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1.
PLoS One ; 13(7): e0200486, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30044860

RESUMO

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.

2.
Hum Genet ; 136(11-12): 1497-1498, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28975356

RESUMO

The article "A multi-stage genome-wide association study of uterine fibroids in African Americans", written by Jacklyn N. Hellwege, was originally published Online First without open access. After publication in volume 136, issue 10, page 1363-1373 the author decided to opt for Open Choice and to make the article an open access publication. Therefore, the copyright of the article has been changed to

3.
Elife ; 62017 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-28895531

RESUMO

Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic BioMe biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, COL27A1, with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease.


Assuntos
Doenças do Colágeno/epidemiologia , Doenças do Colágeno/genética , Colágenos Fibrilares/genética , Epidemiologia Molecular , Linhagem , Adolescente , Adulto , Idoso , Criança , Feminino , Genótipo , Heterozigoto , Hispano-Americanos , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica , Doenças Musculoesqueléticas/epidemiologia , Doenças Musculoesqueléticas/genética , Cidade de Nova Iorque/epidemiologia , Cidade de Nova Iorque/etnologia , Sequenciamento Completo do Genoma , Adulto Jovem
4.
Hum Genet ; 136(10): 1363-1373, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28836065

RESUMO

Uterine fibroids are benign tumors of the uterus affecting up to 77% of women by menopause. They are the leading indication for hysterectomy, and account for $34 billion annually in the United States. Race/ethnicity and age are the strongest known risk factors. African American (AA) women have higher prevalence, earlier onset, and larger and more numerous fibroids than European American women. We conducted a multi-stage genome-wide association study (GWAS) of fibroid risk among AA women followed by in silico genetically predicted gene expression profiling of top hits. In Stage 1, cases and controls were confirmed by pelvic imaging, genotyped and imputed to 1000 Genomes. Stage 2 used self-reported fibroid and GWAS data from 23andMe, Inc. and the Black Women's Health Study. Associations with fibroid risk were modeled using logistic regression adjusted for principal components, followed by meta-analysis of results. We observed a significant association among 3399 AA cases and 4764 AA controls at rs739187 (risk-allele frequency = 0.27) in CYTH4 (OR (95% confidence interval) = 1.23 (1.16-1.30), p value = 7.82 × 10-9). Evaluation of the genetic association results with MetaXcan identified lower predicted gene expression of CYTH4 in thyroid tissue as significantly associated with fibroid risk (p value = 5.86 × 10-8). In this first multi-stage GWAS for fibroids among AA women, we identified a novel risk locus for fibroids within CYTH4 that impacts gene expression in thyroid and has potential biological relevance for fibroids.


Assuntos
Afro-Americanos/genética , Moléculas de Adesão Celular , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Fatores de Troca do Nucleotídeo Guanina , Leiomioma , Proteínas de Neoplasias , Neoplasias Uterinas , Adulto , Alelos , Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Fatores de Troca do Nucleotídeo Guanina/biossíntese , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Leiomioma/genética , Leiomioma/metabolismo , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Fatores de Risco , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo
5.
J Biomed Inform ; 67: 80-89, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28193464

RESUMO

OBJECTIVE: Design and implement a HIPAA and Integrating the Healthcare Enterprise (IHE) profile compliant automated pipeline, the integrated Genomics Anesthesia System (iGAS), linking genomic data from the Mount Sinai Health System (MSHS) BioMe biobank to electronic anesthesia records, including physiological data collected during the perioperative period. The resulting repository of multi-dimensional data can be used for precision medicine analysis of physiological readouts, acute medical conditions, and adverse events that can occur during surgery. MATERIALS AND METHODS: A structured pipeline was developed atop our existing anesthesia data warehouse using open-source tools. The pipeline is automated using scheduled tasks. The pipeline runs weekly, and finds and identifies all new and existing anesthetic records for BioMe participants. RESULTS: The pipeline went live in June 2015 with 49.2% (n=15,673) of BioMe participants linked to 40,947 anesthetics. The pipeline runs weekly in minimal time. After eighteen months, an additional 3671 participants were enrolled in BioMe and the number of matched anesthetic records grew 21% to 49,545. Overall percentage of BioMe patients with anesthetics remained similar at 51.1% (n=18,128). Seven patients opted out during this time. The median number of anesthetics per participant was 2 (range 1-144). Collectively, there were over 35 million physiologic data points and 480,000 medication administrations linked to genomic data. To date, two projects are using the pipeline at MSHS. CONCLUSION: Automated integration of biobank and anesthetic data sources is feasible and practical. This integration enables large-scale genomic analyses that might inform variable physiological response to anesthetic and surgical stress, and examine genetic factors underlying adverse outcomes during and after surgery.


