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1.
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
2.
Circulation ; 138(13): 1343-1355, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-29593015

RESUMO

BACKGROUND: Elevated levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for cardiovascular disease via its contribution to the development and progression of atherosclerotic lesions. Although the genetic basis of LDL-C has been studied extensively, currently known genetic variants account for only ≈20% of the variation in LDL-C levels. METHODS: Through an array-based association analysis in 1102 Amish subjects, we identified a variant strongly associated with LDL-C levels. Using a combination of genetic analyses, zebrafish models, and in vitro experiments, we sought to identify the causal gene driving this association. RESULTS: We identified a founder haplotype associated with a 15 mg/dL increase in LDL-C on chromosome 5. After recombination mapping, the associated region contained 8 candidate genes. Using a zebrafish model to evaluate the relevance of these genes to cholesterol metabolism, we found that expression of the transcribed pseudogene, APOOP1, increased LDL-C and vascular plaque formation. CONCLUSIONS: Based on these data, we propose that APOOP1 regulates levels of LDL-C in humans, thus identifying a novel mechanism of lipid homeostasis.

3.
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
4.
J Clin Epigenet ; 3(2)2017.
Artigo em Inglês | MEDLINE | ID: mdl-29376147

RESUMO

Introduction: Type 2 Diabetes (T2D) is a common chronic disease with substantial disease burden and economic impact. Lifestyle changes can significantly alter the course of the disease, if detected at an early stage. DNA methylation signature may serve as a biomarker for early detection of increased T2D risk. Design: DNA methylation profiling was performed using the Illumina Infinium Human Methylation 450K Bead chip array in 24 normoglycemic Old Order Amish (OOA) individuals who later developed Impaired Fasting Glucose (IFG) (cases), and 24 OOA individuals who remained normoglycemic after an average follow up of 10 years (controls). Cases and controls were matched on age, sex, BMI, baseline fasting glucose, and glucose level after 2 h from 75 g Oral Glucose Tolerance Test (OGTT). Results: Association analysis found no significant difference in either global methylation or individual probe methylation between cases and controls, however, the top 34 suggestive significant sites were located in genes with interesting biological links to T2D and glycemic traits. These genes include BTC that plays a role in pancreatic cell proliferation and insulin secretion, ITGA1 a known bone mineral density gene that was recently found to be associated also with T2D and glycemic traits, and may explain the link between T2D and BMD, and RPTOR and TSC2 both of which are part of insulin signaling pathway. Conclusions: These results may shed light on the initiation and development of hyperglycemia and T2D and help to identify high risk individuals for early intervention; however, further studies are required for validation.

5.
Diabetes ; 65(10): 3200-11, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27416945

RESUMO

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.


Assuntos
Quimiocinas CC/genética , Estudo de Associação Genômica Ampla/métodos , Resistência à Insulina/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Quimiocinas CC/fisiologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/fisiologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia
6.
Menopause ; 22(1): 108-13, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25026114

RESUMO

OBJECTIVE: An increase in the use of selective serotonin reuptake inhibitors (SSRIs) and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) to relieve menopausal hot flashes (HFs) has been observed recently. However, response to them has been heterogeneous. We hypothesized that this heterogeneity might be partially attributed to genetic variations in genes encoding the serotonin and/or norepinephrine transporters (SLC6A4 and SLC6A2). As a first step in testing the role of genetics in response to SSRIs/SNRIs, we examined the association between HFs and genetic variants within these two genes. METHODS: We tested 29 haplotype-tagging single nucleotide polymorphisms within SLC6A4 and SLC6A2 for their association with HFs separately for European-American (396 cases and 392 controls) and African-American (125 cases and 81 controls) premenopausal and perimenopausal women. RESULTS: We found that the minor allele of SLC6A4_rs11080121 was associated with protection against HFs (odds ratio, 0.75; 95% CI, 0.60-0.94) only in European-American women. Bioinformatics analyses indicated that rs11080121 is fully correlated with rs1042173 in the 3' untranslated region of SLC6A4. The minor allele of rs1042173 seems to disrupt a conserved binding site for hsa-miR-590-3p microRNA. CONCLUSIONS: Disruption of a microRNA binding site leads to higher expression of SLC6A4, higher expression of SLC6A4 leads to depletion of serotonin in synaptic clefts, and depletion of serotonin triggers the presynaptic autoreceptor feedback mechanism to produce more serotonin, which is protective against HFs. This is the first study to test the association between HFs in both European-American and African-American premenopausal and perimenopausal women and genetic variants in two neurotransmitter transporter genes, SLC6A2 and SLC6A4. This information can be used in tailoring the pharmaceutical use of SSRIs/SNRIs for HF relief.


