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1.
Int Heart J ; 60(5): 1113-1122, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31484864

RESUMO

Occurring in about 1% of all live births, congenital heart defects (CHDs) represent the most frequent type of developmental abnormality and account for remarkably increased infant morbidity and mortality. Aggregating studies demonstrate that genetic components have a key role in the occurrence of CHDs. Nevertheless, due to pronounced genetic heterogeneity, the genetic causes of CHDs remain unclear in most patients. In this research, 114 unrelated patients affected with CHDs and 218 unrelated individuals without CHDs served as controls were recruited. The coding regions and splicing donors/acceptors of the ISL1 gene, which codes for a transcription factor required for proper cardiovascular development, were screened for mutations by sequencing in all study participants. The functional characteristics of an identified ISL1 mutation were delineated with a dual-luciferase reporter assay system. As a result, a new heterozygous ISL1 mutation, NM_002202.2: c.225C>G; p. (Tyr75*), was discovered in an index patient with double outlet right ventricle and ventricular septal defect. Analysis of the proband's family unveiled that the mutation co-segregated with the CHD phenotype. The nonsense mutation was absent in the 436 control chromosomes. Biological analysis showed that the mutant ISL1 protein had no transcriptional activity. Furthermore, the mutation nullified the synergistic activation between ISL1 and TBX20, another CHD-associated transcription factor. This research for the first time links an ISL1 loss-of-function mutation to double outlet right ventricle in humans, which adds insight to the molecular pathogenesis underpinning CHDs, suggesting potential implications for timely personalized management of CHD patients.


Assuntos
Dupla Via de Saída do Ventrículo Direito/genética , Genes Reporter/genética , Predisposição Genética para Doença/epidemiologia , Proteínas com Homeodomínio LIM/genética , Mutação com Perda de Função/genética , Fatores de Transcrição/genética , Estudos de Casos e Controles , Causalidade , Pré-Escolar , China/epidemiologia , Dupla Via de Saída do Ventrículo Direito/diagnóstico por imagem , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Heterozigoto , Hospitais Universitários , Humanos , Incidência , Lactente , Masculino , Mutação , Linhagem , Prognóstico , Estudos Retrospectivos , Medição de Risco
2.
Int Heart J ; 60(5): 1083-1090, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31447468

RESUMO

Contemporary studies have identified rs10494366 in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene as a new genetic marker in modulating the QT interval and sudden cardiac death (SCD) in general populations. However, the conclusions were not coincident. Therefore, we conducted for the first time a system evaluation of the relativity of rs10494366, the QT interval, and sudden death by meta-analysis. In our study, the meta-analysis displayed the GG genotype of rs10494366 correlated with the QT interval in women with no heterogeneity, and in diabetes mellitus (DM) patients with minor heterogeneity. In the Caucasian population, the correlation of rs10494366 and sudden death was significant. The heterogeneity referred to the relevance between rs10494366 and sudden death in the Asian population. In conclusion, the minor allele of rs10494366 may have an impact on the QT interval in women or DM patients and may have a potential role in sudden death in the Caucasian population.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Morte Súbita Cardíaca/epidemiologia , Predisposição Genética para Doença/epidemiologia , Síndrome do QT Longo/genética , Síndrome do QT Longo/mortalidade , Polimorfismo de Nucleotídeo Único/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , China , Morte Súbita Cardíaca/etnologia , Eletrocardiografia , Feminino , Genótipo , Humanos , Masculino , Análise de Sobrevida
3.
Medicine (Baltimore) ; 98(25): e16135, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232967

RESUMO

BACKGROUND: TP53 gene polymorphism could increase risks of several kinds of cancer. But it remained controversial whether TP53 gene codon72 polymorphism was associated with the susceptibility to prostate cancer. Thus, we conducted a meta-analysis that evaluated the association between TP53 gene codon72 polymorphism and prostate cancer risk. METHOD: A comprehensive research was performed from PubMed, Embase, Web of Science and China National Knowledge Infrastructure (CNKI) up to December 31, 2018. A random effect model was used to evaluate the effect of the outcome. The statistical analyses were performed with Review Manager 5.3.0 and Stata 14.0. The sensitivity analysis and publication bias tests were also performed to confirm the reliability of this meta-analysis. RESULTS: 22 studies included 3146 cases and 4010 controls were involved in this meta-analysis. Overall, no association was observed between TP53 gene codon72 polymorphism and prostate cancer risk (Arg vs Pro: odds ratio [OR] = 1.12, 95% confidence interval [CI] = 0.98-1.30; ArgArg vs ProPro: OR = 1.26, 95% CI = 0.90-1.75; ProPro vs ArgArg+ ArgPro: OR = 1.17, 95% CI = 0.86-1.57; ArgPro+ ProPro vs ArgArg: OR = 1.21, 95% CI = 0.97-1.51). Subgroup analyses, based on ethnicity, source of control and Hardy-Weinberg equilibrium (HWE) status, showed consistent results. CONCLUSION: The meta-analysis we performed showed that there was no association of TP53 gene codon72 polymorphism with prostate cancer risk.


