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1.
Neurology ; 97(6): e619-e628, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34031205

RESUMO

OBJECTIVE: To construct a polygenic risk score (PRS) for stroke and evaluate its utility in risk stratification and primary prevention for stroke. METHODS: Using a meta-analytic approach and large genome-wide association results for stroke and stroke-related traits in East Asians, we generated a combined PRS (metaPRS) by incorporating 534 genetic variants in a training set of 2,872 patients with stroke and 2,494 controls. We then validated its association with incident stroke using Cox regression models in large Chinese population-based prospective cohorts comprising 41,006 individuals. RESULTS: During a total of 367,750 person-years (mean follow-up 9.0 years), 1,227 participants developed stroke before age 80 years. Individuals with high polygenic risk had an about 2-fold higher risk of incident stroke compared with those with low polygenic risk (hazard ratio [HR] 1.99, 95% confidence interval [CI] 1.66-2.38), with the lifetime risk of stroke being 25.2% (95% CI 22.5%-27.7%) and 13.6% (95% CI 11.6%-15.5%), respectively. Individuals with both high polygenic risk and family history displayed lifetime risk as high as 41.1% (95% CI 31.4%-49.5%). Individuals with high polygenic risk achieved greater benefits in terms of absolute risk reductions from adherence to ideal fasting blood glucose and total cholesterol than those with low polygenic risk. Maintaining favorable cardiovascular health (CVH) profile could substantially mitigate the increased risk conferred by high polygenic risk to the level of low polygenic risk (from 34.6% to 13.2%). CONCLUSIONS: Our metaPRS has great potential for risk stratification of stroke and identification of individuals who may benefit more from maintaining ideal CVH. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that metaPRS is predictive of stroke risk.


Assuntos
Predisposição Genética para Doença , Fatores de Risco de Doenças Cardíacas , Medição de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China/epidemiologia , Estudos de Coortes , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Modelos Estatísticos , Herança Multifatorial , Reprodutibilidade dos Testes , Medição de Risco/métodos , Medição de Risco/normas , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/prevenção & controle
2.
Mayo Clin Proc ; 96(6): 1407-1417, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33890576

RESUMO

OBJECTIVE: To assess the presence of clinically actionable results and other genetic findings in an otherwise healthy population of adults seen in a medical practice setting and offered "predictive" genomic testing. PATIENTS AND METHODS: In 2014, a predictive genomics clinic for generally healthy adults was launched through the Mayo Clinic Executive Health Program. Self-identified interested patients met with a genomic nurse and genetic counselor for pretest advice and education. Two genome sequencing platforms and one gene panel-based health screen were offered. Posttest genetic counseling was available for patients who elected testing. From March 1, 2014, through June 1, 2019, 1281 patients were seen and 301 (23.5%) chose testing. Uptake rates increased to 36.3% [70 of 193]) in 2019 from 11.8% [2 of 17] in 2014. Clinically actionable results and genetic findings were analyzed using descriptive statistics. RESULTS: Clinically actionable results were detected in 11.6% of patients (35 of 301), and of those, 51.7% (15 of 29) with a cancer or cardiovascular result = did not have a personal or family history concerning for a hereditary disorder. The most common actionable results were in the BCHE, BRCA2, CHEK2, LDLR, MUTYH, and MYH7 genes. A carrier of at least one recessive condition was found in 53.8% of patients (162 of 301). At least one variant associated with multifactorial disease was found in 44.5% (134 of 301) (eg, 25 patients were heterozygous for the F5 factor V Leiden variant associated with thrombophilia risk). CONCLUSION: Our predictive screening revealed that 11.6% of individuals will test positive for a clinically actionable, likely pathogenic/pathogenic variant. This finding suggests that wider knowledge and adoption of predictive genomic services could be beneficial in medical practice, although additional studies are needed.