Assuntos
Variação Genética , Fogachos/genética , Perimenopausa/fisiologia , Pré-Menopausa/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Afro-Americanos/genética , Alelos , Sítios de Ligação/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Haplótipos , Humanos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Polimorfismo de Nucleotídeo Único/genética
7.
J Lipid Res ; 55(11): 2242-53, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25201834

RESUMO

Hyperlipidemia and arterial cholesterol accumulation are primary causes of cardiovascular events. Monogenic forms of hyperlipidemia and recent genome-wide association studies indicate that genetics plays an important role. Zebrafish are a useful model for studying the genetic susceptibility to hyperlipidemia owing to conservation of many components of lipoprotein metabolism, including those related to LDL, ease of genetic manipulation, and in vivo observation of lipid transport and vascular calcification. We sought to develop a genetic model for lipid metabolism in zebrafish, capitalizing on one well-understood player in LDL cholesterol (LDL-c) transport, the LDL receptor (ldlr), and an established in vivo model of hypercholesterolemia. We report that morpholinos targeted against the gene encoding ldlr effectively suppressed its expression in embryos during the first 8 days of development. The ldlr morphants exhibited increased LDL-c levels that were exacerbated by feeding a high cholesterol diet. Increased LDL-c was ameliorated in morphants upon treatment with atorvastatin. Furthermore, we observed significant vascular and liver lipid accumulation, vascular leakage, and plaque oxidation in ldlr-deficient embryos. Finally, upon transcript analysis of several cholesterol-regulating genes, we observed changes similar to those seen in mammalian systems, suggesting that cholesterol regulation may be conserved in zebrafish. Taken together, these observations indicate conservation of ldlr function in zebrafish and demonstrate the utility of transient gene knockdown in embryos as a genetic model for hyperlipidemia.


Assuntos
Vasos Sanguíneos/metabolismo , LDL-Colesterol/metabolismo , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética , Peixe-Zebra , Animais , Atorvastatina , Sequência de Bases , Vasos Sanguíneos/efeitos dos fármacos , Modelos Animais de Doenças , Embrião não Mamífero , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Hepatomegalia/complicações , Ácidos Heptanoicos/farmacologia , Hipercolesterolemia/complicações , Fígado/efeitos dos fármacos , Fígado/metabolismo , Dados de Sequência Molecular , Morfolinos/genética , Oxirredução/efeitos dos fármacos , Pirróis/farmacologia , Veias/efeitos dos fármacos , Veias/metabolismo
8.
PLoS One ; 9(3): e92468, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24658007

RESUMO

Chronic kidney disease (CKD) can be a consequence of diabetes, hypertension, immunologic disorders, and other exposures, as well as genetic factors that are still largely unknown. Glomerular filtration rate (GFR), which is widely used to measure kidney function, has a heritability ranging from 25% to 75%, but only 1.5% of this heritability is explained by genetic loci that have been identified to date. In this study we tested for associations between GFR and 234 SNPs in 26 genes from pathways of blood pressure regulation in 3,025 rural Chinese participants of the "Genetic Epidemiology Network of Salt Sensitivity" (GenSalt) study. We estimated GFR (eGFR) using baseline serum creatinine measurements obtained prior to dietary intervention. We identified significant associations between eGFR and 12 SNPs in 6 genes (ACE, ADD1, AGT, GRK4, HSD11B1, and SCNN1G). The cumulative effect of the protective alleles was an increase in mean eGFR of 4 mL/min per 1.73 m2, while the cumulative effect of the risk alleles was a decrease in mean eGFR of 3 mL/min per 1.73 m2. In addition, we identified a significant interaction between SNPs in CYP11B1 and ADRB2. We have identified common variants in genes from pathways that regulate blood pressure and influence kidney function as measured by eGFR, providing new insights into the genetic determinants of kidney function. Complex genetic effects on kidney function likely involve interactions among genes as we observed for CYP11B1 and ADRB2.