Assuntos
Neoplasias da Próstata/diagnóstico , Medição de Risco/normas , Proteína Supressora de Tumor p53/genética , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Reprodutibilidade dos Testes , Medição de Risco/métodos , Proteína Supressora de Tumor p53/análise
4.
Environ Sci Pollut Res Int ; 26(21): 21983-21992, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31144180

RESUMO

The development of congenital heart disease (CHD) is a complicated process and affected by multiple environmental factors, as genetic factors, and the interactions among those factors. Previous studies have shown that intrauterine hypoxic environment exposure is a risk factor of CHD, but the genetic factors involved in the process are not clear. In this study, given that tetralogy of Fallot (TOF) is a CHD with hypoxemia as its primary pathophysiological manifestation, an in silico analysis was performed to reveal the relationship between potential target genes (miR-124) with the energy metabolism in non-syndromic TOF patients' cardiomyocyte. Furthermore, the study investigated the correlation between the primary miR-124 (rs531564) polymorphism and CHD susceptibility in 432 sporadic patients and 450 controls from two different altitude provinces (city) in China. Our study indicated that the minor C allele of rs531564 correlated with reduced risk of CHD in the low altitude city. Besides, the C allele has elevated frequency in the high-altitude group. Therefore, our findings suggest that the minor C allele of rs531564 SNP may be involved in the reduction of the risk of CHD in a way that interacts with the intrauterine hypoxic environmental factors.


Assuntos
Altitude , Predisposição Genética para Doença/epidemiologia , Cardiopatias Congênitas/genética , MicroRNAs/genética , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China/epidemiologia , Simulação por Computador , Feminino , Cardiopatias Congênitas/epidemiologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco
5.
Acta Diabetol ; 56(9): 1037-1044, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30989380

RESUMO

AIMS: Observational studies indicated that resting heart rate (RHR) was associated with diabetes mellitus (DM) risk; however, it remains unclear whether the association between RHR and DM is causal. We aimed to examine whether there was causal association of RHR with DM risk. METHODS: A prospective study including 16,201 middle-aged and older Chinese (7031 males and 9170 females) derived from the Dongfeng-Tongji cohort was performed. Cox proportional hazard regression models were conducted to estimate the associations between RHR and incident DM risk. In 7481 participants, 65 single nucleotide polymorphisms related to RHR were genotyped. A genetic risk score (GRS) of RHR was calculated based on the RHR-associated variants. The causal associations of RHR with DM risk were investigated by Mendelian randomization analysis. RESULTS: During a mean (SD) follow-up of 4.5 (0.5) years, 1110 diabetes were identified. Compared with the referential RHR group (≤ 60 beats per minute [bpm]), individuals with RHR > 80 bpm have a higher incident diabetes risk, with a hazard ratio of 1.40 (95% confidence interval [CI], 1.05-1.88). With per SD increase in the weighted genetic risk score, the resting heart rate increased by 0.71 bpm (95% CI 0.49-0.93). By using the GRS to estimate the unconfounded effect, we found that higher resting heart rate did not have a causal effect on diabetes risk (OR 1.00 [95% CI 0.95-1.05]). CONCLUSIONS: The present study supported a positive but not a causal association of RHR with incident diabetes risk. More studies are needed to verify our findings.


Assuntos
Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatologia , Frequência Cardíaca/genética , Polimorfismo de Nucleotídeo Único , Descanso/fisiologia , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , China/epidemiologia , Estudos de Coortes , Feminino , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Predisposição Genética para Doença/epidemiologia , Genótipo , Humanos , Incidência , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
6.
Respir Res ; 20(1): 64, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940143

RESUMO

BACKGROUND: A growing number of studies clearly demonstrate a substantial association between chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CVD), although little is known about the shared genetics that contribute to this association. METHODS: We conducted a large-scale cross-trait genome-wide association study to investigate genetic overlap between COPD (Ncase = 12,550, Ncontrol = 46,368) from the International COPD Genetics Consortium and four primary cardiac traits: resting heart rate (RHR) (N = 458,969), high blood pressure (HBP) (Ncase = 144,793, Ncontrol = 313,761), coronary artery disease (CAD)(Ncase = 60,801, Ncontrol = 123,504), and stroke (Ncase = 40,585, Ncontrol = 406,111) from UK Biobank, CARDIoGRAMplusC4D Consortium, and International Stroke Genetics Consortium data. RESULTS: RHR and HBP had modest genetic correlation, and CAD had borderline evidence with COPD at a genome-wide level. We found evidence of local genetic correlation with particular regions of the genome. Cross-trait meta-analysis of COPD identified 21 loci jointly associated with RHR, 22 loci with HBP, and 3 loci with CAD. Functional analysis revealed that shared genes were enriched in smoking-related pathways and in cardiovascular, nervous, and immune system tissues. An examination of smoking-related genetic variants identified SNPs located in 15q25.1 region associated with cigarettes per day, with effects on RHR and CAD. A Mendelian randomization analysis showed a significant positive causal effect of COPD on RHR (causal estimate = 0.1374, P = 0.008). CONCLUSION: In a set of large-scale GWAS, we identify evidence of shared genetics between COPD and cardiac traits.


