Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 84
Filtrar
1.
Am J Hum Genet ; 107(5): 849-863, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33031748

RESUMO

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%-54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10-10, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEVrange = 1%-22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology.

2.
Genome Med ; 12(1): 84, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32988399

RESUMO

BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. METHODS: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. RESULTS: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10- 8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10- 8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10- 12), as well as the TFAM knockout methylation (P = 4.41 × 10- 4) and expression (P = 4.30 × 10- 4) studies. CONCLUSIONS: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

3.
J Autism Dev Disord ; 2020 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-32892263

RESUMO

Using data from 266 age- and sex-matched pairs of Jamaican children with autism spectrum disorder (ASD) and typically developing (TD) controls (2-8 years), we investigated whether glutathione S-transferase theta 1 (GSTT1) modifies the association between blood manganese concentrations (BMC) and ASD. After adjusting conditional logistic regression models for socioeconomic status and the interaction between GSTT1 and GSTP1 (glutathione S-transferase pi 1), using a recessive genetic model for GSTT1 and either a co-dominant or dominant model for GSTP1, the interaction between GSTT1 and BMC was significant (P = 0.02, P = 0.01, respectively). Compared to controls, ASD cases with GSTT1-DD genotype had 4.33 and 4.34 times higher odds of BMC > 12 vs. ≤ 8.3 µg/L, respectively. Replication in other populations is warranted.

4.
Epigenomics ; 12(17): 1483-1499, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32901515

RESUMO

Aim: We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist-to-hip ratio and waist-to-height ratio adjusted for body mass index, in 2684 African-American adults in the Atherosclerosis Risk in Communities study. Materials & methods: We validated significantly associated cytosine-phosphate-guanine methylation sites (CpGs) among adults using the Women's Health Initiative and Framingham Heart Study participants (combined n = 5743) and generalized associations in adolescents from The Raine Study (n = 820). Results & conclusion: We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and two in adolescents, including CpG site associations near TXNIP, ADCY7, SREBF1 and RAP1GAP2 that had not previously been associated with obesity-related traits.

6.
Am J Clin Nutr ; 112(1): 57-65, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32469399

RESUMO

BACKGROUND: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies. OBJECTIVES: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort. METHODS: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 y who were free of diabetes and other major chronic diseases at baseline (2008-2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores. RESULTS: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR Q4 versus Q1 = 2.40; 95% CI: 1.24, 4.65; P-trend = 0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR Q4 versus Q1 = 3.15; 95% CI: 1.75, 5.67; P-trend <0.001) both were positively associated with risk of diabetes, whereas scores of glycosylceramides, lactosylceramides, or other unsaturated sphingomyelins (even if having an SFA base) were not associated with risk of diabetes. After additional adjustment for numerous traditional risk factors (especially triglycerides), both associations were attenuated and only the saturated-sphingomyelin score remained associated with risk of diabetes (RR Q4 versus Q1 = 1.98; 95% CI: 1.09, 3.59; P-trend = 0.031). CONCLUSIONS: Our findings suggest that a cluster of saturated sphingomyelins may be associated with elevated risk of diabetes beyond traditional risk factors, which needs to be verified in other population studies. This study was registered at clinicaltrials.gov as NCT02060344.


Assuntos
Diabetes Mellitus/sangue , Diabetes Mellitus/etnologia , Esfingolipídeos/sangue , Adolescente , Adulto , Idoso , Diabetes Mellitus/epidemiologia , Feminino , Hispano-Americanos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologia , Estados Unidos/etnologia , Adulto Jovem
7.
Hum Mol Genet ; 29(11): 1922-1932, 2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32436959

RESUMO

Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to BP. We constructed maps of putative cis-regulatory elements (CREs) using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative CREs within 50 Kb of the start or end of 'expressed' genes in these tissues or cell types using public expression data and use deltaSVM scores as weights in the group-wise sequence kernel association test to identify candidates. We test for association with both BP traits and expression within these tissues or cell types of interest and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study, as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.

