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1.
Am J Hypertens ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31545351

RESUMO

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment resistant hypertension (aTRH) have been described. METHODS: We conducted a case-control genome-wide association study (GWAS) of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic (SBP)≥140 mm Hg and/or diastolic (DBP)≥90 mm Hg) or 4 or more medication classes regardless of BP control (nEA =931, nAA= 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14210, nAA= 2480) and had SBP/DBP <140/90 mm Hg. Treatment-responsive controls (nEA = 5266, nAA= 1817) had BP at goal (<140/90 mm Hg) while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site and principal components for ancestry to examine the association of SNPs with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL. RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P=1.1*10-8) and in the race-combined analysis (P=1.5*10-9) using the normotensive control group (rs12046278 OR=0.71[95% CI 0.6-0.8]). SNPs in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

2.
PLoS One ; 14(6): e0217796, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31251759

RESUMO

BACKGROUND: The electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored. METHODS: We performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis. RESULTS: We identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top SNP in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was with intronic SNP rs3922344 (P = 1.19x10-24) in SCN5A/SCN10A. Three other previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos. CONCLUSIONS: Our QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.

3.
Nature ; 570(7762): 514-518, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31217584

RESUMO

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.

4.
Diabetes Res Clin Pract ; 151: 96-105, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30954511

RESUMO

AIMS: To conduct a meta-analysis of statin-associated type 2 diabetes mellitus (T2D) risk among randomized controlled trials (RCTs) and observational studies (OBSs), excluding studies conducted among secondary prevention populations. METHODS: Studies were identified by searching PubMed (1994-present) and EMBASE (1994-present). Articles had to meet the following criteria: (1) follow-up >one year; (2) >50% of participants free of clinically diagnosed ASCVD; (3) adult participants ≥30 years old; (4) reported statin-associated T2D effect estimates; and (5) quantified precision using 95% confidence interval. Data were pooled using random-effects model. RESULTS: We identified 23 studies (35% RCTs) of n = 4,012,555 participants. OBS participants were on average younger (mean difference = 6.2 years) and had lower mean low-density lipoprotein cholesterol (LDL-C, mean difference = 20.6 mg/dL) and mean fasting plasma glucose (mean difference = 5.2 mg/dL) compared to RCT participants. There was little evidence for publication bias (P > 0.1). However, evidence of heterogeneity was observed overall and among OBSs and RCTs (PCochran = <0.05). OBS designs, younger baseline mean ages, lower LDL-C concentrations, and high proportions of never or former smokers were significantly associated with increased statin-associated T2D risk. CONCLUSIONS: Potentially elevated statin-associated T2D risk in younger populations with lower LDL-C merits further investigation in light of evolving statin guidelines targeting primary prevention populations.


Assuntos
Diabetes Mellitus Tipo 2/induzido quimicamente , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Adulto , Idoso , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Sleep ; 42(3)2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544165

RESUMO

Acculturation may shape the disproportionate burden of poor sleep among Latinos in the United States. Existing studies are limited by unidimensional acculturation proxies that are incapable of capturing cultural complexities across generations. Understanding how acculturation relates to sleep may lead to the identification of modifiable intervention targets. We used multivariable regression and latent class methods to examine cross-sectional associations between a validated multidimensional scale of US acculturation and self-reported poor sleep measures. We analyzed an intergenerational cohort: first-generation (GEN1) older Latinos (Sacramento Area Latino Study on Aging; N = 1,716; median age: 69.5) and second-generation (GEN2) middle-aged offspring and relatives of GEN1 (Niños Lifestyle and Diabetes Study; N = 670; median age: 54.0) in Sacramento, California. GEN1 with high US acculturation, compared with high acculturation towards another origin/ancestral country, had less restless sleep (prevalence ratio [PR] [95% confidence interval (CI)]: 0.67 [0.54, 0.84]) and a higher likelihood of being in the best sleep class than the worst (OR [95% CI]: 1.62 [1.09, 2.40]), but among nonmanual occupations, high intergenerational US acculturation was associated with more general fatigue (PR [95% CI: 1.86 [1.11, 3.10]). GEN2 with high intergenerational US acculturation reported shorter sleep (PR [95% CI]: 2.86 [1.02, 7.99]). High US acculturation shaped sleep differentially by generation, socioeconomic context, and intergenerational acculturative status. High US acculturation was associated with better sleep among older, lower socioeconomic Latinos, but with shorter sleep duration among middle-aged, higher socioeconomic Latinos; results also differed by parental acculturation status. Upon replication, future studies should incorporate prospective and intergenerational designs to uncover sociobehavioral pathways by which acculturation may shape sleep to ultimately inform intervention efforts.