Assuntos
Doenças Cardiovasculares/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Doença Pulmonar Obstrutiva Crônica/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Bases de Dados Genéticas/tendências , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Característica Quantitativa Herdável
7.
Hum Genet ; 138(4): 425-435, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30941497

RESUMO

Heritability is the most commonly used measure of genetic contribution to disease outcomes. Being the fraction of the variance of latent trait liability attributable to genetic factors, heritability of binary traits is a difficult technical concept that is sometimes misinterpreted as the more-easily understandable concept of attributable fraction. In this paper we use the liability threshold model to describe the analytical relationship between heritability and attributable fraction. Towards this end, we consider a hypothetical intervention that is aimed to reduce the genetic risk of the disease for a specified target group of the population. We show how the relation between the heritability and the attributable fraction depends on the disease prevalence, the intervention effect and the size of the target group. We use two real examples to illustrate the practical implications of our theoretical results.


Assuntos
Predisposição Genética para Doença/epidemiologia , Modelos Genéticos , Modelos Estatísticos , Herança Multifatorial , Característica Quantitativa Herdável , Causalidade , Doença/etiologia , Doença/genética , Humanos , Fenótipo , Densidade Demográfica , Prevalência , Fatores de Risco , Tamanho da Amostra
8.
Turk J Med Sci ; 49(2): 472-477, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30887796

RESUMO

Background/aim: The distribution of Mediterranean fever (MEFV) gene mutations in Turkish familial Mediterranean fever (FMF) patients varies according to geographic area of Turkey. There is a need for highly representative data for Turkish FMF patients. The aim of our study was to investigate the distribution of the common MEFV mutations in Turkish FMF patients in a nationwide, multicenter study. Materials and methods: Data of the 2246 FMF patients, from 15 adult rheumatology clinics located in different parts of the country, were evaluated retrospectively. The following mutations have been tested in all patients: M694V, M680I, M694I, V726A, and E148Q. Results: There were 1719 FMF patients with available genetic testing. According to the genotyping, homozygous M694V, present in 413 patients (24%), was the most common mutation . One hundred and fifty-four (9%) of patients had no detectable mutations. Allele frequencies of common mutations were: M694V (n = 1529, 44.5%), M680I (n = 423, 12.3%), V726A (n = 315, 9.2%), E148Q (n = 214, 1%), and M694I (n = 12, <1%). Conclusion: In this large-scale multicenter study, we provided information about the frequencies of common MEFV gene mutations obtained from adult Turkish FMF patients. Nearly half of the patients were carrying at least one M694V mutations in their alleles.


Assuntos
Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/genética , Genética Populacional , Mutação/genética , Pirina/genética , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/diagnóstico , Feminino , Frequência do Gene , Predisposição Genética para Doença/epidemiologia , Testes Genéticos , Genética Populacional/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Estudos Retrospectivos , Turquia/epidemiologia , Adulto Jovem
9.
Ital J Pediatr ; 45(1): 37, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30867013

RESUMO

BACKGROUND: Neural tube defects (NTDs) are birth defects of the brain, spine, or spinal cord invoked by the insufficient intake of folic acid in the early stages of pregnancy and have a complex etiology involving both genetic and environmental factors. So the study aimed to explore the association between alterations in maternal one-carbon metabolism and NTDs in the offspring. METHODS: We conducted a case-control study to get a deeper insight into this association, as well as into the role of genetic polymorphisms. Plasma concentrations of folate, homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and genotypes and alleles distributions of 52 SNPs in 8 genes were compared for 61 women with NTDs-affected offspring and 61 women with healthy ones. RESULTS: There were significant differences between groups with regard to plasma folate, SAM, SAH and SAM/SAH levels. Logistic regression results revealed a significant association between maternal plasma folate level and risk of NTDs in the offspring. For MTHFD1 rs2236225 polymorphism, mothers having GA genotype and A allele exhibited an increased risk of NTDs in the offspring (OR = 2.600, 95%CI: 1.227-5.529; OR = 1.847, 95%CI: 1.047-3.259). For MTHFR rs1801133 polymorphism, mothers having TT and CT genotypes were more likely to affect NTDs in the offspring (OR = 4.105, 95%CI: 1.271-13.258; OR = 3.333, 95%CI: 1.068-10.400). Moreover, mothers carrying T allele had a higher risk of NTDs in the offspring (OR = 1.798, 95%CI: 1.070-3.021). For MTRR rs1801394 polymorphism, the frequency of G allele was significantly higher in cases than in controls (OR = 1.763, 95%CI: 1.023-3.036). Mothers with NTDs-affected children had higher AG genotype in RFC1 rs1051226 polymorphism than controls, manifesting an increased risk for NTDs (OR = 3.923, 95%CI: 1.361-11.308). CONCLUSION: Folic acid deficiency, MTHFD1 rs2236225, MTHFR rs1801133, MTRR rs1801349 and RFC1 rs1051226 polymorphisms may be maternal risk factors of NTDs.


