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1.
Am J Hypertens ; 32(12): 1146-1153, 2019 Nov 15.
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 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 BP ≥ 140 mm Hg and/or diastolic BP ≥ 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 = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) 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 single-nucleotide polymorphisms 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, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms 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.
Sci Rep ; 9(1): 11410, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388106

RESUMO

Lower extremity peripheral artery disease (PAD) burden differs by race/ethnicity. Although familial aggregation and heritability studies suggest a genetic basis, little is known about the genetic susceptibility to PAD, especially in non-European descent populations. Genome-wide association studies (GWAS) of the ankle brachial index (ABI) and PAD (defined as an ABI < 0.90) have not been conducted in Hispanics/Latinos. We performed a GWAS of PAD and the ABI in 7,589 participants aged >45 years from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We also performed GWAS for ABI stratified by Hispanic/Latino ethnic subgroups: Central American, Mexican, and South American (Mainland group), and Cuban, Dominican, and Puerto Rican (Caribbean group). We detected two genome-wide significant associations for the ABI in COMMD10 in Puerto Ricans, and at SYBU in the Caribbean group. The lead SNP rs4466200 in the COMMD10 gene had a replication p = 0.02 for the ABI in Multi-Ethnic Study of Atherosclerosis (MESA) African Americans, but it did not replicate in African Americans from the Cardiovascular Health Study (CHS). In a regional look-up, a nearby SNP rs12520838 had Bonferroni adjusted p = 0.05 (unadjusted p = 7.5 × 10-5) for PAD in MESA Hispanics. Among three suggestive associations (p < 10-7) in subgroup-specific analyses, DMD on chromosome X, identified in Central Americans, replicated in MESA Hispanics (p = 2.2 × 10-4). None of the previously reported ABI and PAD associations in whites generalized to Hispanics/Latinos.

4.
Hum Genet ; 138(2): 199-210, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30671673

RESUMO

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10-4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.


Assuntos
Pressão Sanguínea/genética , Cromossomos Humanos Par 16/genética , Exoma , Ligação Genética , Variação Genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Processamento Alternativo/genética , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fatores de Processamento de RNA/genética , Recombinases/genética
5.
Nat Commun ; 9(1): 5141, 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510157

RESUMO

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

6.
PLoS One ; 13(10): e0204352, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30289950

RESUMO

BACKGROUND: We previously reported association of SCARB1 SNP rs10846744 with common carotid IMT (cIMT) and cardiovascular disease (CVD) events. Since rs10846744 has been reported in association with Lp-PLA2 mass and activity, we hypothesized that inflammatory pathways might mediate the association of rs10846744 with atherosclerosis. METHODS: We first examined association of rs10846744 in CVD in multiple large-scale consortium-based genome-wide association studies. We further examined 27 parameters of interest, including Lp-PLA2 mass and activity, inflammatory markers, and plasma phospholipid fatty acids, and fatty acid ratios in participants from the Multi-Ethnic Study of Atherosclerosis (MESA), as potential mediators in the pathway linking rs10846744 with cIMT and incident CVD. Finally, we examined the association of rs10846744 with Lp-PLA2 activity, cardiovascular outcomes, and interaction with the Lp-PLA2 inhibitor, darapladib, in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) and Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) studies. RESULTS: SCARB1 rs10846744 was associated with coronary artery disease events in CARDIoGRAMplusC4D (odds ratio 1.05; 95% CI [1.02, 1.07]; P = 1.4x10-4). In combined analysis across race/ethnic groups in MESA, rs10846744 was associated with Lp-PLA2 mass (P = 0.04) and activity (P = 0.001), homocysteine (P = 0.03), LDL particle number (P = 0.01), docosahexaenoic acid [DHA] (P = 0.01), docosapentaenoic acid [DPA] (P = 0.04), DPA/ eicosapentaenoic acid [EPA] ratio (P = 0.002), and DHA/EPA ratio (P = 0.008). Lp-PLA2 activity was identified as a mediator of rs10846744 with cIMT in a basic model (P = 8x10-5), but not after adjustment for CVD risk factors. There was no interaction or modifier effect of the Lp-PLA2 inhibitor darapladib assignment on the relationship between rs10846744 and major CVD events in either STABILITY or SOLID-TIMI 52. SUMMARY: SCARB1 rs10846744 is significantly associated with Lp-PLA2 activity, atherosclerosis, and CVD events, but Lp-PLA2 activity is not a mediator in the association of rs10846744 with cIMT in MESA.

8.
Am J Hum Genet ; 101(6): 888-902, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29198723

RESUMO

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.


