eligible studies were included in our meta-analysis. We found rs5275 gene polymorphism decreased the risk of lung cancer under heterozygote model (OR: 0.91, 95% CI: 0.84-0.98, P = .02). COX-2 rs689466 gene polymorphism was also related to a significantly reduced risk under allele (OR: 0.88, 95% CI: 0.82-0.95, P = .001), homozygote (OR: 0.81, 95% CI: 0.68-0.95, P = .01), heterozygote (OR: 0.81, 95% CI: 0.72-0.91, P < .001), and dominant model (OR: 0.81, 95% CI: 0.72-0.91, P < .001), except for recessive model. Subgroup analysis suggested a similar association in Asians, but not in Caucasians. Polymorphism of rs5275 was strongly associated with a reduced risk of lung adenocarcinoma according to stratified analysis by pathological types. Egger test identified no significant publication bias. CONCLUSIONS: Our meta-analysis demonstrated that COX-2 rs5275 and rs689466 polymorphism significantly decrease the risk of lung cancer in Asians but not in Caucasians, indicating COX-2 could serve as a potential diagnostic marker for lung cancer.


Assuntos
Ciclo-Oxigenase 2/genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença/etnologia , Heterozigoto , Homozigoto , Humanos , Neoplasias Pulmonares/etnologia , Razão de Chances , Fatores de Risco
15.
J Genet ; 97(2): 411-417, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29932061

RESUMO

TBX22 is a gene which contribute to cleft lip/palate, and many mutation sites of TBX22 have been reported. However, the exact role of TBX22 mutation in Chinese nonsyndromic cleft lip/palate (NSCL/P) family was not clearly explored. In this study, we tried to investigate the profiles and effects of TBX22 mutation in Chinese NSCL/P family. Members of two Chinese NSCL/P families and 200 normal controls were enrolled in this study. Further, DNA sequence and bioinformatic analysis for TBX22 were performed. The results showed that a novel and essential splicing site mutation, IVS6-1G>C , was detected in a family with cleft palate. The bioinformatic analysis results showed that this mutation would lead to abnormal transcription or translation, followed by a loss of function of TBX22. In addition, a hemizygous missense mutation, c.874G>A (p.D292N), was first reported in another Chinese family, which may exhibit aggravated effects on the phenotypes of CL/P. Taking these findings together, this study provides a profile of TBX22 mutation in Chinese NSCL/P families, and further confirmed the important role of TBX22 in familial cases with X-linked cleft palate.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Predisposição Genética para Doença/genética , Mutação , Proteínas com Domínio T/genética , Sequência de Aminoácidos , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , China , Fenda Labial/etnologia , Fissura Palatina/etnologia , Análise Mutacional de DNA , Saúde da Família , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/etnologia , Predisposição Genética para Doença/etnologia , Humanos , Masculino , Linhagem , Homologia de Sequência de Aminoácidos
16.
Fa Yi Xue Za Zhi ; 34(2): 142-146, 2018 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-29923378

RESUMO

OBJECTIVES: To explore the effects of ADH1B and ALDH2 gene polymorphism and type of alcoholic beverage on ethanol metabolism, to provide data support for cases involving the interpretation of ethanol metabolism or back calculation of blood ethanol concentration in forensic practice. METHODS: A total of 81 volunteers were selected. The genotypes of ADH1B, ADH1C and ALDH2 were obtained by a multiplex SNaPshot genotyping method. Each subject was administered with 1.0 g/kg of alcohol. About 1 mL venous blood was collected before and after the alcohol consumption at 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h and 8 h, respectively. The concentrations of ethanol and acetaldehyde in blood were determined by headspace gas chromatography. The peak times of blood ethanol concentration (Tmax), the peak mass concentrations of ethanol (Cmax), the area under curve (AUC) of ethanol (AUCethanol), AUCacetaldehyde and ethanol elimination rates (ß) were calculated. In order to eliminate the influence of ADH1C, the ADH1C*1/*1 carriers were grouped based on the genotype of ADH1B and ALDH2. The data of each group were evaluated by one-way analysis of variance and pairwise comparison tests were performed by least significant difference method. The gene interactions were evaluated by two-way analysis of variance. Each parameter of three kinds of alcoholic beverage (white wine, red wine and beer) among groups was analysed by variance analysis with randomized block design. RESULTS: There were no differences in the value of Tmax and Cmax between the groups with different ADH1B and ALDH2 genotype. The differences in the values of AUCethanol, ß and AUCacetaldehyde among some groups carrying different ADH1B and ALDH2 genotype had statistical significance, while no significant difference was observed in these parameters when one individual taking same dose of different alcoholic beverage type. CONCLUSIONS: The ethanol metabolism is associated with the related gene polymorphism, which is barely affected by alcoholic beverage type.


Assuntos
Álcool Desidrogenase/genética , Alcoolismo/genética , Polimorfismo Genético/genética , Polimorfismo de Nucleotídeo Único/genética , Acetaldeído/sangue , Álcool Desidrogenase/metabolismo , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/etnologia , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Bebidas Alcoólicas , Alcoolismo/epidemiologia , Alcoolismo/etnologia , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Aldeído-Desidrogenase Mitocondrial , China/epidemiologia , Etanol/administração & dosagem , Etanol/sangue , Frequência do Gene/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino
17.
J Orthop Surg Res ; 13(1): 109, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29764467