8.
PLoS One ; 15(1): e0228166, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32004343

RESUMO

Mitochondrial DNA copy number (mtDNA-CN), a measure of the number of mitochondrial genomes per cell, is a minimally invasive proxy measure for mitochondrial function and has been associated with several aging-related diseases. Although quantitative real-time PCR (qPCR) is the current gold standard method for measuring mtDNA-CN, mtDNA-CN can also be measured from genotyping microarray probe intensities and DNA sequencing read counts. To conduct a comprehensive examination on the performance of these methods, we use known mtDNA-CN correlates (age, sex, white blood cell count, Duffy locus genotype, incident cardiovascular disease) to evaluate mtDNA-CN calculated from qPCR, two microarray platforms, as well as whole genome (WGS) and whole exome sequence (WES) data across 1,085 participants from the Atherosclerosis Risk in Communities (ARIC) study and 3,489 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). We observe mtDNA-CN derived from WGS data is significantly more associated with known correlates compared to all other methods (p < 0.001). Additionally, mtDNA-CN measured from WGS is on average more significantly associated with traits by 5.6 orders of magnitude and has effect size estimates 5.8 times more extreme than the current gold standard of qPCR. We further investigated the role of DNA extraction method on mtDNA-CN estimate reproducibility and found mtDNA-CN estimated from cell lysate is significantly less variable than traditional phenol-chloroform-isoamyl alcohol (p = 5.44x10-4) and silica-based column selection (p = 2.82x10-7). In conclusion, we recommend the field moves towards more accurate methods for mtDNA-CN, as well as re-analyze trait associations as more WGS data becomes available from larger initiatives such as TOPMed.


Assuntos
DNA Mitocondrial/genética , Dosagem de Genes , Genômica/métodos , Idoso , DNA Mitocondrial/isolamento & purificação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
J Am Soc Nephrol ; 31(1): 102-116, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31727850

RESUMO

BACKGROUND: GSTM1 encodes glutathione S-transferase µ-1 (GSTM1), which belongs to a superfamily of phase 2 antioxidant enzymes. The highly prevalent GSTM1 deletion variant is associated with kidney disease progression in human cohorts: the African American Study of Kidney Disease and Hypertension and the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: We generated a Gstm1 knockout mouse line to study its role in a CKD model (involving subtotal nephrectomy) and a hypertension model (induced by angiotensin II). We examined the effect of intake of cruciferous vegetables and GSTM1 genotypes on kidney disease in mice as well as in human ARIC study participants. We also examined the importance of superoxide in the mediating pathways and of hematopoietic GSTM1 on renal inflammation. RESULTS: Gstm1 knockout mice displayed increased oxidative stress, kidney injury, and inflammation in both models. The central mechanism for kidney injury is likely mediated by oxidative stress, because treatment with Tempol, an superoxide dismutase mimetic, rescued kidney injury in knockout mice without lowering BP. Bone marrow crosstransplantation revealed that Gstm1 deletion in the parenchyma, and not in bone marrow-derived cells, drives renal inflammation. Furthermore, supplementation with cruciferous broccoli powder rich in the precursor to antioxidant-activating sulforaphane significantly ameliorated kidney injury in Gstm1 knockout, but not wild-type mice. Similarly, among humans (ARIC study participants), high consumption of cruciferous vegetables was associated with fewer kidney failure events compared with low consumption, but this association was observed primarily in participants homozygous for the GSTM1 deletion variant. CONCLUSIONS: Our data support a role for the GSTM1 enzyme in the modulation of oxidative stress, inflammation, and protective metabolites in CKD.