Assuntos
Pressão Sanguínea/genética , Metilação de DNA/genética , Proteínas do Tecido Nervoso/genética , Tetraspaninas/genética , Idoso , Ilhas de CpG/genética , Estudos Transversais , Epigênese Genética/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Locos de Características Quantitativas/genética
9.
PLoS One ; 12(12): e0189858, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29253899

RESUMO

In whites, the minor G allele of the atrial natriuretic peptide (ANP) genetic variant rs5068 is associated with higher circulating levels of ANP and B-type natriuretic peptide (BNP), lower risk of hypertension, higher high-density lipoprotein (HDL) cholesterol plasma levels, and lower prevalence of obesity and metabolic syndrome. The observed phenotype is consistent with the blood pressure lowering and metabolic properties of ANP and BNP. The cardiovascular and metabolic phenotype associated with rs5068 genotypes in African Americans is undefined. We genotyped 1631 African Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) for rs5068 and investigated their phenotype. Genotype frequencies of rs5068 were 93.2% AA (n = 1520), 6.7% AG (n = 110) and 0.1% GG (n = 1). All subsequent analyses are AG + GG versus AA genotype. Using a Bonferroni corrected level of significance of 0.005, the prevalence of metabolic syndrome (23% vs 38%, age-sex-adjusted p = 0.002) and triglycerides plasma values (76 vs 90 mg/dl, age-sex-BMI adjusted p = 0.004) were both significantly lower in the AG+GG genotypes. In the AG+GG genotypes, the prevalence of diabetes (8% vs 18%, age-sex-BMI-adjusted p = 0.02) and insulin plasma levels tended to be lower (4.8 vs 5.7 µU/ml, age-sex-BMI adjusted p = 0.04) whereas HDL-cholesterol levels tended to be higher (55 vs 50 mg/dl, age-sex-BMI-adjusted p = 0.04). No association was found with hypertension. The association between the rs5068 G allele and a favorable metabolic phenotype is now shown in African Americans. The rs5068 AG+GG genotypes are associated with lower prevalence of metabolic syndrome and lower triglycerides values.


Assuntos
Aterosclerose/etnologia , Aterosclerose/genética , Fator Natriurético Atrial/genética , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Afro-Americanos , Idoso , Idoso de 80 Anos ou mais , Alelos , Sistema Cardiovascular , HDL-Colesterol/sangue , Estudos de Coortes , Grupos Étnicos , Feminino , Genótipo , Geografia , Humanos , Insulina/sangue , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Obesidade/sangue , Obesidade/genética , Fenótipo , Prevalência , Triglicerídeos/sangue , Estados Unidos
10.
Circ Cardiovasc Genet ; 10(5)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29030403

RESUMO

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.


Assuntos
Pressão Sanguínea/genética , Loci Gênicos , Antiporters/genética , Moléculas de Adesão Celular Neuronais/genética , Bases de Dados Factuais , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Proteínas dos Microfilamentos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores de Retorno de Linfócitos/genética
11.
Genet Epidemiol ; 41(8): 801-810, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29076270

RESUMO

Over the past few years, an increasing number of studies have identified rare variants that contribute to trait heritability. Due to the extreme rarity of some individual variants, gene-based association tests have been proposed to aggregate the genetic variants within a gene, pathway, or specific genomic region as opposed to a one-at-a-time single variant analysis. In addition, in longitudinal studies, statistical power to detect disease susceptibility rare variants can be improved through jointly testing repeatedly measured outcomes, which better describes the temporal development of the trait of interest. However, usual sandwich/model-based inference for sequencing studies with longitudinal outcomes and rare variants can produce deflated/inflated type I error rate without further corrections. In this paper, we develop a group of tests for rare-variant association based on outcomes with repeated measures. We propose new perturbation methods such that the type I error rate of the new tests is not only robust to misspecification of within-subject correlation, but also significantly improved for variants with extreme rarity in a study with small or moderate sample size. Through extensive simulation studies, we illustrate that substantially higher power can be achieved by utilizing longitudinal outcomes and our proposed finite sample adjustment. We illustrate our methods using data from the Multi-Ethnic Study of Atherosclerosis for exploring association of repeated measures of blood pressure with rare and common variants based on exome sequencing data on 6,361 individuals.