Assuntos
Pressão Sanguínea/genética , Taxa de Filtração Glomerular/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Genes , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos beta 2/genética , Esteroide 11-beta-Hidroxilase/genética
9.
Nat Genet ; 45(11): 1345-52, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24097064

RESUMO

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.


Assuntos
HDL-Colesterol/genética , LDL-Colesterol/genética , Doença da Artéria Coronariana/sangue , Triglicerídeos/sangue , Triglicerídeos/genética , Transporte Biológico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Triglicerídeos/metabolismo
10.
Nat Genet ; 45(11): 1274-1283, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24097068

RESUMO

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.


Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Lipídeos/sangue , Lipídeos/genética , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Triglicerídeos/sangue , Triglicerídeos/genética
11.
Nat Genet ; 45(6): 621-31, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23583979

RESUMO

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.


Assuntos
Arritmias Cardíacas/genética , Frequência Cardíaca/genética , Animais , Arritmias Cardíacas/fisiopatologia , Frequência do Gene , Loci Gênicos , Estudo de Associação Genômica Ampla , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Redes e Vias Metabólicas , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
12.
Nat Genet ; 44(9): 991-1005, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22885924

RESUMO

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.


Assuntos
Glicemia/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Redes e Vias Metabólicas/genética , Locos de Características Quantitativas , Adulto , Animais , Glicemia/metabolismo , Jejum/sangue , Jejum/metabolismo , Feminino , Frequência do Gene , Humanos , Insulina/sangue , Masculino , Camundongos , Concentração Osmolar , Locos de Características Quantitativas/fisiologia
13.
Nat Genet ; 44(6): 659-69, 2012 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-22581228

RESUMO

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and ß-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.


Assuntos
Glicemia/metabolismo , Índice de Massa Corporal , Resistência à Insulina/genética , Insulina/metabolismo , Polimorfismo de Nucleotídeo Único , HDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Humanos
14.
Circ Cardiovasc Genet ; 5(1): 100-12, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22199011

RESUMO

BACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts. METHODS AND RESULTS: Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (ß=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026). CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.


Assuntos
Índice Tornozelo-Braço , Cromossomos Humanos Par 9 , Estudo de Associação Genômica Ampla , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Coortes , Inibidor de Quinase Dependente de Ciclina p15/genética , Feminino , Genótipo , Projeto HapMap , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fatores Sexuais
15.
J Clin Hypertens (Greenwich) ; 13(11): 795-800, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22051423

RESUMO

Although the beneficial effects of lowering salt intake in hypertensive patients are widely appreciated, the impact of promoting dietary salt restriction for blood pressure (BP) reduction at the population level remains controversial. The authors used 24-hour ambulatory BP monitoring to characterize the determinants of systolic BP (SBP) response to low-salt intake in a large, relatively healthy Amish population. Patients received a high- and low-sodium diet for 6 days each, separated by a 6- to 14-day washout period. Variance component analysis was used to assess the association of several variables with SBP response to low-salt diet. Mean SBP was 0.7 ± 5.8 mm Hg and 1.3 ± 6.1 mm Hg lower on the low-salt compared with the high-salt diet during daytime (P=.008) and nighttime (P<.0001), respectively. SBP response to a low-salt diet was significantly associated with increasing age and pre-intervention SBP, in both daytime and nighttime, while the association with female sex and SBP response to cold pressor test (CPT) was significant only during nighttime. Our results suggest that salt reduction may have greater BP-lowering effects on women, older individuals, individuals with higher SBP, and individuals with higher SBP response to CPT.