Assuntos
Anestesia Geral/efeitos adversos , Registros Eletrônicos de Saúde , Genômica/tendências , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Coleta de Dados , Bases de Dados Factuais , Assistência à Saúde , Genoma , Humanos , Armazenamento e Recuperação da Informação
6.
Heart Rhythm ; 14(4): 572-580, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27988371

RESUMO

BACKGROUND: The electrocardiographically measured QT interval (QT) is heritable and its prolongation is an established risk factor for several cardiovascular diseases. Yet, most QT genetic studies have been performed in European ancestral populations, possibly reducing their global relevance. OBJECTIVE: To leverage diversity and improve biological insight, we fine mapped 16 of the 35 previously identified QT loci (46%) in populations of African American (n = 12,410) and Hispanic/Latino (n = 14,837) ancestry. METHODS: Racial/ethnic-specific multiple linear regression analyses adjusted for heart rate and clinical covariates were examined separately and in combination after inverse-variance weighted trans-ethnic meta-analysis. RESULTS: The 16 fine-mapped QT loci included on the Illumina Metabochip represented 21 independent signals, of which 16 (76%) were significantly (P-value≤9.1×10-5) associated with QT. Through sequential conditional analysis we also identified three trans-ethnic novel SNPs at ATP1B1, SCN5A-SCN10A, and KCNQ1 and three Hispanic/Latino-specific novel SNPs at NOS1AP and SCN5A-SCN10A (two novel SNPs) with evidence of associations with QT independent of previous identified GWAS lead SNPs. Linkage disequilibrium patterns helped to narrow the region likely to contain the functional variants at several loci, including NOS1AP, USP50-TRPM7, and PRKCA, although intervals surrounding SLC35F1-PLN and CNOT1 remained broad in size (>100 kb). Finally, bioinformatics-based functional characterization suggested a regulatory function in cardiac tissues for the majority of independent signals that generalized and the novel SNPs. CONCLUSION: Our findings suggest that a majority of identified SNPs implicate gene regulatory dysfunction in QT prolongation, that the same loci influence variation in QT across global populations, and that additional, novel, population-specific QT signals exist.


Assuntos
Afro-Americanos/genética , Sistema de Condução Cardíaco , Hispano-Americanos/genética , Síndrome do QT Longo , Eletrocardiografia/métodos , Estudo de Associação Genômica Ampla , Sistema de Condução Cardíaco/fisiologia , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Desequilíbrio de Ligação , Síndrome do QT Longo/etnologia , Síndrome do QT Longo/genética , Polimorfismo de Nucleotídeo Único , Análise de Sequência , Estados Unidos
7.
Curr Opin Lipidol ; 27(2): 99-104, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26844526

RESUMO

PURPOSE OF REVIEW: Rare variant association studies (RVAS) target the class of genetic variation with frequencies less than 1%. Recently, investigators have used exome sequencing in RVAS to identify rare alleles responsible for Mendelian diseases but have experienced greater difficulty discovering such alleles for complex diseases. In this review, we describe what we have learned about lipoprotein metabolism and coronary heart disease through the conduct of RVAS. RECENT FINDINGS: Rare protein-altering genetic variation can provide important insights that are not as easily attainable from common variant association studies. First, RVAS can facilitate gene discovery by identifying novel rare protein-altering variants in specific genes that are associated with disease. Second, rare variant associations can provide supportive evidence for putative drug targets for novel therapies. Finally, rare variants can uncover new pathways and reveal new biologic mechanisms. SUMMARY: The field of human genetics has already made tremendous progress in understanding lipoprotein metabolism and the causes of coronary heart disease in the context of rare variants. As next generation sequencing becomes more cost-effective, RVAS with larger sample sizes will be conducted. This will lead to more novel rare variant discoveries and the translation of genomic data into biological knowledge and clinical insights for cardiovascular disease.