Assuntos
Aterosclerose/genética , Modelos Genéticos , Aterosclerose/etnologia , Aterosclerose/patologia , Pressão Sanguínea/genética , Proteínas de Ligação a DNA/genética , Grupos Étnicos/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único
12.
Hypertension ; 70(4): 743-750, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28784648

RESUMO

Hypertension represents a major cardiovascular risk factor. The pathophysiology of increased blood pressure (BP) is not yet completely understood. Transcriptome profiling offers possibilities to uncover genetics effects on BP. Based on 2 populations including 2549 individuals, a meta-analyses of monocytic transcriptome-wide profiles were performed to identify transcripts associated with BP. Replication was performed in 2 independent studies of whole-blood transcriptome data including 1990 individuals. For identified candidate genes, a direct link between long-term changes in BP and gene expression over time and by treatment with BP-lowering therapy was assessed. The predictive value of protein levels encoded by candidate genes for subsequent cardiovascular disease was investigated. Eight transcripts (CRIP1, MYADM, TIPARP, TSC22D3, CEBPA, F12, LMNA, and TPPP3) were identified jointly accounting for up to 13% (95% confidence interval, 8.7-16.2) of BP variability. Changes in CRIP1, MYADM, TIPARP, LMNA, TSC22D3, CEBPA, and TPPP3 expression associated with BP changes-among these, CRIP1 gene expression was additionally correlated to measures of cardiac hypertrophy. Assessment of circulating CRIP1 (cystein-rich protein 1) levels as biomarkers showed a strong association with increased risk for incident stroke (hazard ratio, 1.06; 95% confidence interval, 1.03-1.09; P=5.0×10-5). Our comprehensive analysis of global gene expression highlights 8 novel transcripts significantly associated with BP, providing a link between gene expression and BP. Translational approaches further established evidence for the potential use of CRIP1 as emerging disease-related biomarker.


Assuntos
Proteínas de Transporte/genética , Hipertensão , Proteínas com Domínio LIM/genética , Acidente Vascular Cerebral , Adulto , Pressão Sanguínea/genética , Determinação da Pressão Arterial/métodos , Determinação da Pressão Arterial/estatística & dados numéricos , Proteínas Estimuladoras de Ligação a CCAAT/genética , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/diagnóstico , Hipertensão/genética , Masculino , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Poli(ADP-Ribose) Polimerases/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Fatores de Transcrição/genética
13.
PLoS Genet ; 13(5): e1006728, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28498854

RESUMO

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.


Assuntos
Pressão Sanguínea/genética , Loci Gênicos , Hipertensão/genética , Herança Multifatorial , Afro-Americanos/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Caderinas/genética , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/etnologia , Masculino , Proteínas de Membrana/genética , Camundongos , Polimorfismo de Nucleotídeo Único
14.
Circ Cardiovasc Genet ; 10(2): e001527, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28348047

RESUMO

BACKGROUND: Genome-wide single marker and gene-based meta-analyses of long-term average (LTA) blood pressure (BP) phenotypes may reveal novel findings for BP. METHODS AND RESULTS: We conducted genome-wide analysis among 18 422 East Asian participants (stage 1) followed by replication study of ≤46 629 participants of European ancestry (stage 2). Significant single-nucleotide polymorphisms and genes were determined by a P<5.0×10-8 and 2.5×10-6, respectively, in joint analyses of stage-1 and stage-2 data. We identified 1 novel ARL3 variant, rs4919669 at 10q24.32, influencing LTA systolic BP (stage-1 P=5.03×10-8, stage-2 P=8.64×10-3, joint P=2.63×10-8) and mean arterial pressure (stage-1 P=3.59×10-9, stage-2 P=2.35×10-2, joint P=2.64×10-8). Three previously reported BP loci (WBP1L, NT5C2, and ATP2B1) were also identified for all BP phenotypes. Gene-based analysis provided the first robust evidence for association of KCNJ11 with LTA systolic BP (stage-1 P=8.55×10-6, stage-2 P=1.62×10-5, joint P=3.28×10-9) and mean arterial pressure (stage-1 P=9.19×10-7, stage-2 P=9.69×10-5, joint P=2.15×10-9) phenotypes. Fourteen genes (TMEM180, ACTR1A, SUFU, ARL3, SFXN2, WBP1L, CYP17A1, C10orf32, C10orf32-ASMT, AS3MT, CNNM2, and NT5C2 at 10q24.32; ATP2B1 at 12q21.33; and NCR3LG1 at 11p15.1) implicated by previous genome-wide association study meta-analyses were also identified. Among the loci identified by the previous genome-wide association study meta-analysis of LTA BP, we transethnically replicated associations of the KCNK3 marker rs1275988 at 2p23.3 with LTA systolic BP and mean arterial pressure phenotypes (P=1.27×10-4 and 3.30×10-4, respectively). CONCLUSIONS: We identified 1 novel variant and 1 novel gene and present the first direct evidence of relevance of the KCNK3 locus for LTA BP among East Asians.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Pressão Sanguínea/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Fenótipo , Polimorfismo de Nucleotídeo Único , Extremo Oriente , Feminino , Humanos , Masculino
16.
Nat Genet ; 48(10): 1162-70, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27618448

RESUMO

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.