6.
Am J Hematol ; 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29905378

RESUMO

Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p<1.7x10-4 ); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans-ethnic fine-mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p=1.9x10-7 ). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations. This article is protected by copyright. All rights reserved.

7.
Hum Mol Genet ; 27(16): 2940-2953, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29878111

RESUMO

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.

8.
J Clin Hypertens (Greenwich) ; 20(6): 1018-1026, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29797488

RESUMO

While much of the chronic kidney disease (CKD) literature focuses on the role of blood pressure reduction in delaying CKD progression, little is known about the benefits of modest population-wide decrements in blood pressure on incident CKD. The authors used multivariable linear regression to characterize the impact on incident CKD of two approaches for blood pressure management: (1) a 1-mm Hg reduction in systolic BP across the entire study population; and (2) a 10% reduction in participants with unaware, untreated, and uncontrolled BP above goal as defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) thresholds. Over a mean of 20 years of follow-up (ARIC [Atherosclerosis Risk in Communities] study, n = 15 390), 3852 incident CKD events were ascertained. After adjustment, a 1-mm Hg decrement in systolic BP across the population was associated with an estimated 11.7 (95% confidence interval [CI], 6.2-17.3) and 13.4 (95% CI, 10.3-16.6) fewer CKD events per 100 000 person-years in blacks and whites, respectively. Among participants with BP above JNC 7 goal, a 10% decrease in unaware, untreated, or uncontrolled BP was associated with 3.2 (95% CI, 2.0-4.9), 2.8 (95% CI, 1.8-4.3), and 5.8 (95% CI, 3.6-8.8) fewer CKD events per 100 000 person-years in blacks and 3.1 (95% CI, 2.3-4.1), 0.7 (95% CI, 0.5-0.9), and 1.0 (95% CI, 1.3-2.4) fewer CKD events per 100 000 person-years in whites. Modest population-wide reductions in systolic BP hold potential for the primary prevention of CKD.

9.
Circ Cardiovasc Qual Outcomes ; 11(4): e004171, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29650716

RESUMO

BACKGROUND: It is unclear whether testing for novel risk factors, such as a cardiovascular genetic risk score (cGRS), improves clinical decision making or health outcomes when used for targeting statin initiation in the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Our objective was to estimate the cost-effectiveness of cGRS testing to inform clinical decision making about statin initiation in individuals with low-to-intermediate (2.5%-7.5%) 10-year predicted risk of ASCVD. METHODS AND RESULTS: We evaluated the cost-effectiveness of testing for a 27-single-nucleotide polymorphism cGRS comparing 4 test/treat strategies: treat all, treat none, test/treat if cGRS is high, and test/treat if cGRS is intermediate or high. We tested a set of clinical scenarios of men and women, aged 45 to 65 years, with 10-year ASCVD risks between 2.5% and 7.5%. Our primary outcome measure was cost per quality-adjusted life-year gained. Under base case assumptions for statin disutility and cost, the preferred strategy is to treat all patients with ASCVD risk >2.5% without cGRS testing. For certain clinical scenarios, such as a 57-year-old man with a 10-year ASCVD risk of 7.5%, cGRS testing can be cost-effective under a limited set of assumptions; for example, when statins cost $15 per month and statin disutility is 0.013 (ie, willing to trade 3 months of life in perfect health to avoid 20 years of statin therapy), the preferred strategy (using a willingness-to-pay threshold of $50 000 per quality-adjusted life-year gained) is to test and treat if cGRS is intermediate or high. Overall, the results were not sensitive to assumptions about statin efficacy and harms. CONCLUSIONS: Testing for a 27-single-nucleotide polymorphism cGRS is generally not a cost-effective approach for targeting statin therapy in the primary prevention of ASCVD for low- to intermediate-risk patients.

10.
Sci Rep ; 8(1): 6238, 2018 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-29651142

RESUMO

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

11.
Sci Rep ; 8(1): 5675, 2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29618737

RESUMO

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10-8) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10-8) and multi-trait analysis (P = 2.9 × 10-9) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