10.
J Gerontol A Biol Sci Med Sci ; 75(3): 473-480, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-31630168

RESUMO

Methylation levels measured at defined sites across the genome have recently been shown to be correlated with an individual's chronological age. Age acceleration, or the difference between age estimated from DNA methylation status and chronological age, has been proposed as a novel biomarker of aging. In this study, the cross-sectional association between two different measures of age acceleration and cognitive function was investigated using whole blood samples from 2,157 African American participants 47-70 years of age in the population-based Atherosclerosis Risk in Communities (ARIC) Study. Cognition was evaluated using three domain-specific tests. A significant inverse association between a 1-year increase in age acceleration calculated using a blood-based age predictor and scores on the Word Fluency Test was found using a general linear model adjusted for chronological age, gender, and years of education (ß = -0.140 words; p = .001) and after adding other potential confounding variables (ß = -0.104 words, p = .023). The results were replicated in 1,670 European participants in the Generation Scotland: Scottish Family Health Study (fully adjusted model: ß = -0.199 words; p = .034). A significant association was also identified in a trans-ethnic meta-analysis across cohorts that included an additional 708 European American ARIC study participants (fully adjusted model: ß = -0.110 words, p = .003). There were no associations found using an estimate of age acceleration derived from multiple tissues. These findings provide evidence that age acceleration is a correlate of performance on a test of verbal fluency in middle-aged adults.

11.
J Autism Dev Disord ; 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31538260

RESUMO

Mode of delivery, preterm birth, and low birth weight (LBW) are hypothesized to be associated with autism spectrum disorder (ASD) in the offspring. Using data from 343 ASD cases (2-8 years) and their age- and sex-matched typically developing controls in Jamaica we investigated these hypotheses. Our statistical analyses revealed that the parish of residence could modify the association between cesarean delivery and ASD, with a difference found in this relationship in Kingston parish [matched odds ratio (MOR) (95% confidence interval (CI)) 2.30 (1.17-4.53)] and other parishes [MOR (95% CI) 0.87 (0.48-1.59)]. Although the associations of LBW and preterm birth with ASD were not significant, we observed a significant interaction between LBW and the household socioeconomic status. These findings require replication.

12.
PLoS One ; 14(9): e0221957, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31532792

RESUMO

BACKGROUND: Hypertension (HTN) disproportionately affects African Americans (AAs), who respond better to thiazide diuretics than other antihypertensives. Variants of the APOL1 gene found in AAs are associated with a higher rate of kidney disease and play a complex role in cardiovascular disease. METHODS: AA subjects from four HTN trials (n = 961) (GERA1, GERA2, PEAR1, and PEAR2) were evaluated for blood pressure (BP) response based on APOL1 genotype after 4-9 weeks of monotherapy with thiazides, beta blockers, or candesartan. APOL1 G1 and G2 variants were determined by direct sequencing or imputation. RESULTS: Baseline systolic BP (SBP) and diastolic BP (DBP) levels did not differ based on APOL1 genotype. Subjects with 1-2 APOL1 risk alleles had a greater SBP response to candesartan (-12.2 +/- 1.2 vs -7.5 +/- 1.8 mmHg, p = 0.03; GERA2), and a greater decline in albuminuria with candesartan (-8.3 +/- 3.1 vs +3.7 +/- 4.3 mg/day, p = 0.02). APOL1 genotype did not associate with BP response to thiazides or beta blockers. GWAS was performed to determine associations with BP response to candesartan depending on APOL1 genotype. While no SNPs reached genome wide significance, SNP rs10113352, intronic in CSMD1, predicted greater office SBP response to candesartan (p = 3.7 x 10-7) in those with 1-2 risk alleles, while SNP rs286856, intronic in DPP6, predicted greater office SBP response (p = 3.2 x 10-7) in those with 0 risk alleles. CONCLUSIONS: Hypertensive AAs without overt kidney disease who carry 1 or more APOL1 risk variants have a greater BP and albuminuria reduction in response to candesartan therapy. BP response to thiazides or beta blockers did not differ by APOL1 genotype. Future studies confirming this initial finding in an independent cohort are required.