Assuntos
Pressão Sanguínea/genética , Variação Genética , Exoma , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hipertensão/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único
17.
Am Heart J ; 175: 112-20, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27179730

RESUMO

BACKGROUND: Multiple genetic loci are associated with clinical cardiovascular (CV) disease and individual CV risk factors. Individuals with ideal levels of all major CV risk factors have very low risk for CV disease morbidity or mortality. Ideal levels of risk factors can be attained by lifestyle modifications; however, little is known about gene variants associated with ideal CV health. Our objective was to carry out a genome-wide association study on the trait. METHODS AND RESULTS: We examined 2 dichotomous phenotypes of ideal CV health-clinical (untreated cholesterol <200 mg/dL, untreated blood pressure <120/<80, not diabetic) and clinical+behavioral (clinical plus: not a current smoker, body mass index <25 kg/m(2))-among white participants aged 50±5 years. We performed a meta-analysis of 4 genome-wide association studies (total n=11,708) from the MESA, CARDIA, ARIC, and Framingham Heart Study cohorts. We identified a single-nucleotide polymorphism (rs445925) in the APOC1/APOE region that was associated with clinical ideal CV health at genome-wide level of significance (P<2.0 × 10(-9)). The significance of this region was validated using exome chip genotyping. The association with ideal CV health was attenuated after adjusting for low-density lipoprotein cholesterol. CONCLUSION: A common single-nucleotide polymorphism in the APOC1/APOE region, previously found to be associated with protective levels of cholesterol and lower CV risk, may be associated with ideal health. In future replication studies, larger sample sizes may be needed to detect loci with more modest effects on ideal CV health. In addition to the important impact of lifestyle modifications, we have identified evidence for gene variation that plays a role in ideal CV health.


Assuntos
Apolipoproteína C-I/genética , Doenças Cardiovasculares/genética , Perfilação da Expressão Gênica/métodos , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Fatores de Proteção
18.
Genet Epidemiol ; 40(5): 404-15, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27230302

RESUMO

Studying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.


Assuntos
Pressão Sanguínea/genética , Interação Gene-Ambiente , Fumar , Estudos de Coortes , Bases de Dados Factuais , Família , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo
19.
Circ Cardiovasc Genet ; 9(1): 64-70, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26658788

RESUMO

BACKGROUND: Rare genetic variants influence blood pressure (BP). METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; ß=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (ß=-4.11; P=2.8×10(-4)), mean arterial pressure (ß=-3.50; P=8.9×10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; ß=-3.30; P=5.0×10(-7)). CONCLUSIONS: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.


Assuntos
Alelos , Pressão Sanguínea/genética , Canais de Cloreto/genética , Exoma , Frequência do Gene , Hipertensão/genética , Grupo com Ancestrais do Continente Africano , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Fatores de Risco
20.
Telemed J E Health ; 21(12): 980-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26114996

RESUMO

BACKGROUND: The Informatics for Diabetes Education and Telemedicine (IDEATel) project demonstrated that a telemedicine intervention can improve glycemic, lipid, and blood pressure control. The focus of the current study was to evaluate factors associated with primary care providers' (PCPs') decision on whether to follow recommendations from the remote diabetes team in Upstate New York. MATERIALS AND METHODS: In the intervention group, diabetes educators videoconferenced with patients monthly to download and review glucose and blood pressure readings, diabetes-related issues, and laboratory data. These were reviewed with an endocrinologist, and recommendations to change therapy were sent to the PCPs. At annual visits, participants completed the Diabetes Symptom Checklist-Type 2 symptom severity score and Impact of Telemedicine surveys. RESULTS: Factors that increase the acceptance rate of IDEATel recommendations included longer time in the study (p=0.0052), changing medication dose as opposed to starting or stopping a medication (p<0.0001), adjusting glucose-lowering agents compared with antihypertensive or antilipid medications (p<0.0001), higher total Diabetes Symptom Checklist-Type 2 symptom severity score (p=0.045), greater number of glucose readings submitted by participants (p=0.014), and high score on surveys measuring impact of telemedicine on patient's knowledge, adherence, and satisfaction (p=0.0023). CONCLUSIONS: Recommendations for change in glycemic control medications, delivered remotely by a diabetes team to PCPs, were better accepted over time. Results support the use of a team-based telemedicine program to help PCPs improve diabetes care.


Assuntos
Atitude do Pessoal de Saúde , Administração de Caso , Diabetes Mellitus Tipo 2/terapia , Atenção Primária à Saúde , Telemedicina , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New York
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