Assuntos
Testes Genéticos , Feminino , Aconselhamento Genético/métodos , Aconselhamento Genético/estatística & dados numéricos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/terapia , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
3.
Nat Rev Rheumatol ; 17(6): 363-374, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33850309

RESUMO

Historically, rheumatic diseases have not received much attention in Africa, particularly in sub-Saharan Africa, possibly owing to a focus on the overwhelming incidence of infectious diseases and the decreased life span of the general population in this region. Global attention and support, together with better health policies and planning, have improved outcomes for many infectious diseases; thus, increasing attention is being turned to chronic non-communicable diseases. Rheumatic diseases were previously considered to be rare among Africans but there is now a growing interest in these conditions, particularly as the number of rheumatologists on the continent increases. This interest has resulted in a growing number of publications from Africa on the more commonly encountered rheumatic diseases, as well as case reports of rare diseases. Despite the limited amount of available data, some aspects of the epidemiology, genetics and clinical and laboratory features of rheumatic diseases in African populations are known, as is some detail on the use of therapeutics. Similarities and differences in these conditions can be seen across the multi-ethnic and genetically diverse African continent, and it is hoped that increased awareness of rheumatic diseases in Africa will lead to earlier diagnosis and better outcomes for patients.


Assuntos
Predisposição Genética para Doença/epidemiologia , Publicações/estatística & dados numéricos , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/epidemiologia , Reumatologistas/estatística & dados numéricos , Adulto , África ao Sul do Saara/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Conscientização , Comorbidade , Gerenciamento Clínico , Meio Ambiente , Feminino , Predisposição Genética para Doença/etnologia , Política de Saúde , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Publicações/provisão & distribuição , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/genética , Fatores de Risco
4.
Front Immunol ; 12: 631298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33732252

RESUMO

Mendelian Susceptibility to Mycobacterial diseases (MSMD) are a group of innate immune defects with more than 17 genes and 32 clinical phenotypes identified. Defects in the IFN-γ mediated immunity lead to an increased susceptibility to intracellular pathogens like mycobacteria including attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains and non-tuberculous environmental mycobacteria (NTM), Salmonella, fungi, parasites like Leishmania and some viruses, in otherwise healthy individuals. Mutations in the IL12RB1 gene are the commonest genetic defects identified. This retrospective study reports the clinical, immunological, and molecular characteristics of a cohort of 55 MSMD patients from 10 centers across India. Mycobacterial infection was confirmed by GeneXpert, Histopathology, and acid fast bacilli staining. Immunological workup included lymphocyte subset analysis, Nitro blue tetrazolium (NBT) test, immunoglobulin levels, and flow-cytometric evaluation of the IFN-γ mediated immunity. Genetic analysis was done by next generation sequencing (NGS). Disseminated BCG-osis was the commonest presenting manifestation (82%) with a median age of presentation of 6 months due to the practice of BCG vaccination at birth. This was followed by infection with Salmonella and non-typhi Salmonella (13%), Cytomegalovirus (CMV) (11%), Candida (7%), NTM (4%), and Histoplasma (2%). Thirty-six percent of patients in cohort were infected by more than one organism. This study is the largest cohort of MSMD patients reported from India to the best of our knowledge and we highlight the importance of work up for IL-12/IL-23/ISG15/IFN-γ circuit in all patients with BCG-osis and suspected MSMD irrespective of age.


Assuntos
Predisposição Genética para Doença/genética , Imunidade Inata/genética , Mutação , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia , Adolescente , Adulto , Vacina BCG/imunologia , Criança , Pré-Escolar , Coinfecção/epidemiologia , Coinfecção/microbiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Humanos , Índia/epidemiologia , Lactente , Recém-Nascido , Masculino , Infecções por Mycobacterium/epidemiologia , Infecções por Mycobacterium/microbiologia , Fenótipo , Receptores de Interleucina-12/genética , Receptores de Interleucina-12/imunologia , Estudos Retrospectivos , Adulto Jovem
5.
Am J Epidemiol ; 190(6): 962-976, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33712835

RESUMO

Epidemiologic studies often rely on questionnaire data, exposure measurement tools, and/or biomarkers to identify risk factors and the underlying carcinogenic processes. An emerging and promising complementary approach to investigate cancer etiology is the study of somatic "mutational signatures" that endogenous and exogenous processes imprint on the cellular genome. These signatures can be identified from a complex web of somatic mutations thanks to advances in DNA sequencing technology and analytical algorithms. This approach is at the core of the Sherlock-Lung study (2018-ongoing), a retrospective case-only study of over 2,000 lung cancers in never-smokers (LCINS), using different patterns of mutations observed within LCINS tumors to trace back possible exposures or endogenous processes. Whole genome and transcriptome sequencing, genome-wide methylation, microbiome, and other analyses are integrated with data from histological and radiological imaging, lifestyle, demographic characteristics, environmental and occupational exposures, and medical records to classify LCINS into subtypes that could reveal distinct risk factors. To date, we have received samples and data from 1,370 LCINS cases from 17 study sites worldwide and whole-genome sequencing has been completed on 1,257 samples. Here, we present the Sherlock-Lung study design and analytical strategy, also illustrating some empirical challenges and the potential for this approach in future epidemiologic studies.