Assuntos
Deficiência de Ácido Fólico/genética , Predisposição Genética para Doença/epidemiologia , Defeitos do Tubo Neural/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Carbono/metabolismo , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China , Feminino , Ferredoxina-NADP Redutase/genética , Deficiência de Ácido Fólico/diagnóstico , Deficiência de Ácido Fólico/epidemiologia , Marcadores Genéticos/genética , Genótipo , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Antígenos de Histocompatibilidade Menor/genética , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/fisiopatologia , Razão de Chances , Gravidez , Valores de Referência
10.
Respir Res ; 20(1): 38, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30791911

RESUMO

BACKGROUND: Asthma is a common complex chronic, inflammatory polygenic disease with heterogeneous manifestations, affecting individuals of all age groups and posing an immense burden on healthcare resources. A number of studies have identified the association between a disintegrin and metalloprotease 33 (ADAM33) polymorphisms and asthma risk, however, the results still remain inconclusive. The objective of the present study was to identify the effect of ADAM33 variants in asthma susceptibility. METHODS: Eligible case-control studies published between January 2000 and June 2018 was searched and retrieved from online electronic databases. The odds ratio (OR) with its 95% confidence interval (CI) was employed to calculate the effect. RESULTS: A total of 63 case-control studies were finally screened out, including 13,280 asthma patients and 13,340 controls. Eleven SNPs of ADAM33 gene were identified. Our results detected a significant association between ADAM33 T2, Q1, F + 1 and AA genotype of T + 1 polymorphisms and asthma risk in total population. Subgroup analysis by ethnicities showed that the alleles and genotypes of T2, Q1 and F + 1 polymorphisms were associated with asthma susceptibility among Asian populations, while V4 polymorphism was associated with asthma among Caucasian populations. Subgroup analysis by ages showed that T2, F + 1 and ST + 4 polymorphisms were associated with childhood asthma, while Q1 and V4 polymorphisms were associated with asthma risk in adults. Subgroup analysis by asthma severity showed that only the G allele of ADAM33 T1 polymorphism was associated with the severity of asthma when compared with the controls. In addition, T2, Q1 and F + 1 polymorphisms of ADAM33 were significantly associated with increased the asthma risk in Chinese asthma patients. CONCLUSIONS: Our results found that T2, Q1 and F + 1 polymorphisms of ADAM33 gene might contribute to asthma risk. Future well-designed case-control studies with large population and more ethnicities are still needed to estimate the association.


Assuntos
Proteínas ADAM/genética , Asma/diagnóstico , Asma/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético/genética , Asma/epidemiologia , Estudos de Casos e Controles , Predisposição Genética para Doença/epidemiologia , Humanos , Fatores de Risco
11.
Turk J Med Sci ; 49(1): 123-128, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30762321

RESUMO

Background/aim: We investigated the association of three IL-10 promoter single-nucleotide polymorphisms and altered IL-10 plasma levels with the risk of head and neck cancer (HNC). Materials and methods: Study subjects comprised 194 HNC patients [137 nasopharyngeal cancer (NPC) and 57 laryngeal cancer (LC)], and 263 healthy controls. Genotyping of rs1800896 (-1082A>G), rs1800871 (-819C>T), and rs1800872 (-592A>C) IL-10 variants was performed by real-time PCR; IL-10 levels were measured by enzyme amplified immuno sensitivity assay (EAISA). Results: Study subjects comprised 194 HNC patients [137 nasopharyngeal cancer (NPC) and 57 laryngeal cancer (LC)], and 263 healthy controls. Genotyping of rs1800896 (-1082A>G), rs1800871 (-819C>T), and rs1800872 (-592A>C) IL-10 variants was performed by real-time PCR; IL-10 levels were measured by enzyme amplified immuno sensitivity assay (EAISA). Conclusion: Our results demonstrate that IL-10-1082, IL-10-819, and IL-10-592 variants, and haplotypes GC and GT constitute biomarkers for early detection of HNC, especially NPC subtype. IL-10 -819T/C and TA haplotype may be used as biomarkers for early detection of LC.