Assuntos
Doença da Artéria Coronariana/genética , Lipoproteínas/metabolismo , Animais , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/metabolismo , Análise Mutacional de DNA , Descoberta de Drogas , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Lipoproteínas/genética , Terapia de Alvo Molecular , Mutação
8.
Pac Symp Biocomput ; : 219-30, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25592583

RESUMO

Elevated levels of plasma fibrinogen are associated with clot formation in the absence of inflammation or injury and is a biomarker for arterial clotting, the leading cause of cardiovascular disease. Fibrinogen levels are heritable with >50% attributed to genetic factors, however little is known about possible genetic modifiers that might explain the missing heritability. The fibrinogen gene cluster is comprised of three genes (FGA, FGB, and FGG) that make up the fibrinogen polypeptide essential for fibrinogen production in the blood. Given the known interaction with these genes, we tested 25 variants in the fibrinogen gene cluster for gene x gene and gene x environment interactions in 620 non-Hispanic blacks, 1,385 non-Hispanic whites, and 664 Mexican Americans from a cross-sectional dataset enriched with environmental data, the Third National Health and Nutrition Examination Survey (NHANES III). Using a multiplicative approach, we added cross product terms (gene x gene or gene x environment) to a linear regression model and declared significance at p < 0.05. We identified 19 unique gene x gene and 13 unique gene x environment interactions that impact fibrinogen levels in at least one population at p < 0.05. Over 90% of the gene x gene interactions identified include a variant in the rate-limiting gene, FGB that is essential for the formation of the fibrinogen polypeptide. We also detected gene x environment interactions with fibrinogen variants and sex, smoking, and body mass index. These findings highlight the potential for the discovery of genetic modifiers for complex phenotypes in multiple populations and give a better understanding of the interaction between genes and/or the environment for fibrinogen levels. The need for more powerful and robust methods to identify genetic modifiers is still warranted.


Assuntos
Fibrinogênio/genética , Fibrinogênio/metabolismo , Adulto , Idoso , Biologia Computacional , Estudos Transversais , Epistasia Genética , Grupos Étnicos/genética , Feminino , Interação Gene-Ambiente , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica , Inquéritos Nutricionais , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversos , Adulto Jovem
9.
Epidemiology ; 25(6): 790-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25166880

RESUMO

BACKGROUND: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations. METHODS: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test. RESULTS: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity. CONCLUSIONS: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.


Assuntos
Grupos de Populações Continentais/genética , Síndrome do QT Longo/etnologia , Síndrome do QT Longo/genética , Polimorfismo de Nucleotídeo Único , Idoso , Eletrocardiografia , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Locos de Características Quantitativas , Característica Quantitativa Herdável , Fatores de Risco
10.
PLoS One ; 9(3): e86931, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24595071

RESUMO

Type 2 diabetes (T2D) is a complex metabolic disease that disproportionately affects African Americans. Genome-wide association studies (GWAS) have identified several loci that contribute to T2D in European Americans, but few studies have been performed in admixed populations. We first performed a GWAS of 1,563 African Americans from the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project as part of the electronic Medical Records and Genomics (eMERGE) network. We successfully replicate an association in TCF7L2, previously identified by GWAS in this African American dataset. We were unable to identify novel associations at p<5.0×10(-8) by GWAS. Using admixture mapping as an alternative method for discovery, we performed a genome-wide admixture scan that suggests multiple candidate genes associated with T2D. One finding, TCIRG1, is a T-cell immune regulator expressed in the pancreas and liver that has not been previously implicated for T2D. We performed subsequent fine-mapping to further assess the association between TCIRG1 and T2D in >5,000 African Americans. We identified 13 independent associations between TCIRG1, CHKA, and ALDH3B1 genes on chromosome 11 and T2D. Our results suggest a novel region on chromosome 11 identified by admixture mapping is associated with T2D in African Americans.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 11 , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/etnologia , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único
11.
Artigo em Inglês | MEDLINE | ID: mdl-25590050

RESUMO

The NAv1.5 sodium channel α subunit is the predominant α-subunit expressed in the heart and is associated with cardiac arrhythmias. We tested five previously identified SCN5A variants (rs7374138, rs7637849, rs7637849, rs7629265, and rs11129796) for an association with PR interval and QRS duration in two unique study populations: the Third National Health and Nutrition Examination Survey (NHANES III, n= 552) accessed by the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) and a combined dataset (n= 455) from two biobanks linked to electronic medical records from Vanderbilt University (BioVU) and Northwestern University (NUgene) as part of the electronic Medical Records & Genomics (eMERGE) network. A meta-analysis including all three study populations (n~4,000) suggests that eight SCN5A associations were significant for both QRS duration and PR interval (p<5.0E-3) with little evidence for heterogeneity across the study populations. These results suggest that published SCN5A associations replicate across different study designs in a meta-analysis and represent an important first step in utility of multiple study designs for genetic studies and the identification/characterization of genetic variants associated with ECG traits in African-descent populations.