Assuntos
Análise Mutacional de DNA/métodos , Predisposição Genética para Doença/epidemiologia , Neoplasias Pulmonares/genética , Medição de Risco/métodos , Sequenciamento Completo do Genoma/métodos , Causalidade , Humanos , Estudos Retrospectivos , Fatores de Risco
6.
Lancet Neurol ; 20(5): 351-361, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33773637

RESUMO

BACKGROUND: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. METHODS: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. FINDINGS: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. INTERPRETATION: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-ß signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. FUNDING: British Heart Foundation.


Assuntos
Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla , Acidente Vascular Cerebral Lacunar/epidemiologia , Acidente Vascular Cerebral Lacunar/genética , Austrália , Europa (Continente) , Predisposição Genética para Doença/genética , Humanos , Imageamento por Ressonância Magnética , Acidente Vascular Cerebral Lacunar/diagnóstico , Estados Unidos
7.
Acta Diabetol ; 58(7): 911-917, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33721078

RESUMO

BACKGROUND: Individuals with type 1 diabetes have a markedly increased risk of stroke. In the general population, genetic predisposition has been linked to increased risk of stroke, but this has not been assessed in type 1 diabetes. Our aim was, therefore, to study how parental risk factors affect the risk of stroke in individuals with type 1 diabetes. METHODS: This study represents an observational follow-up of 4011 individuals from the Finnish Diabetic Nephropathy Study, mean age at baseline 37.6 ± 11.9 years. All strokes during follow-up were verified from medical records or death certificates. The strokes were classified as either ischemic or hemorrhagic. All individuals filled out questionnaires concerning their parents' medical history of hypertension, diabetes, stroke, and/or myocardial infarction. RESULTS: During a median follow-up of 12.4 (10.9-14.2) years, 188 individuals (4.6%) were diagnosed with their first ever stroke; 134 were ischemic and 54 hemorrhagic. In Cox regression analysis, a history of maternal stroke increased the risk of hemorrhagic stroke, hazard ratio 2.86 (95% confidence interval 1.27-6.44, p = 0.011) after adjustment for sex, age, BMI, retinal photocoagulation, and diabetic kidney disease. There was, however, no association between maternal stroke and ischemic stroke. No other associations between parental risk factors and ischemic or hemorrhagic stroke were observed. CONCLUSION: A history of maternal stroke increases the risk of hemorrhagic stroke in individuals with type 1 diabetes. Other parental risk factors seem to have limited impact on the risk of stroke.


Assuntos
Diabetes Mellitus Tipo 1 , Fatores de Risco de Doenças Cardíacas , Pais , Acidente Vascular Cerebral/etiologia , Adulto , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/genética , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Feminino , Finlândia/epidemiologia , Seguimentos , Predisposição Genética para Doença/epidemiologia , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/genética , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética
8.
Drug Alcohol Depend ; 221: 108556, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33561667

RESUMO

BACKGROUND: High alcohol consumption and alcohol dependence are only partly genetically correlated and they differ considerably in their correlations with other traits. The existence of genetic correlation among alcohol dependence and psychiatric disorders may be attributed to the presence of a general psychopathology factor, the p factor. This study investigates the relationship of polygenic risk to general psychopathology and to high alcohol consumption on alcohol dependence. METHODS: Participants were 524 alcohol-dependent patients and 729 controls. Polygenic risk scores (PRS) were computed for alcohol consumption (drinks per week) and nine psychiatric disorders. Principal component analysis (PCA) applied to the psychiatric PRS was used to calculate the first principal component as a proxy of the polygenic p factor. RESULTS: Both the polygenic p factor and the drinks per week PRS were associated with alcohol dependence in our sample. Both variables are only weakly correlated, contributing additively to the risk for alcohol dependence. Sensitivity analyses showed that the polygenic p factor was also associated with alcohol dependence in the subset of patients without any psychiatric or substance use comorbidity. CONCLUSIONS: Polygenic risk for alcohol dependence can be split at least into two components, involved in general psychopathology and high alcohol consumption. The first component of PCA based on PRS for different psychiatric disorders allows estimation of the contribution of the polygenic p factor to alcohol dependence. The pleiotropic effects of genetic variants across psychiatric disorders are mainly manifested as alcohol dependence in some patients.