RESUMO

BACKGROUND: In our previous whole-genome sequencing study of 30 unrelated northern Chinese Han patients, we identified six single nucleotide polymorphisms (SNPs) in the interleukin 17 receptor C (IL17RC) and collagen type VI α1 chain (COL6A1) genes that were potentially associated with thoracic ossification of the posterior longitudinal ligament (T-OPLL). To determine whether these six SNPs are associated with susceptibility to T-OPLL in the northern Chinese Han population, we performed a case-control association study to confirm specific susceptible loci in the expanded samples. METHODS: The six SNPs in the IL17RC and COL6A1 genes were analyzed in 200 northern Chinese individuals (100 patients and 100 control subjects) using the Sequenom system. RESULTS: The genotype distributions and allele frequencies of each SNP in the control and patient groups were compared. rs201153092, rs13051496, rs199772854, rs76999397, and rs189013166 showed potential pathogenic loci for T-OPLL in the northern Chinese Han population, whereas rs151158105 did not. At the genotype level, the differences in the genotype frequencies of rs201153092, rs13051496, rs199772854, rs76999397, and rs189013166 between T-OPLL cases and controls reached statistical significance. CONCLUSIONS: To the best of our knowledge, this is the first association study of susceptibility genes in Han Chinese patients with T-OPLL. The results revealed five SNPs in the IL17RC and COL6A1 genes that represented potentially pathogenic mutations in patients with T-OPLL.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Colágeno Tipo VI/genética , Predisposição Genética para Doença/genética , Ossificação do Ligamento Longitudinal Posterior/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Interleucina/genética , Grupo com Ancestrais do Continente Asiático/etnologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/etnologia , Humanos , Masculino , Pessoa de Meia-Idade , Ossificação do Ligamento Longitudinal Posterior/etnologia , Vértebras Torácicas
18.
Yonsei Med J ; 59(4): 519-523, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29749135

RESUMO

PURPOSE: Kawasaki disease (KD) is a mucocutaneous lymph node syndrome. It is mainly seen in young children under the age of five. KD is a multifactorial disorder that includes genetic variants. The present study investigated the association between KD and single nucleotide polymorphisms (SNPs) in the candidate gene early B cell factor 2 (EBF2), which is associated with inflammation markers. MATERIALS AND METHODS: An SNP analysis was performed by whole exon sequencing of the EBF2 gene. Our study comprised a total of 495 subjects (295 KD patients and 200 unrelated normal controls) from a Korean population. Tag SNPs were discovered using the Haploview program. Genotyping of the EBF2 gene was performed with the TaqMan® assay with real-time PCR methods. RESULTS: Polymorphism of rs10866845 showed a significant difference in allele frequency between KD patients and controls (p=0.040). The EBF2 gene polymorphisms were significantly associated with KD on logistic regression analysis. CONCLUSION: EBF2 gene variants can contribute to KD in the Korean population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Predisposição Genética para Doença/etnologia , Síndrome de Linfonodos Mucocutâneos/etnologia , Síndrome de Linfonodos Mucocutâneos/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Humanos , Lactente
19.
BMC Res Notes ; 11(1): 211, 2018 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-29606121

RESUMO

OBJECTIVE: Earlier, GLIS3 gene polymorphisms have been shown to be associated with the development of maturity onset diabetes of the young (MODY). We screened GLIS3 gene sequences among patients with MODY to identify probably pathogenic variants by whole-exome sequencing. We estimated frequency of rare single-nucleotide variants in the coding region of GLIS3 in a Caucasian population and among individuals with carbohydrate metabolism disorders in Russia. RESULTS: We identified 15 single-nucleotide variants in GLIS3. Three rare variants (minor allele frequency < 1%) rs806052, rs143051164, and rs149840771 were genotyped in 126 cases of MODY, in 188 patients with type 2 diabetes mellitus (DM2), and 564 randomly selected Caucasian individuals in Russia. A heterozygous rs806052 variant was identified in one patient with DM2; c.1270T frequency was 0.003. Prevalence of rs143051164 c.844G was 0.003 in the control population and 0.004 and 0.003 in MODY and DM2 samples, respectively. Prevalence of rs149840771 c.2096A was 0.003 and 0.004 in the control population and among MODY patients, respectively. In DM2 patients, rs149840771 c.2096A was not identified. We did not detect any associations of rs806052, rs143051164, and rs149840771 with carbohydrate metabolism disorders among patients with MODY and DM2 in Russia.


Assuntos
Metabolismo dos Carboidratos , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Idoso , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Federação Russa
20.
DNA Cell Biol ; 37(6): 543-550, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29653063

RESUMO

ZNF350, a BRCA1-interacting protein, could mediate BRCA1-induced sequence-specific transcriptional repression of several genes, including GADD45α. As a potential breast cancer susceptibility gene, single nucleotide polymorphisms (SNPs), especially missense SNPs, may influence the transcriptional repression of its target tumor suppressor genes and individuals' breast cancer risk. Using the gene-based haplotype-tagging SNPs strategy, we evaluated the association between six ZNF350 polymorphisms and breast cancer risk in a case-control set from a northern Chinese population. The impact of ZNF350 variations on transcriptional repression of GADD45α was also examined. It was found that ZNF350 rs2278420 (L66P) and rs2278415 (S501R) missense genetic variants are in complete linkage disequilibrium and have a significant impact on inter-individual susceptibility to breast cancer. Additionally, ZNF350 GGCGT or GGCGC haplotype is also associated with a significantly increased breast cancer risk compared with the GGCAC haplotype. ZNF350 L66P variant modifies the risk of breast cancer not only by itself but also in a gene-environment interaction manner with age, age at menarche, menopause status, or estrogen receptor status. Interestingly, we observed that ZNF350 L66P and S501R SNPs could weaken the capability of ZNF350-mediated GADD45α transcription repression and it may be an underlying mechanism of the observed epidemiological associations. Our results highlight ZNF350 as an important gene in human mammary oncogenesis and ZNF350 missense genetic polymorphisms confer susceptibility to breast cancer.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Neoplasias da Mama/etnologia , Estudos de Casos e Controles , China , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Pessoa de Meia-Idade
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