12.
Am Heart J ; 167(1): 101-108.e1, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24332148

RESUMO

BACKGROUND: Postoperative atrial fibrillation (PoAF) after cardiac surgery is common and associated with increased morbidity and mortality. Increased sympathetic activation after surgery contributes to PoAF, and ß-blockers are the first-line recommendation for its prevention. We examined the hypothesis that common functional genetic variants in the ß1-adrenoreceptor, the mediator of cardiac sympathetic activation and drug target of ß-blockers, are associated with the risk for PoAF and with the protective effect of ß-blockers. METHODS: In a prospective cohort study, we studied 947 adult European Americans who underwent cardiac surgery at Vanderbilt University between 1999 and 2005. We genotyped 2 variants in the ß1-adrenoreceptor, rs1801253 (Arg389Gly) and rs1801252 (Ser49Gly), and used logistic regression to examine the association between genotypes and PoAF occurring within 14 days after surgery, before and after adjustment for demographic and clinical covariates. RESULTS: Postoperative atrial fibrillation occurred in 239 patients (25.2%) and was associated with rs1801253 genotype (adjusted P = .008), with Gly389Gly having an odds ratio of 2.63 (95% CI 1.42-4.89) for PoAF compared to the common Arg389Arg (P = .002). In a predefined subgroup analysis, this association appeared to be stronger among patients without ß-blocker prophylaxis (adjusted odds ratio 7.00, 95% CI 1.82-26.96, P = .005) compared to patients with ß-blocker prophylaxis, among whom the association between rs1801253 genotype and PoAF was not statistically significant (adjusted P = .11). CONCLUSION: The Gly389 variant in the ß1-adrenoreceptor is associated with PoAF, and this association appears to be modulated by ß-blocker therapy. Future studies of the association of other adrenergic pathway genes with PoAF will be of interest.


Assuntos
Fibrilação Atrial/genética , Variação Genética , Complicações Pós-Operatórias/genética , Receptores Adrenérgicos beta 1/genética , Adulto , Idoso , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/cirurgia , Procedimentos Cirúrgicos Cardíacos , Grupo com Ancestrais do Continente Europeu/genética , Genótipo , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Fatores de Risco
13.
Ann Hum Genet ; 77(4): 321-32, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23534349

RESUMO

Electrocardiographic (ECG) measurements vary by ancestry. Genome-wide association studies (GWAS) have identified loci that contribute to ECG measurements; however, most are performed in Europeans collected from population-based cohorts or surveys. The strongest associations reported are in NOS1AP with QT interval and SCN10A with PR and QRS durations. The extent to which these associations can be generalized to African Americans has yet to be determined. Using electronic medical records, PR and QT intervals, QRS duration, and heart rate were determined in 455 African Americans as part of the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project. We tested for an association between these ECG traits and >930K SNPs. We identified a total 36 novel associations with PR interval, QRS duration, QT interval, and heart rate at p < 1.0 × 10(-6). Using published GWAS data, we compared our results with those previously identified in other populations. Five associations originally identified in other populations generalized with respect to statistical significance and direction of effect. A total of 43 associations have a consistent direction of effect with European and/or Asian populations. This work provides a catalogue of generalized versus nongeneralized associations, a necessary step in prioritizing GWAS-identified regions for further fine-mapping in diverse populations.


Assuntos
Afro-Americanos/genética , Eletrocardiografia , Variação Genética , Estudo de Associação Genômica Ampla , Característica Quantitativa Herdável , Adulto , Alelos , Mapeamento Cromossômico , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
14.
PLoS Genet ; 8(8): e1002870, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22912591

RESUMO

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.