Assuntos
Alcoolismo/epidemiologia , Predisposição Genética para Doença/epidemiologia , Adulto , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Alcoolismo/psicologia , Comorbidade , Etanol , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Fenótipo , Psicopatologia , Transtornos Relacionados ao Uso de Substâncias/genética
9.
Biomed Res Int ; 2021: 6629060, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33564677

RESUMO

Introduction: Human ABO blood type antigens exhibit alternative phenotypes and genetically derived glycoconjugate structures that are located on the red cell surface which play an active role in the cells' physiology and pathology. Associations between the blood type and disease have been studied since the early 1900s when researchers determined that antibodies and antigens are inherited. However, due to lack of antigens of some blood groups, there have been some contentious issues with the association between the ABO blood group and vulnerability to certain infectious and noninfectious diseases. Objective: To review different literatures that show the association between ABO blood groups and different diseases. Method: Original, adequate, and recent articles on the same field were researched, and the researcher conducted a comprehensive review on this topic. Thus, taking out critical discussions, not only a descriptive summary of the topic but also contradictory ideas were fully retrieved and presented in a clear impression. In addition, some relevant scientific papers published in previous years were included. The article search was performed by matching the terms blood types/groups with a group of terms related to different diseases. The articles were screened and selected based on the title and abstract presented. Results: The susceptibility to various diseases, such as cancer, cardiovascular diseases, infections and hematologic disorders, cognitive disorders, circulatory diseases, metabolic diseases, and malaria, has been linked with ABO blood groups. Moreover, blood group AB individuals were found to be susceptible to an increased risk of cognitive impairment which was independent of geographic region, age, race, and gender. Disorders such as hypertension, obesity, dyslipidemia, cardiovascular disease (CVD), and diabetes were also more prevalent in individuals with cognitive impairment. Early etiological studies indicated that blood type O has a connection with increased incidence of cholera, plague, tuberculosis infections, and mumps, whereas blood type A is linked with increased incidence of smallpox and Pseudomonas aeruginosa infection; blood type B is also associated with increased incidence of gonorrhea, tuberculosis, and Streptococcus pneumoniae, E. coli, and salmonella infections; and blood type AB is associated with increased incidence of smallpox and E. coli and salmonella infections. Diabetes mellitus, hypercholesterolemia, arterial hypertension, and family history for ischemic heart disease are the most common risk factors for cardiovascular diseases and can be genetically transmitted to offspring. Higher incidence of cancers in the stomach, ovaries, salivary glands, cervix, uterus, and colon/rectum was common in blood type A people than in O type people. The link between the ABO blood type and thromboembolic diseases and bleeding risk are intervened by the glycosyltransferase activity and plasma levels and biologic activity of vWF (Von Willebrand factor), a carrier protein for coagulation factor VIII which is low in O type. Conclusion: Several studies related to the ABO phenotype show that genetically determined human ABO blood groups were correspondingly linked with an increased risk of various infectious and noninfectious diseases. However, further investigations are needed particularly on the molecular level of ABO blood groups and their association with various diseases.


Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Infecções Bacterianas/sangue , Predisposição Genética para Doença/epidemiologia , Adolescente , Infecções Bacterianas/genética , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/epidemiologia , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Dislipidemias/sangue , Dislipidemias/epidemiologia , Feminino , Humanos , Hipertensão/sangue , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/epidemiologia , Fatores de Risco
10.
PLoS One ; 16(2): e0246462, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33544778

RESUMO

Genetic risk of substance abuse is encoded mainly by central neurochemical pathways(mostly dopaminergic system) related to reinforcement and reward. In this study a functionalpolymorphism in Catechol-O-methyltransferase (COMT) (Val158Met) and the Dopamine receptor D4 gene (DRD4) (120 bp tandem duplication) has been studied in substance abused subjects. The study was carried out with 183 substance abused subjects and 175 healthy persons with no history of substance abuse. DNA was extracted and polymorphisms were analyzed using allele-specific PCR. The impact of these two polymorphisms was also analyzed on addictive characteristics (age of starting abuse, a pattern of drug habit, and period of addiction). It was found that only the heterozygous variant of COMT polymorphism (Val/Met) (p<0.05, OR = 1.66, 95% CI = 1.044-2.658) and both homozygous (p<0.05, OR = 0.43, 95% CI = 0.193-0.937) and heterozygous (p<0.05, OR = 0.37, 95% CI = 0.172-0.826) derived variants of DRD4 120 bp tandem duplication were significantly associated with risk of substance abuse compared to controls. In case of association of these polymorphisms with an age of onset, no significant difference was found among three different genotypic groups of COMT polymorphism. Whereas, the homozygous derived variant (240 bp/240 bp) of DRD4 gene was found to have a later age of onset (20.5±0.8) for substance abuse compared to heterozygous (120 bp/240 bp) (19.1±0.8) and wild type homozygous variant (120 bp/120 bp) (16.0±0.5), which was statistically significant (p<0.05). Again, in the case of the pattern of drug habit, the frequency of the Val/Val genotype is higher in polysubstance abused (>2 drugs) subjects (p<0.05) compared to the heterozygous Val/Met containing variants. An association of period of addiction was analyzed with an individual type of substance abuse and found that heroin abused subjects have a significantly higher period of addiction (11.6±1.0) compared to other abusers (p<0.01). Further, it was found that Met/Met containing variants of COMT polymorphism has a more extended period of addiction than other genetic variants in heroin abused subjects. These results indicate that genetic variability may influence the susceptibility to the risk of substance abuse and addictive characteristics.


Assuntos
Catecol O-Metiltransferase/genética , Receptores de Dopamina D4/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Adolescente , Adulto , Bangladesh/epidemiologia , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco , Adulto Jovem
12.
Medicine (Baltimore) ; 100(6): e23305, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578508

RESUMO

BACKGROUND: Brain-derived neurotrophic factor (BDNF) rs6265 polymorphism has been previously suggested to be associated with the susceptibility of type 2 diabetes mellitus (T2DM), but results remained controversial. We aim to provide a more reliable conclusion about the association between BDNF rs6265 polymorphism and T2DM risk by using a meta-analysis. METHODS: Electronic databases such as Pubmed, Embase, CNKI, and Wanfang were searched for relevant articles published up to May 06, 2020. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the associations. Subgroup analysis was carried out according to source of controls and quality score of included studies. A trial sequential analysis was conducted to reduce the risk of type I error. RESULTS: A total of 8 case-control studies (7 conducted in China) with 1576 T2DM patients and 1866 controls were included. Overall, our results indicated no significant association between BDNF rs6265 polymorphism and T2DM risk with the random-effects model (allele model: pooled OR = 1.14, 95% CI = 0.79-1.65, homozygote model: pooled OR = 1.13, 95% CI = 0.57-2.21, heterozygote model: pooled OR = 1.07, 95% CI = 0.78-1.48, dominant model: pooled OR = 1.14, 95% CI = 0.74-1.75 and recessive model: pooled OR = 1.10, 95% CI = 0.67-1.80). Subgroup analysis by source of controls and quality score also showed no significant association between BDNF rs6265 polymorphism and T2DM risk. Trial sequential analysis results confirmed the null association and further studies were unnecessary. CONCLUSION: This meta-analysis study indicated that no significant association between BDNF rs6265 polymorphism and T2DM risk.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Alelos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estudos de Casos e Controles , China/epidemiologia , Ensaios Clínicos como Assunto , Dinamarca/epidemiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
13.
Nat Commun ; 12(1): 886, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563987

RESUMO

Large studies such as UK Biobank are increasingly used for GWAS and Mendelian randomization (MR) studies. However, selection into and dropout from studies may bias genetic and phenotypic associations. We examine genetic factors affecting participation in four optional components in up to 451,306 UK Biobank participants. We used GWAS to identify genetic variants associated with participation, MR to estimate effects of phenotypes on participation, and genetic correlations to compare participation bias across different studies. 32 variants were associated with participation in one of the optional components (P < 6 × 10-9), including loci with links to intelligence and Alzheimer's disease. Genetic correlations demonstrated that participation bias was common across studies. MR showed that longer educational duration, older menarche and taller stature increased participation, whilst higher levels of adiposity, dyslipidaemia, neuroticism, Alzheimer's and schizophrenia reduced participation. Our effect estimates can be used for sensitivity analysis to account for selective participation biases in genetic or non-genetic analyses.