Assuntos
Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço , Interleucina-10/genética , Neoplasias Laríngeas , Neoplasias Nasofaríngeas , Detecção Precoce de Câncer , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/genética , Humanos , Neoplasias Laríngeas/epidemiologia , Neoplasias Laríngeas/genética , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/epidemiologia , Neoplasias Nasofaríngeas/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Tunísia/epidemiologia
12.
Turk J Med Sci ; 49(1): 206-211, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30761886

RESUMO

Background/aim: Interferon-induced helicase (IFIH1) is a gene locus that has been recently defined as a candidate for susceptibility to generalized vitiligo (GV). The objectives of this study were to assess the association of IFIH1 gene, rs2111485, and rs1990760 single-nucleotide polymorphisms (SNP) with susceptibility to GV and the autoimmune diseases accompanying GV. Materials and methods: We prospectively studied GV patients and frequency-matched healthy controls by age and sex. The genotypes of the participants were determined for rs1990760 and rs2111485 SNPs of IFIH1. Dominant, recessive, and additive models were evaluated for each SNP adjusted for age and sex. Results: The patients and their controls were observed to be in the Hardy­Weinberg equilibrium for SNP1 (2q24.2, rs1990760, IFIH1, T/C) and SNP2 (2q24.2, rs2111485, IFIH1, G/A), respectively (all P > 0.7). For SNP1, every T allel addition was significantly associated with 1.53 times protectiveness in terms of vitiligo risk (P = 0.033). As for SNP2, every G allel addition was associated with 1.42 times protectiveness, close to statistical significance (P = 0.100). Conclusions: We detected that for SNP1, each T allel and for SNP2, each G allel are protective in terms of vitiligo development. Hereby, we confirmed that IFIH1 gene locus has a role in GV susceptibility.


Assuntos
Predisposição Genética para Doença , Helicase IFIH1 Induzida por Interferon/genética , Polimorfismo de Nucleotídeo Único/genética , Vitiligo , Adulto , Doenças Autoimunes/complicações , Doenças Autoimunes/epidemiologia , Estudos de Casos e Controles , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Pessoa de Meia-Idade , Vitiligo/complicações , Vitiligo/epidemiologia , Vitiligo/genética
13.
J Pediatr Nurs ; 44: 50-55, 2019 Jan - Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30683281

RESUMO

PROBLEM: Cardiovascular disease (CVD) is the leading cause of death in the U.S. and in most Western countries. Early identification and treatment of individuals with elevated levels of atherogenic cholesterol, a major contributor to CVD, have been shown to be effective and safe in reducing premature morbidity and mortality, especially in familial hypercholesterolemia (FH). Cholesterol screening of youth also provides a unique means of identifying affected family members through reverse cascade screening (RCS). ELIGIBILITY CRITERIA: A PubMed review of all relevant articles from 2000 to 2016 was conducted of familial hypercholesterolemia and cholesterol screening of youth. RESULTS: We provide an overview of cholesterol screening, outline the role of the pediatric nurse in the lipid clinic, and discuss effectiveness and potential barriers, including cost and confidentiality considerations of RCS. CONCLUSIONS: Early identification and effective intervention of youth with FH, including adoption of a heart-healthy lifestyle, has the potential of 1) markedly reducing or eliminating atherosclerotic cardiovascular disease and related events in future generations and 2) provides a unique means of identifying affected family members. IMPLICATIONS: Pediatric nurses play a vital role in the education and care coordination of children diagnosed with FH and screening of relatives. Identification of a child with FH with effective screening of relatives combines the benefits of universal and cascade screening, and has the potential of detecting all living cases of FH. While potentially providing significant benefit to those at risk for premature CVD, a RCS program needs to carefully consider ethical, psychological, and financial implications as well.


Assuntos
Diagnóstico Precoce , Predisposição Genética para Doença/epidemiologia , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Programas de Rastreamento/métodos , Adolescente , Fatores Etários , Doenças Cardiovasculares/prevenção & controle , Criança , Feminino , Seguimentos , Testes Genéticos/métodos , Humanos , Hiperlipoproteinemia Tipo II/genética , Incidência , Masculino , Programas de Rastreamento/enfermagem , Papel do Profissional de Enfermagem , Enfermagem Pediátrica/métodos , Medição de Risco , Fatores Sexuais
14.
JAMA Dermatol ; 155(2): 211-215, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30601876