Assuntos
Afro-Americanos , Grupo com Ancestrais do Continente Europeu , Locos de Características Quantitativas , Característica Quantitativa Herdável , Taquicardia/etnologia , Taquicardia/genética , Idoso , Biologia Computacional , Eletrocardiografia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Metagenômica , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Estados Unidos/epidemiologia
15.
PLoS One ; 7(2): e32338, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22384221

RESUMO

BACKGROUND: Despite a greater burden of risk factors, atrial fibrillation (AF) is less common among African Americans than European-descent populations. Genome-wide association studies (GWAS) for AF in European-descent populations have identified three predominant genomic regions associated with increased risk (1q21, 4q25, and 16q22). The contribution of these loci to AF risk in African American is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We studied 73 African Americans with AF from the Vanderbilt-Meharry AF registry and 71 African American controls, with no history of AF including after cardiac surgery. Tests of association were performed for 148 SNPs across the three regions associated with AF, and 22 SNPs were significantly associated with AF (P<0.05). The SNPs with the strongest associations in African Americans were both different from the index SNPs identified in European-descent populations and independent from the index European-descent population SNPs (r(2)<0.40 in HapMap CEU): 1q21 rs4845396 (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.13-0.67, P = 0.003), 4q25 rs4631108 (OR 3.43, 95% CI 1.59-7.42, P = 0.002), and 16q22 rs16971547 (OR 8.1, 95% CI 1.46-45.4, P = 0.016). Estimates of European ancestry were similar among cases (23.6%) and controls (23.8%). Accordingly, the probability of having two copies of the European derived chromosomes at each region did not differ between cases and controls. CONCLUSIONS/SIGNIFICANCE: Variable European admixture at known AF loci does not explain decreased AF susceptibility in African Americans. These data support the role of 1q21, 4q25, and 16q22 variants in AF risk for African Americans, although the index SNPs differ from those identified in European-descent populations.


Assuntos
Afro-Americanos/genética , Fibrilação Atrial/genética , Estudo de Associação Genômica Ampla , Grupo com Ancestrais do Continente Africano/genética , Fibrilação Atrial/etnologia , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Genótipo , Projeto HapMap , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Modelos Estatísticos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Risco
16.
Thromb Haemost ; 107(3): 458-67, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22273812

RESUMO

Previous genetic association studies of the fibrinogen gene cluster have identified associations with plasma fibrinogen levels. These studies are typically limited to plasma fibrinogen measured among European-descent populations. We sought to replicate previous well-known associations with fibrinogen variants and plasma fibrinogen. We then sought to identify and characterise novel associations with fibrinogen variants with plasma fibrinogen and several haematological traits in three racial/ethnic populations. We genotyped 25 single nucleotide polymorphisms (SNPs) in the fibrinogen gene cluster in 2,631 non-Hispanic whites, 2,108 non-Hispanic blacks, and 2,073 Mexican-Americans from the Third National Health and Nutrition Examination Survey (NHANES). We performed single SNP tests of association for plasma fibrinogen, mean platelet volume, platelet distribution width, platelet count, white blood cell count, and serum triglycerides. Five previously identified associations with plasma fibrinogen replicated in our study in non-Hispanic whites and blacks. We identified two novel associations between genetic variants and decreased plasma fibrinogen: rs2227395 (p=0.0007; non-Hispanic whites) and rs2070022 (p=0.001; Mexican-Americans). Several fibrinogen SNPs were also associated with haematological traits: rs6050 with decreased platelet distribution width in non-Hispanic whites; rs6050 and rs2066879 with decreased and increased platelet distribution width, respectively, in non-Hispanic whites;rs2227409 with increased mean platelet volume, rs2070017 with decreased platelet count, and rs6063 with increased platelet distribution width in non-Hispanic blacks; and rs4220 and rs2227395 with decreased white blood cell count, rs2227409 with increased platelet distribution width, rs2066860 and rs1800792 with increased and decreased triclyceride levels, respectively, and rs1800792 with decreased platelet counts in Mexican-Americans. We successfully replicated and identified novel associations with fibrinogen variants and plasma fibrinogen. These data confirm the importance of the fibrinogen gene cluster for plasma fibrinogen levels as well as suggest this gene cluster may have pleiotropic effects on haematological traits.