Assuntos
Bancos de Espécimes Biológicos/estatística & dados numéricos , Participação da Comunidade/estatística & dados numéricos , Predisposição Genética para Doença/epidemiologia , Feminino , Loci Gênicos , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fatores de Risco , Viés de Seleção , Reino Unido/epidemiologia
14.
Medicine (Baltimore) ; 100(6): e24647, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578591

RESUMO

PURPOSE: Presently, whether interleukin-6 (IL-6) gene-174 G/C promoter polymorphism is correlated to the susceptibility of multiple myeloma (MM) remains controversial. For this reason, the method of meta-analysis was applied to exploring the association between IL-6 gene-174 G/C promoter polymorphism and MM. METHOD: Two independent researchers systematically searched PubMed, EMBASE, Google academic, Cochrane Library and Chinese literature databases to screen case-control studies on IL-6 gene-174 G/C promoter polymorphism and MM susceptibility. The retrieval period was limited from the formation of the database to January 2020, and data analysis was conducted by employing Stata 11.0 software. RESULT: Seven articles were ultimately included in the present study, including 594 MM patients and 681 controls. Integration analysis exhibited that compared with GC or CC genotype, GG genotype did not increase MM susceptibility (OR = 0.95, 95% CI 0.75-1.22; OR = 0.79, 95% CI 0.52-1.19, respectively). Further, in comparison with CC genotype, GC genotype also presented no effect on increasing MM susceptibility (OR = 0.79, 95% CI 0.53-1.16), while compared with GC+CC genotype, GG genotype had no significant relationship with MM susceptibility (OR = 0.94, 95% CI 0.75-1.19). In subsequent analysis, an observation was made that allele G or C was not related to MM susceptibility (OR = 0.92, 95% CI 0.76-1.12). Funnel chart and Begg test did not reveal publication bias in the included articles. CONCLUSION: The results of the present study advocate that there is no testimony to support the relationship between IL-6 gene-174 G/C promoter polymorphism and MM susceptibility.


Assuntos
Interleucina-6/genética , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Estudos de Casos e Controles , China/epidemiologia , Gerenciamento de Dados , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Fatores de Risco
15.
Respir Res ; 22(1): 23, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33472618

RESUMO

BACKGROUND: When infected with Mycobacterium tuberculosis, only a small proportion of the population will develop active TB, and the role of host genetic factors in different TB infection status was not fully understood. METHODS: Forty-three patients with active tuberculosis and 49 with latent tuberculosis were enrolled in the prospective cohort. Expressing levels of 27 candidate mRNAs, which were previously demonstrated to differentially expressed in latent and active TB, were measured by dual color reverse transcription multiplex ligation dependent probe amplification assay (dcRT-MLPA). Using expression levels of these mRNAs as quantitative traits, associations between expression abundance and genome-wild single nucleotide polymorphisms (SNPs) were calculated. Finally, identified candidate SNPs were further assessed for their associations with TB infection status in a validation cohort with 313 Chinese Han cases. RESULTS: We identified 9 differentially expressed mRNAs including il7r, il4, il8, tnfrsf1b, pgm5, ccl19, il2ra, marco and fpr1 in the prospective cohort. Through expression quantitative trait loci mapping, we screened out 8 SNPs associated with these mRNAs. Then, CG genotype of the SNP rs62292160 was finally verified to be significantly associated with higher transcription levels of IL4 in LTBI than in TB patients. CONCLUSION: We reported that the SNP rs62292160 in Chinese Han population may link to higher expression of il4 in latent tuberculosis. Our findings provided a new genetic variation locus for further exploration of the mechanisms of TB and a possible target for TB genetic susceptibility studies, which might aid the clinical decision to precision treatment of TB.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Locos de Características Quantitativas/genética , DNA Polimerase Dirigida por RNA/genética , Tuberculose/genética , Adulto , China/epidemiologia , Estudos de Coortes , Feminino , Expressão Gênica , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Tuberculose/diagnóstico , Tuberculose/epidemiologia
16.
J Endocrinol Invest ; 44(5): 951-956, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32936429