RESUMO

Importance: Shared gene variants in benign-malignant process pairs, such as BRAF mutations common to benign nevi and melanoma, are associated with differing phenotypic manifestations. Study of gene mechanisms underlying cherry angioma may uncover previously unknown disease relationships. Objective: To identify somatic mutations present in cherry angioma specimens by using targeted next-generation sequencing. Design, Setting, and Participants: In a single-center case series, 10 formalin-fixed, paraffin-embedded cherry angioma specimens from biopsies performed at Massachusetts General Hospital in Boston from July 10, 2016, to January 23, 2018, were obtained and underwent sequencing across a panel of 323 genes most relevant to cancer. Somatic mutations were curated by excluding variants that were presumed to be germline or of low mapping quality. Main Outcomes and Measures: Identification of somatic mutations associated with cherry angiomas. Results: In 10 cherry angioma tissue samples originating from 6 female and 4 male patients with a median (range) age of 54 (26-79) years, 5 samples (50%) revealed somatic missense mutations in GNAQ (Q209H, Q209R, and R183G) and GNA11 (Q209H). Individually, these mutational hot spots are known to be involved in entities that include congenital and anastomosing hemangiomas, hepatic small-vessel neoplasms (Q209), port-wine stains, and Sturge-Weber syndrome (R183). Both hot spots are associated with blue nevi, melanoma associated with blue nevus, and uveal melanoma. Conclusions and Relevance: In this case series study, the high prevalence of 5 known genetic drivers within the benign cherry angioma entity appears to support the context-dependent role of gene alterations in both benign and malignant proliferations from various cellular origins.


Assuntos
Hemangioma/genética , Hemangioma/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação de Sentido Incorreto , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Adulto , Fatores Etários , Idoso , Boston , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Medição de Risco , Amostragem , Fatores Sexuais , Inclusão do Tecido
15.
Paediatr Perinat Epidemiol ; 33(2): 129-136, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30663124

RESUMO

BACKGROUND: Some cardiovascular disease risk factors are associated with both risk of preeclampsia and having been born to a younger or older mother. We examined whether mother's age at delivery predicts a primiparous daughter's risk of preeclampsia. METHODS: The analysis included 39 803 Sister Study participants (designated as "daughters") born between 1930 and 1974. Using log-binomial regression, we estimated relative risks (RR) of preeclampsia in the first pregnancy ending in birth ("primiparous preeclampsia") associated with mother's age at the daughter's birth. Models included: number of older full and maternal half-siblings, income level growing up, daughter's age at delivery, race/ethnicity, and 5-year birth cohort. We examined self-reported relative weight at age 10 (heavier than peers versus not) as a potential effect measure modifier. RESULTS: Overall, 6.2% of daughters reported preeclampsia. Compared with those who had been born to 20-24-year old mothers, daughters of teenage mothers had a relative risk of 1.20 (95% confidence interval (CI) 1.01, 1.43) and daughters of mothers ≥25 had a ~10% lower risk. Relative weight at age 10 modified the association, with an inverse association between mother's age at delivery and preeclampsia seen only among daughters with low/normal childhood relative weight. In this subset, results were consistent across strata of daughter's age at menarche and age at first birth. CONCLUSIONS: These findings, based on self-reported data, require replication. Nevertheless, as women increasingly delay childbearing, they provide some reassurance that having been born to an older mother is not, per se, a risk factor for primiparous preeclampsia.


Assuntos
Predisposição Genética para Doença/epidemiologia , Idade Materna , Núcleo Familiar , Pré-Eclâmpsia/epidemiologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez , Risco , Irmãos
16.
Turk Kardiyol Dern Ars ; 47(1): 29-37, 2019 01.
Artigo em Turco | MEDLINE | ID: mdl-30628898

RESUMO

OBJECTIVE: Recent studies indicate that macrophage migration inhibitory factor (MIF) is a potent proinflammatory cytokine which mediates the inflammatory process during atherosclerosis. The purpose of the study was to investigate an association between MIF gene polymorphism and type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) in the Turkish population. METHODS: A total of 139 unselected Turkish patients with significant CAD (coronary lesion with 50-100% stenosis) and 120 control participants (coronary lesion with <30% stenosis) were genotyped for MIF rs755622 polymorphisms using hybridization probes in a Roche LightCycler 480 Real-Time Polymerase Chain Reaction 480 device. Blood samples were drawn before coronary angiography. Gensini and SYNTAX scores were used to determine the angiographic extent and severity of CAD. RESULTS: When the groups were stratified according to T2DM, polymorphism of MIF was not associated with T2DM in CAD patients (p>0.05). In the same subgroups, carriers of the MIF common allele in the control group demonstrated a protection against developing T2DM compared with noncarriers (p<0.05). In addition, MIF C allele carriage was associated with higher glycated hemoglobin (HbA1c) in the T2DM group (p=0.038). CONCLUSION: The MIF rs755622 polymorphism was associated with HbA1c. This result suggests that the MIF gene variant may contribute to CAD risk through diabetes in the Turkish population.


Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Predisposição Genética para Doença , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Idoso , Estudos de Casos e Controles , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Turquia/epidemiologia
17.
J Surg Oncol ; 119(6): 687-693, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30644554

RESUMO

BACKGROUND AND OBJECTIVES: Recently, a comprehensive study presented evidence that a long-disputed REarranged during Transfection (RET) variant, RET Y791F, should be classified as nonpathogenic. In spite of this, several subsequently published papers, including the revised American Thyroid Association guidelines for medullary thyroid carcinoma, refer to the variant as pathogenic. This study presents data from a unique national Danish cohort of RET Y791F carriers who have been followed by watchful waiting instead of being subjected to early thyroidectomy, to determine if any carrier shows evidence of multiple endocrine neoplasia 2A (MEN2A) at long-term follow-up. METHODS: A national cohort of all patients tested for RET mutations in Denmark from September 1994 to October 2017 was searched for carriers of RET Y791F. Medical records and laboratory reports of carriers were reviewed for signs of MEN2A at latest follow-up (medullary thyroid carcinoma, primary hyperparathyroidism, pheochromocytoma, cutaneous lichen amyloidosis, or Hirschsprung's disease). RESULTS: In total, twenty RET Y791F-carriers were identified, none of whom showed any evidence of MEN2A, despite an age range from 7 to 87 years. CONCLUSIONS: Our national cohort study of all Danish RET Y791F carriers substantiates the claim that the RET Y791F variant is nonpathogenic.


Assuntos
Predisposição Genética para Doença/epidemiologia , Heterozigoto , Mutação , Proteínas Proto-Oncogênicas c-ret/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Medular/genética , Criança , Estudos de Coortes , Dinamarca/epidemiologia , Seguimentos , Humanos , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/genética , Feocromocitoma/genética , Neoplasias da Glândula Tireoide/genética , Adulto Jovem
18.
JAMA Dermatol ; 155(2): 188-195, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30566178

RESUMO

Importance: Information on risk factors of subsequent melanomas would be helpful to identify patients at risk after the diagnosis of their first melanomas. Objective: To determine risk factors of subsequent melanomas. Design, Setting, and Participants: In this retrospective case-control study, 1648 participants with histologically verified cutaneous melanoma diagnosed from January 1, 1968, though March 16, 2015, were recruited from a tertiary referral center as part of the Molecular Markers of Melanoma study. CDKN2A was sequenced in 514 and MC1R in 953 participants. Data were analyzed from March 7, 2008, through March 25, 2015. Main Outcomes and Measures: Phenotypic traits and internal and external risk factors for the development of a second, third, or fourth melanoma. Results: In total, 1648 patients (53.6% men; mean [SD] age, 54 [15] years) were enrolled, including 1349 with single and 299 with multiple primary melanoma. Mean (SD) age at recruitment was 57 (15) years for the single-melanoma and 62 (14) years for the multiple-melanoma groups. From the internal risk factors, family history (odds ratio [OR], 1.76; 95% CI, 1.22-2.55; P = .006), CDKN2A high-risk mutations (OR, 4.03; 95% CI, 1.28-12.70; P = .02), and high numbers of nevi as a phenotypic risk factor (ORs, 2.23 [95% CI, 1.56-3.28, P < .001] for 20-30 smaller nevi and 2.56 [95% CI, 1.50-4.36; P = .003] for 20-30 larger nevi) were significantly associated with the risk of developing a subsequent primary melanoma using multivariate logistic regression analysis. Nonmelanoma skin cancer (OR, 2.57; 95% CI, 1.84-3.58; P < .001) and signs of actinic skin damage, particularly on the back (ORs, 1.91 [95% CI, 1.12-3.25; P = .04] for freckling and 1.92 [95% CI, 1.29-3.08; P = .007] for solar lentigines), additionally increased risk of a subsequent melanoma. All those factors were also associated with an earlier development of the second melanoma. Patients with 3 melanomas developed their second melanoma earlier than patients with only 2 melanomas (mean [SD] age, 55 [15] years for those with 2 primary melanomas; 52 [15] years for those with 3 primary melanomas). Time spent outdoors, solarium use, outdoor occupation, and hair color had no significant associations in these models. Conclusions and Relevance: According to the results of this study, internal factors (family history and genetic variants), number of nevi, and actinic damage on the back are more relevant for the development of subsequent melanomas than skin phototype or hair color. Patients with many nevi were younger at the time of the diagnosis of their first melanoma. This finding could help to identify persons at increased risk of developing multiple primary melanomas.