Assuntos
Plaquetas/patologia , Fibrinogênio/genética , Americanos Mexicanos , Característica Quantitativa Herdável , Triglicerídeos/biossíntese , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Europeu , Feminino , Estudos de Associação Genética , Variação Genética , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica/genética , Inquéritos Nutricionais , Triglicerídeos/sangue , Triglicerídeos/genética , Estados Unidos , Adulto Jovem
17.
J Am Med Inform Assoc ; 18(4): 387-91, 2011 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21672908

RESUMO

OBJECTIVE: DNA biobanks linked to comprehensive electronic health records systems are potentially powerful resources for pharmacogenetic studies. This study sought to develop natural-language-processing algorithms to extract drug-dose information from clinical text, and to assess the capabilities of such tools to automate the data-extraction process for pharmacogenetic studies. MATERIALS AND METHODS: A manually validated warfarin pharmacogenetic study identified a cohort of 1125 patients with a stable warfarin dose, in which 776 patients were managed by Coumadin Clinic physicians, and the remaining 349 patients were managed by their providers. The authors developed two algorithms to extract weekly warfarin doses from both data sets: a regular expression-based program for semistructured Coumadin Clinic notes; and an advanced weekly dose calculator based on an existing medication information extraction system (MedEx) for narrative providers' notes. The authors then conducted an association analysis between an automatically extracted stable weekly dose of warfarin and four genetic variants of VKORC1 and CYP2C9 genes. The performance of the weekly dose-extraction program was evaluated by comparing it with a gold standard containing manually curated weekly doses. Precision, recall, F-measure, and overall accuracy were reported. Associations between known variants in VKORC1 and CYP2C9 and warfarin stable weekly dose were performed with linear regression adjusted for age, gender, and body mass index. RESULTS: The authors' evaluation showed that the MedEx-based system could determine patients' warfarin weekly doses with 99.7% recall, 90.8% precision, and 93.8% accuracy. Using the automatically extracted weekly doses of warfarin, the authors successfully replicated the previous known associations between warfarin stable dose and genetic variants in VKORC1 and CYP2C9.


Assuntos
Anticoagulantes/administração & dosagem , Mineração de Dados/métodos , Bases de Dados de Ácidos Nucleicos , Cálculos da Dosagem de Medicamento , Registros Eletrônicos de Saúde , Processamento de Linguagem Natural , Varfarina/administração & dosagem , Algoritmos , Hidrocarboneto de Aril Hidroxilases/genética , Citocromo P-450 CYP2C9 , Estudo de Associação Genômica Ampla , Humanos , Modelos Lineares , Oxigenases de Função Mista/genética , Farmacogenética , Medicina de Precisão , Estados Unidos , Vitamina K Epóxido Redutases
18.
Circ Cardiovasc Genet ; 4(2): 139-44, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21325150

RESUMO

BACKGROUND: Understanding variation in the normal electric activity of the heart, assessed by the ECG, may provide a starting point for studies of susceptibility to serious arrhythmias such as sudden cardiac death during myocardial infarction or drug therapy. Recent genetic association studies of one ECG trait, the QT interval, have identified common variation in European-descent populations, but little is known about the genetic determinants of ECG traits in populations of African descent. METHODS AND RESULTS: To identify genetic risk factors, we have undertaken a candidate gene study of ECG traits in collaboration with the Jackson Heart Study, a longitudinal study of 5301 blacks ascertained from the Jackson, Mississippi, area. Nine quantitative ECG traits were evaluated: P, PR, QRS, QT, and QTc durations, heart rate, and P, QRS, and T axes. We genotyped 72 variations in the predominant sodium channel gene expressed in heart, SCN5A, encoding the Na(v)1.5 voltage-gated sodium channel in 4558 subjects. Both rare and common variants in this gene have previously been associated with inherited arrhythmia syndromes and variable conduction. Adjusting for age, sex, and European ancestry, we performed tests of association in 3054 unrelated participants and identified 14 significant associations (P<1.0×10(-4)), of which 13 are independent, based on linkage disequilibrium. These variants explain up to 2% of the variation in ECG traits in the Jackson Heart Study. CONCLUSIONS: These results suggest that SCN5A variation contributes to ECG trait distributions in blacks, and these same variations may be risk or protective factors associated with susceptibility to arrhythmias.


Assuntos
Eletrocardiografia , Canais de Sódio/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Feminino , Genótipo , Frequência Cardíaca/fisiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5 , Polimorfismo de Nucleotídeo Único , Fatores de Risco
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