Assuntos
Monitorização Ambulatorial da Pressão Arterial , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Dieta Hipossódica , Cloreto de Sódio na Dieta/farmacologia , Adulto , Fatores Etários , Amish/etnologia , Ritmo Circadiano/fisiologia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pré-Hipertensão/etnologia , Pré-Hipertensão/fisiopatologia , Caracteres Sexuais
16.
Am J Hypertens ; 24(9): 1035-40, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21654856

RESUMO

BACKGROUND: Blood pressure (BP) homeostasis involves complex interactions among genetic and nongenetic factors, providing major challenges to dissection of the genetic components that influence BP and hypertension. In this study, we examine the effects of interaction of genetic variants with physical activity on BP in a relatively genetically homogenous cohort of rural Chinese villagers. METHODS: Generalized estimating equations analysis was used to test for associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with variants in 24 genes in BP pathways (196 single-nucleotide polymorphisms (SNPs)) among 3,142 Chinese participants divided according to physical activity (active vs. inactive groups). RESULTS: In the physically active group, two SNPs in NR3C2 were significantly associated with lower SBP, and a SNP in SCNN1B was significantly associated with lower SBP and DBP. In the physically inactive group, a SNP in APLNR was associated with lower SBP, a SNP in GNB3 (guanine nucleotide binding protein, ß polypeptide 3) was associated with higher SBP and DBP, and a SNP in BDKRB2 (bradykinin receptor B2) was associated with lower DBP. Cumulative effects in carriers of minor alleles of these SNPs showed reductions of SBP and DBP as large as 8 and 5 mm Hg, respectively, in the active individuals compared to inactive individuals carrying the same number of minor alleles. CONCLUSIONS: We found that physical activity modifies the effects of genetic variants on BP. However, our results also show that active individuals with specific genotypes always have lower BP than inactive individuals with the same genotypes, demonstrating the overall beneficial effects of physical activity on BP.


Assuntos
Pressão Sanguínea/genética , Canais Epiteliais de Sódio/genética , Hipertensão/genética , Atividade Motora/genética , Receptores de Mineralocorticoides/genética , Adolescente , Adulto , Idoso , Receptores de Apelina , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Coortes , Feminino , Proteínas Heterotriméricas de Ligação ao GTP/genética , Humanos , Masculino , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Polimorfismo de Nucleotídeo Único , Receptor B2 da Bradicinina/genética , Receptores Acoplados a Proteínas-G/genética , População Rural
17.
Arterioscler Thromb Vasc Biol ; 31(7): 1661-7, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21474826

RESUMO

OBJECTIVE: We investigated the influence of genetic variants (rare and common) in the gene encoding periostin (POSTN) on atherosclerosis as measured in arterial specimens from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. METHODS AND RESULTS: A comprehensive survey of common POSTN variants (87 single-nucleotide polymorphisms [SNPs]) in PDAY subjects (n = 2527) identified numerous SNPs associated with raised lesions in abdominal aorta and with fatty streaks in thoracic aorta. These SNPs belonged to a small number of correlation bins that spanned the entire locus. To examine effects of rare variants, we resequenced POSTN functional regions in PDAY cases with raised lesions (n = 291) and controls with no raised lesions (n = 294). However, we found no significant associations with case-control status for carriers of POSTN rare variants using the weighted-sum method for rare variant analysis. CONCLUSIONS: We identified common variants in POSTN that are associated with arterial lesions in young persons from the PDAY study. This finding strongly supports a role for periostin in atherogenesis, as suggested by recent proteomics analysis that found abundant expression of periostin in atherosclerotic lesions. Genetic variation may influence atherosclerosis via periostin's known involvement in multiple relevant pathways, including angiogenesis, vascular remodeling, and stimulation of migration and differentiation of vascular smooth muscle cells.