Assuntos
Afro-Americanos/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Apolipoproteína L1/genética , Benzimidazóis/uso terapêutico , Hipertensão/tratamento farmacológico , Tetrazóis/uso terapêutico , Adulto , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hipertensão/etnologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Resultado do Tratamento
13.
eNeurologicalSci ; 16: 100201, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31384675

RESUMO

Objective: The incidence and prevalence of cognitive decline and dementia are significantly higher among African Americans compared with non-Hispanic Whites. The aim of this study was to determine whether inheritance of the sickle cell trait (SCT) i.e. heterozygosity for the sickle cell mutation increases the risk of cognitive decline or dementia Among African Americans. Methods: We studied African American participants enrolled in the Atherosclerosis Risk in Communities study. SCT genotype at baseline and outcome data from cognitive assessments at visits 2, 4 and 5, and an MRI performed at visit 5 were analyzed for the association between SCT and risk of cognitive impairment and/or dementia. Results: There was no significant difference in risk factors profile between participants with SCT (N = 176) and those without SCT (N = 2532). SCT was not independently associated with a higher prevalence of global or domain-specific cognitive impairment at baseline or with more rapid cognitive decline. Participants with SCT had slightly lower incidence of dementia (HR = 0.63 [0.38, 1.05]). On the other hand, SCT seems to interact with the apolipoprotein E ε4 risk allele resulting in poor performance on digit symbol substitution test at baseline (z-score = -0.08, Pinteraction = 0.05) and over time (z-score = -0.12, Pinteraction = 0.04); and with diabetes mellitus leading to a moderately increased risk of dementia (HR = 2.06 [0.89, 4.78], Pinteraction = 0.01). Conclusions: SCT was not an independent risk factor for prevalence or incidence of cognitive decline or dementia, although it may interact with and modify other putative risk factors for cognitive decline and dementia.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31261817

RESUMO

Environmental exposure to lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) has been associated with neurodevelopmental disorders including autism spectrum disorder (ASD). We conducted a pilot study during May 2015-May 2107 to estimate blood concentrations of six metals (Pb, Hg, As, Cd, Mn, and Al) and identify their associated factors for children with ASD or suspected of having ASD in Romania. Sixty children, age 2-8 years, were administered versions of ADOS or ADI-R translated from English to Romanian. After assessment, 2-3 mL of blood was obtained and analyzed for the concentrations of the six metals. The mean age of children was 51.9 months and about 90% were male. More than half (65%) of the children were born in Bucharest. Over 90% of concentrations of As and Cd were below limits of detection. Geometric mean concentrations of Pb, Mn, Al, and Hg were 1.14 µg/dL, 10.84 µg/L, 14.44 µg/L, and 0.35 µg/L, respectively. Multivariable linear regression analysis revealed that children who were female, had less educated parents, exhibited pica, and ate cold breakfast (e.g., cereal), watermelon, and lamb had significantly higher concentrations of Pb compared to their respective referent categories (all p < 0.05 except for eating lamb, which was marginally significant, p = 0.053). Although this is the first study that provides data on concentrations of the six metals for Romanian children with ASD, the findings from this study could be useful for designing future epidemiologic studies for investigating the role of these six metals in ASD in Romanian children.


Assuntos
Transtorno do Espectro Autista/sangue , Metais Pesados/sangue , Alumínio/sangue , Arsênico/sangue , Cádmio/sangue , Criança , Pré-Escolar , Exposição Ambiental/análise , Feminino , Humanos , Chumbo/sangue , Limite de Detecção , Masculino , Manganês/sangue , Mercúrio/sangue , Projetos Piloto , Romênia
15.
Biom J ; 61(4): 934-954, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31058353