12.
Sci Rep ; 8(1): 2782, 2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-29426885

RESUMO

To examine the ability of total cholesterol (TC), a low-density lipoprotein cholesterol (LDL-C) proxy widely used in public health initiatives, to capture important population-level shifts away from ideal and intermediate LDL-C throughout adulthood. We estimated age (≥20 years)-, race/ethnic (Caucasian, African American, and Hispanic/Latino)-, and sex- specific net transition probabilities between ideal, intermediate, and poor TC and LDL-C using National Health and Nutrition Examination Survey (2007-2014; N = 13,584) and Hispanic Community Health Study/Study of Latinos (2008-2011; N = 15,612) data in 2016 and validated and calibrated novel Markov-type models designed for cross-sectional data. At age 20, >80% of participants had ideal TC, whereas the race/ethnic- and sex-specific prevalence of ideal LDL-C ranged from 39.2%-59.6%. Net transition estimates suggested that the largest one-year net shifts away from ideal and intermediate LDL-C occurred approximately two decades earlier than peak net population shifts away from ideal and intermediate TC. Public health and clinical initiatives focused on monitoring TC in middle-adulthood may miss important shifts away from ideal and intermediate LDL-C, potentially increasing the duration, perhaps by decades, that large segments of the population are exposed to suboptimal LDL-C.

13.
BMC Cancer ; 18(1): 82, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29338703

RESUMO

BACKGROUND: Metastases play a role in about 90% of cancer deaths. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells might provide diagnostic information about the likelihood that cancer cells have detached from the primary tumor. Used together with established diagnostic tests of detachment-lymph node evaluation and radiologic imaging-EMT marker measurements might improve the ability of clinicians to assess the patient's risk of metastatic disease. Translation of EMT markers to clinical use has been hampered by a lack of valid analyses of clinically-informative parameters. Here, we demonstrate a rigorous approach to estimating the sensitivity, specificity, and prediction increment of an EMT marker to assess cancer cell detachment from primary tumors. METHODS: We illustrate the approach using immunohistochemical measurements of the EMT marker E-cadherin in a set of colorectal primary tumors from a population-based prospective cohort in North Carolina. Bayesian latent class analysis was used to estimate sensitivity and specificity in a setting of multiple imperfect diagnostic tests and no gold standard. Risk reclassification analysis was used to assess the extent to which addition of the marker to the panel of established diagnostic tests would improve mortality prediction. We explored how changing the latent class conditional dependence assumptions and definition of marker positivity would impact the results. RESULTS: All diagnostic accuracy and prediction increment statistics varied with the choice of cut point to define marker positivity. When comparing different definitions of marker positivity to each other, numerous trade-offs were observed in terms of sensitivity, specificity, predictive discrimination, and prediction model calibration. We then discussed several implementation considerations and the plausibility of analytic assumptions. CONCLUSIONS: The approaches presented here can be extended to any EMT marker, to most forms of cancer, and to different kinds of EMT marker measurements, such as RNA or gene methylation data. These methods provide valid, clinically-informative assessment of whether and how to use a given EMT marker to refine tumor staging and consequent treatment decisions.


Assuntos
Biomarcadores Tumorais/genética , Caderinas/genética , Neoplasias Colorretais/diagnóstico , Transição Epitelial-Mesenquimal/genética , Adulto , Idoso , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fatores de Risco
14.
Paediatr Perinat Epidemiol ; 32(1): 1-12, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28881463

RESUMO

BACKGROUND: Preeclampsia is thought to originate during placentation, with incomplete remodelling and perfusion of the spiral arteries leading to reduced placental vascular capacity. Nitric oxide (NO) and carbon monoxide (CO) are powerful vasodilators that play a role in the placental vascular system. Although family clustering of preeclampsia has been observed, the existing genetic literature is limited by a failure to consider both mother and child. METHODS: We conducted a nested case-control study within the Norwegian Mother and Child Birth Cohort of 1545 case-pairs and 995 control-pairs from 2540 validated dyads (2011 complete pairs, 529 missing mother or child genotype). We selected 1518 single-nucleotide polymorphisms (SNPs) with minor allele frequency >5% in NO and CO signalling pathways. We used log-linear Poisson regression models and likelihood ratio tests to assess maternal and child effects. RESULTS: One SNP met criteria for a false discovery rate Q-value <0.05. The child variant, rs12547243 in adenylate cyclase 8 (ADCY8), was associated with an increased risk (relative risk [RR] 1.42, 95% confidence interval [CI] 1.20, 1.69 for AG vs. GG, RR 2.14, 95% CI 1.47, 3.11 for AA vs. GG, Q = 0.03). The maternal variant, rs30593 in PDE1C was associated with a decreased risk for the subtype of preeclampsia accompanied by early delivery (RR 0.45, 95% CI 0.27, 0.75 for TC vs. CC; Q = 0.02). None of the associations were replicated after correction for multiple testing. CONCLUSIONS: This study uses a novel approach to disentangle maternal and child genotypic effects of NO and CO signalling genes on preeclampsia.