RESUMO

BACKGROUND: The recent emergence of COVID-19 poses a global health emergency. One of the most frequently reported data is sex-related severity and mortality: according to the last available analysis on 239,709 patients in Italy, lethality is 17.7% in men and 10.8% in women, with 59% of total deaths being men. Interestingly, the infection rate is lower in males than in females, with 45.8% and 54.2% of positive cases, respectively, suggesting that gender-related factor may worsen disease evolution. A tentative hypothesis to explain these findings is the role of angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 involved in viral infection. PURPOSE: In this review, we summarize the available evidence pointing to gender-related differences in ACE2 and TMPRSS2 expression, from both genetic and endocrine points of view. RESULTS: Altogether, available evidence points toward two not-mutually exclusive mechanisms in gender susceptibility to COVID-19 by sex hormonal regulation of ACE2 and TMPRSS2. On one hand, ACE2 expression could be increased in women, either by estrogens or constitutively by X chromosome inactivation escape or by reduced methylation, providing a larger reservoir of ACE2 to maintain the fundamental equilibrium of RAS regulatory axis. On the other, low levels of androgens in women may keep at low levels TMPRSS2 expression, representing a further protective factor for the development of COVID-19 infection, despite the increased expression of ACE2, which represents the Trojan horse for SARS-CoV-2 entry. CONCLUSIONS: Both mechanisms consistently point to the role of sex hormones and sex chromosomes in the differential severity and lethality of COVID-19 in men and women.


Assuntos
COVID-19/epidemiologia , COVID-19/genética , Cromossomos Humanos X/genética , Predisposição Genética para Doença/epidemiologia , Hormônios Esteroides Gonadais , Enzima de Conversão de Angiotensina 2/sangue , Enzima de Conversão de Angiotensina 2/genética , Feminino , Humanos , Masculino , Serina Endopeptidases/sangue , Serina Endopeptidases/genética , Caracteres Sexuais , Fatores Sexuais
17.
Clin Neurol Neurosurg ; 200: 106325, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33160714

RESUMO

OBJECTIVE: Dozens of reports on the associations of vitamin D receptor (VDR) gene polymorphisms and susceptibility to spinal degenerative disease (SDD) were conducted with inconsistent findings. This study aimed to elucidate the associations through a meta-analysis approach. METHODS: Databases of PubMed, EMBASE, Web of Science, CNKI, and Wanfang were searched until July 10, 2020. Study quality was evaluated by using Newcastle-Ottawa Scale (NOS). Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated to evaluate the associations under allelic model (1 vs. 2), homozygous model (11 vs. 22), heterozygous model (12 vs. 22), dominant model (11 + 12 vs. 22), and recessive model (11 vs. 12 + 22). RESULTS: A total of 5021 cases and 5746 controls from 35 studies were eligible to this meta-analysis. According to NOS, the included studies were in excellent quality. In the overall population, the pooled data indicated that ApaI was associated with a reduced SDD susceptibility (AA vs. Aa + aa, OR = 0.83, 95%CI 0.71 - 0.96, P = 0.010). But the association was not observed in FokI, TaqI, and BsmI polymorphisms. Subgroup analysis suggested that TaqI polymorphism was correlated to an elevated SDD risk in Asians (TT + Tt vs. tt, OR = 2.55, 95%CI 1.90 - 3.44, P < 0.001). CONCLUSION: The present study indicates that ApaI polymorphism may contribute to a reduced risk to SDD in the overall population, and TaqI polymorphism confers an elevated susceptibility to SDD in Asians. While, BsmI and FokI polymorphisms appear to have no significant association with SDD.