Assuntos
Doenças da Aorta/genética , Aterosclerose/genética , Moléculas de Adesão Celular/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idade de Início , Aorta Abdominal/patologia , Aorta Torácica/patologia , Doenças da Aorta/epidemiologia , Doenças da Aorta/patologia , Aterosclerose/epidemiologia , Aterosclerose/patologia , Autopsia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Modelos Lineares , Masculino , Fenótipo , Medição de Risco , Fatores de Risco , Estados Unidos , Adulto Jovem
18.
J Hypertens ; 28(4): 748-55, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19996987

RESUMO

OBJECTIVE: Although beneficial effects of potassium intake on blood pressure (BP) are well established, little is known about genetic factors that underlie interindividual variability in BP response to dietary potassium. In a previous study, we reported the first evidence for significant heritabilities for BP response in a dietary intervention study in rural Chinese. In this report, we extend our genetic studies to examine associations with polymorphisms in genes in vascular endothelial pathways. METHODS: We genotyped study participants for 23 single nucleotide polymorphisms (SNPs) in endothelin 1 (EDN1), nitric oxide synthase 3, and E selectin (SELE). We tested 17 of these SNPs for associations with BP response to potassium supplementation in 1843 participants. Association tests used population-based [generalized estimation equation (GEE)] and family-based (quantitative transmission disequilibrium test) methods, as well as tests for gene-by-gene (GxG) interaction (generalized multifactor dimensionalilty reduction and GEE). RESULTS: Single SNP analysis identified significant associations for several SNPs in EDN1 with multiple measures of BP response to potassium supplementation. The cumulative effects of the minor EDN1 alleles that showed significant associations were to reduce measures of BP response by 0.5-0.9 mmHg. We found significant evidence for effects of GxG interactions between EDN1 and SELE, even in the absence of individual associations with SELE variants. CONCLUSION: Our results implicate variability in EDN1 and SELE as genetic factors that influence BP response to potassium intake. Although such epidemiological studies do not allow direct determination of physiologic mechanisms, our findings of joint effects identify EDN1 and SELE as targets for functional studies to determine their interactions in BP response to potassium intake.


Assuntos
Pressão Sanguínea/genética , Endotelina-1/genética , Variação Genética , Potássio na Dieta/farmacologia , População Rural/estatística & dados numéricos , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático , Pressão Sanguínea/fisiologia , China , Selectina E/genética , Estudos Epidemiológicos , Feminino , Genótipo , Humanos , Masculino , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único , Potássio na Dieta/administração & dosagem
19.
J Hypertens ; 27(3): 491-501, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19330903

RESUMO

OBJECTIVE: Our objective was to investigate the influence of gene by smoking (GxS) interaction on hypertension and blood pressure (BP) using genome-wide linkage analysis in Mexican-Americans, followed by single nucleotide polymorphism (SNP) fine mapping of candidate genes in the linked chromosomal region. METHODS: We used nonparametric methods to test for linkage of microsatellites with hypertension and BP measures in smokers, nonsmokers, and the combined group. To begin fine mapping of a major quantitative trait locus (QTL) for systolic blood pressure (SBP) on chromosome 15q that showed strong evidence for GxS interaction, we genotyped 55 SNPs in nine candidate genes for association studies using two population-based statistical methods. RESULTS: The strongest evidence for GxS interaction (P = 0.0004) was found for SBP on chromosome 15q, where a major QTL (LOD = 3.36) was identified only in nonsmokers. Follow-up studies identified three SNPs in three genes (ANPEP, IGF1R, and SLCO3A1) that showed associations with SBP only in nonsmokers, cumulatively accounting for a 7 mmHg increase in SBP. However, conditional linkage analyses that accounted for phenotypic effects of these SNPs only slightly reduced the original LOD score. CONCLUSION: The detection of a major QTL on chromosome 15q for SBP in nonsmokers indicates the presence of loci that influence BP via GxS interactions. However, identification of the genes that underlie such QTL effects remains a challenge. Although we found three candidate genes that showed significant associations with SBP in nonsmokers, further studies are required to identify the gene(s) that underlie the chromosome 15q QTL that influences SBP via GxS interactions.


Assuntos
Pressão Sanguínea/genética , Cromossomos Humanos Par 15/genética , Hipertensão/genética , Americanos Mexicanos/genética , Locos de Características Quantitativas , Fumar/genética , Idoso , Feminino , Ligação Genética , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Mapeamento Físico do Cromossomo , Polimorfismo de Nucleotídeo Único , Estatísticas não Paramétricas , Texas
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