Assuntos
Predisposição Genética para Doença/epidemiologia , Melanoma/epidemiologia , Melanoma/genética , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Distribuição por Idade , Análise de Variância , Áustria , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Melanoma/patologia , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prevalência , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Neoplasias Cutâneas/patologia , Análise de Sobrevida
19.
JAMA Dermatol ; 155(2): 196-203, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30586139

RESUMO

Importance: Children with epidermolysis bullosa (EB) comprise a rare population with high morbidity and mortality. An improved understanding of the clinical trajectory of patients with EB, including age at time of clinical diagnosis and major clinical events, is needed to refine best practices and improve quality of life and clinical outcomes for patients with EB. Objectives: To describe demographics, clinical characteristics, milestone diagnostic and clinical events (such as initial esophageal dilation), and outcomes in patients with EB using the Epidermolysis Bullosa Clinical Characterization and Outcomes Database and to determine what characteristics may be associated with overall EB severity and/or disease progression. Design, Setting, and Participants: This cohort study included data on patients with EB who were enrolled in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database from January 1, 2011, to June 30, 2017; 17 participating EB centers in the United States and Canada contributed data to this study. Exposures: Type of EB, including recessive dystrophic epidermolysis bullosa (RDEB), junctional epidermolysis bullosa (JEB), dominant dystrophic epidermolysis bullosa (DDEB), and epidermolysis bullosa simplex (EBS). Main Outcomes and Measures: Demographic information, clinical characteristics (including age at onset of signs of EB and subsequent clinical diagnosis), types of diagnostic testing performed, and milestone clinical events for patients with RDEB. Results: Of 644 enrolled patients from 17 sites included in this study, 323 were male (50.2%), with a mean (SD) age of 14.4 (11.7) years; 283 (43.9%) had RDEB, 194 (30.1%) had EBS, 104 (16.2%) had DDEB, and 63 (9.8%) had JEB. Signs of disease were present at birth in 202 patients with RDEB (71.4%), 39 with JEB (61.9%), 60 with DDEB (57.7%), and 74 with EBS (38.1%). For those with signs of disease at birth, a clinical diagnosis was made at the time of birth in 135 patients with RDEB (67.0%), 31 with DDEB (52.6%), 35 with EBS, (47.3%) and 18 with JEB (46.2%). Patients with JEB had the highest rate of any confirmatory testing (51 of 63 [81.0%]), followed by RDEB (218 of 283 [77.0%]), DDEB (71 of 104 [68.3%]), and EBS (100 of 194 [51.5%]). For all types of EB, both electron microscopy and immunofluorescence microscopy were performed at younger ages than genetic analysis. Among 283 patients with RDEB, 157 (55.5%) had esophageal dilation, 104 (36.7%) had gastrostomy tube placement, 62 (21.9%) had hand surgery, 18 (6.4%) developed squamous cell carcinoma, and 19 (6.7%) died. Conclusions and Relevance: The findings suggest that diagnostic testing for EB is more common for patients with severe phenotypes. Earlier diagnostic testing may enable improved characterizations of patients so that appropriate counseling and clinical care may be offered, especially pertaining to milestone events for those with RDEB.


Assuntos
Epidermólise Bolhosa/epidemiologia , Epidermólise Bolhosa/genética , Epidermólise Bolhosa/patologia , Predisposição Genética para Doença/epidemiologia , Adolescente , Distribuição por Idade , Biópsia por Agulha , Canadá , Criança , Pré-Escolar , Estudos de Coortes , Bases de Dados Factuais , Progressão da Doença , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Incidência , Lactente , Masculino , América do Norte/epidemiologia , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Análise de Sobrevida , Adulto Jovem
20.
Magy Onkol ; 62(4): 214-221, 2018 Dec 12.
Artigo em Húngaro | MEDLINE | ID: mdl-30540863

RESUMO

Acute lymphoblastic leukemia (ALL) is the most frequent malignancy in children. In Hungary 60-70 new cases are diagnosed annually. The survival rate is 85-90% in developed countries with current treatment protocols. The most common genetic category of childhood ALL is the high hyperdiploid subtype (HHD) with chromosome numbers of 51 to 67. It accounts for approximately 25% of all cases. The prognosis is very good, though relapse occurs in ~15% of cases and there are data on the heterogeneity of this subgroup as well. In this paper we give an overview of the cytogenetic, clinical, epidemiological and prognostic features of this subgroup. We also demonstrate our interphase fluorescent in situ hybridization (iFISH) analysis performed retrospectively on 168 untreated bone marrow samples of precursor B pediatric ALL patients to reveal the numerical aberrations of chromosomes 4, 6, 10, 14, 17, 18, 21 and X, which are most frequently affected by gain in HHD ALL. Data from 48 high hyperdiploid patients indicated that high modal number (>55 chromosomes) and specific chromosomal gains (+4, +4/+6, +4/+17, +4/+18) exhibited significance in terms of beneficial overall survival.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Diploide , Predisposição Genética para Doença/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Biópsia por Agulha , Medula Óssea/patologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Hungria , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Medição de Risco , Análise de Sobrevida
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