Assuntos
Predisposição Genética para Doença/genética , Degeneração do Disco Intervertebral/genética , Polimorfismo Genético/genética , Receptores de Calcitriol/genética , Estudos de Casos e Controles , Estudos de Coortes , Predisposição Genética para Doença/epidemiologia , Humanos , Degeneração do Disco Intervertebral/diagnóstico , Degeneração do Disco Intervertebral/epidemiologia
18.
Spine (Phila Pa 1976) ; 46(5): E288-E293, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33156271

RESUMO

STUDY DESIGN: A case-control study. OBJECTIVES: To investigate the association of urotensin II (UTS2) signals with the susceptibility of adolescent idiopathic scoliosis (AIS) in the Chinese Han population. SUMMARY OF BACKGROUND DATA: Dysregulated UTS2 signals induced by impaired cerebrospinal fluid flow have been implicated in the development of idiopathic scoliosis through studies on zebrafish. Furthermore, mutations in urotensin II receptor (UTS2R) were reported to cause severe scoliosis in zebrafish. In spite of the evidence presented in animal models, there is still a lack of knowledge concerning the role of UTS2 signaling related genes in AIS. METHODS: In the discovery stage, exons of UTS2, UTS2R, and UTS2D were sequenced for 200 AIS patients and 200 healthy controls. Newly identified mutations were further genotyped in another independent cohort of 1000 AIS patients and 1000 controls by allelic-specific multiple ligase detection reactions. Gene expression analysis was performed in 36 AIS patients and 36 age-matched congenital scoliosis patients. The Chi-square test was used to compare the genotyping data between the groups. Gene expression analysis was compared with the Student t test. RESULTS: Association between two novel mutations (rs11654140, c.51T > C; rs568196624, c.1146C > G) and the development of AIS was identified. Allele C of rs11654140 and allele G of rs568196624 were significantly associated with the risk of AIS (1.5% vs. 0.5%, odds ratio = 3.02, P = 0.01 for rs11654140; 1.41% vs. 0.58%, odds ratio = 2.29, P = 0.04 for rs568196624). The mRNA expression of UTS2R in the AIS group was significantly higher as compared with that in the control group (0.059 ±â€Š0.015 vs. 0.035 ±â€Š0.013, P < 0.01). CONCLUSIONS: Rare mutations in UTS2R were significantly associated with AIS. Expression of UTS2R was significantly increased in AIS patients. The role of UTS2 signaling in the development of AIS is worthy of further investigation.Level of Evidence: N/A.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Mutação/genética , Vigilância da População , Receptores Acoplados a Proteínas G/genética , Escoliose/epidemiologia , Escoliose/genética , Adolescente , Estudos de Casos e Controles , Criança , China/epidemiologia , Estudos de Coortes , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Vigilância da População/métodos , Escoliose/diagnóstico
20.
Neurology ; 96(4): e600-e609, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33208543

RESUMO

OBJECTIVE: To assess the burden of rare genetic variants and to estimate the contribution of known amyotrophic lateral sclerosis (ALS) genes in an Italian population-based cohort, we performed whole genome sequencing in 959 patients with ALS and 677 matched healthy controls. METHODS: We performed genome sequencing in a population-based cohort (Piemonte and Valle d'Aosta Registry for ALS [PARALS]). A panel of 40 ALS genes was analyzed to identify potential disease-causing genetic variants and to evaluate the gene-wide burden of rare variants among our population. RESULTS: A total of 959 patients with ALS were compared with 677 healthy controls from the same geographical area. Gene-wide association tests demonstrated a strong association with SOD1, whose rare variants are the second most common cause of disease after C9orf72 expansion. A lower signal was observed for TARDBP, proving that its effect on our cohort is driven by a few known causal variants. We detected rare variants in other known ALS genes that did not surpass statistical significance in gene-wise tests, thus highlighting that their contribution to disease risk in our cohort is limited. CONCLUSIONS: We identified potential disease-causing variants in 11.9% of our patients. We identified the genes most frequently involved in our cohort and confirmed the contribution of rare variants in disease risk. Our results provide further insight into the pathologic mechanism of the disease and demonstrate the importance of genome-wide sequencing as a diagnostic tool.


Assuntos
Esclerose Amiotrófica Lateral/epidemiologia , Esclerose Amiotrófica Lateral/genética , Análise Mutacional de DNA/métodos , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Vigilância da População , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/diagnóstico , Proteína C9orf72/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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