Assuntos
Monóxido de Carbono/metabolismo , Óxido Nítrico/metabolismo , Pré-Eclâmpsia/genética , Transdução de Sinais/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Genes/genética , Predisposição Genética para Doença/genética , Técnicas de Genotipagem , Humanos , Recém-Nascido , Noruega/epidemiologia , Distribuição de Poisson , Polimorfismo de Nucleotídeo Único/genética , Gravidez
15.
Heart ; 104(11): 904-911, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29127183

RESUMO

OBJECTIVE: PR interval (PR) is a heritable electrocardiographic measure of atrial and atrioventricular nodal conduction. Changes in PR duration may be associated with atrial fibrillation, heart failure and all-cause mortality. Hispanic/Latino populations have high burdens of cardiovascular morbidity and mortality, are highly admixed and represent exceptional opportunities for novel locus identification. However, they remain chronically understudied. We present the first genome-wide association study (GWAS) of PR in 14 756 participants of Hispanic/Latino ancestry from three studies. METHODS: Study-specific summary results of the association between 1000 Genomes Phase 1 imputed single-nucleotide polymorphisms (SNPs) and PR assumed an additive genetic model and were adjusted for global ancestry, study centre/region and clinical covariates. Results were combined using fixed-effects, inverse variance weighted meta-analysis. Sequential conditional analyses were used to identify independent signals. Replication of novel loci was performed in populations of Asian, African and European descent. ENCODE and RoadMap data were used to annotate results. RESULTS: We identified a novel genome-wide association (P<5×10-8) with PR at ID2 (rs6730558), which replicated in Asian and European populations (P<0.017). Additionally, we generalised 10 previously identified PR loci to Hispanics/Latinos. Bioinformatics annotation provided evidence for regulatory function in cardiac tissue. Further, for six loci that generalised, the Hispanic/Latino index SNP was genome-wide significant and identical to (or in high linkage disequilibrium with) the previously identified GWAS lead SNP. CONCLUSIONS: Our results suggest that genetic determinants of PR are consistent across race/ethnicity, but extending studies to admixed populations can identify novel associations, underscoring the importance of conducting genetic studies in diverse populations.

16.
Sci Rep ; 7(1): 17075, 2017 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-29213071

RESUMO

QT interval prolongation is a heritable risk factor for ventricular arrhythmias and can predispose to sudden death. Most genome-wide association studies (GWAS) of QT were performed in European ancestral populations, leaving other groups uncharacterized. Herein we present the first QT GWAS of Hispanic/Latinos using data on 15,997 participants from four studies. Study-specific summary results of the association between 1000 Genomes Project (1000G) imputed SNPs and electrocardiographically measured QT were combined using fixed-effects meta-analysis. We identified 41 genome-wide significant SNPs that mapped to 13 previously identified QT loci. Conditional analyses distinguished six secondary signals at NOS1AP (n = 2), ATP1B1 (n = 2), SCN5A (n = 1), and KCNQ1 (n = 1). Comparison of linkage disequilibrium patterns between the 13 lead SNPs and six secondary signals with previously reported index SNPs in 1000G super populations suggested that the SCN5A and KCNE1 lead SNPs were potentially novel and population-specific. Finally, of the 42 suggestively associated loci, AJAP1 was suggestively associated with QT in a prior East Asian GWAS; in contrast BVES and CAP2 murine knockouts caused cardiac conduction defects. Our results indicate that whereas the same loci influence QT across populations, population-specific variation exists, motivating future trans-ethnic and ancestrally diverse QT GWAS.

18.
Circ Cardiovasc Genet ; 10(4)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28794112

RESUMO

BACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies. METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction. CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.


Assuntos
Eletrocardiografia , Loci Gênicos , Estudo de Associação Genômica Ampla , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Caveolina 1/genética , Caveolina 2/genética , Genótipo , Átrios do Coração/metabolismo , Humanos , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Proteínas com Domínio T/genética
19.
Circ Cardiovasc Genet ; 10(4): e001632, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28768753

RESUMO

BACKGROUND: PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy. METHODS AND RESULTS: These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11-16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28-0.92) in blacks and 0.82 (95% CI, 0.63-1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80-1.41 in whites). CONCLUSIONS: PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Doença das Coronárias/genética , Grupo com Ancestrais do Continente Europeu/genética , Pró-Proteína Convertase 9/genética , Idoso , Idoso de 80 Anos ou mais , LDL-Colesterol/sangue , Estudos de Coortes , Doença das Coronárias/patologia , Doença das Coronárias/prevenção & controle , Feminino , Variação Genética , Genótipo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Fatores de Risco , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia
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