RESUMO

A weighted quantile sum (WQS) regression has been used to assess the associations between environmental exposures and health outcomes. However, the currently available WQS approach, which is based on additive effects, does not allow exploring for potential interactions of exposures with other covariates in relation to a health outcome. In addition, the current WQS cannot account for clustering, thus it may not be valid for analysis of clustered data. We propose a generalized WQS approach that can assess interactions by estimating stratum-specific weights of exposures in a mixture, while accounting for potential clustering effect of matched pairs of cases and controls as well as censored exposure data due to being below the limits of detection. The performance of the proposed method in identifying interactions is evaluated through simulations based on various scenarios of correlation structures among the exposures and with an outcome. We also assess how well the proposed method performs in the presence of the varying levels of censoring in exposures. Our findings from the simulation study show that the proposed method outperforms the traditional WQS, as indicated by higher power of detecting interactions. We also find no strong evidence that the proposed method falsely identifies interactions when there are no true interactive effects. We demonstrate application of the proposed method to real data from the Epidemiological Research on Autism Spectrum Disorder (ASD) in Jamaica (ERAJ) by examining interactions between exposure to manganese and glutathione S-transferase family gene, GSTP1 in relation to ASD.


Assuntos
Biometria/métodos , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Glutationa S-Transferase pi/genética , Humanos , Jamaica/epidemiologia , Manganês/farmacologia , Modelos Estatísticos , Análise de Regressão
16.
Proc Natl Acad Sci U S A ; 116(22): 10636-10645, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31068470

RESUMO

The rationale for genome-wide association study (GWAS) results is sequence variation in cis-regulatory elements (CREs) modulating a target gene's expression as the major cause of trait variation. To understand the complete molecular landscape of one of these GWAS loci, we performed in vitro reporter screens in cardiomyocyte cell lines for CREs overlapping nearly all common variants associated with any of five independent QT interval (QTi)-associated GWAS hits at the SCN5A-SCN10A locus. We identified 13 causal CRE variants using allelic reporter activity, cardiomyocyte nuclear extract-based binding assays, overlap with human cardiac tissue DNaseI hypersensitive regions, and predicted impact of sequence variants on DNaseI sensitivity. Our analyses identified at least one high-confidence causal CRE variant for each of the five sentinel hits that could collectively predict SCN5A cardiac gene expression and QTi association. Although all 13 variants could explain SCN5A gene expression, the highest statistical significance was obtained with seven variants (inclusive of the five above). Thus, multiple, causal, mutually associated CRE variants can underlie GWAS signals.


Assuntos
Regulação da Expressão Gênica/genética , Coração/fisiopatologia , Miocárdio/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Alelos , Animais , Linhagem Celular , Eletrocardiografia , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Miocárdio/química , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico/genética
17.
Hum Mol Genet ; 28(7): 1212-1224, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30624610

RESUMO

Interpretation of genetic association results is difficult because signals often lack biological context. To generate hypotheses of the functional genetic etiology of complex cardiometabolic traits, we estimated the genetically determined component of gene expression from common variants using PrediXcan (1) and determined genes with differential predicted expression by trait. PrediXcan imputes tissue-specific expression levels from genetic variation using variant-level effect on gene expression in transcriptome data. To explore the value of imputed genetically regulated gene expression (GReX) models across different ancestral populations, we evaluated imputed expression levels for predictive accuracy genome-wide in RNA sequence data in samples drawn from European-ancestry and African-ancestry populations and identified substantial predictive power using European-derived models in a non-European target population. We then tested the association of GReX on 15 cardiometabolic traits including blood lipid levels, body mass index, height, blood pressure, fasting glucose and insulin, RR interval, fibrinogen level, factor VII level and white blood cell and platelet counts in 15 755 individuals across three ancestry groups, resulting in 20 novel gene-phenotype associations reaching experiment-wide significance across ancestries. In addition, we identified 18 significant novel gene-phenotype associations in our ancestry-specific analyses. Top associations were assessed for additional support via query of S-PrediXcan (2) results derived from publicly available genome-wide association studies summary data. Collectively, these findings illustrate the utility of transcriptome-based imputation models for discovery of cardiometabolic effect genes in a diverse dataset.


Assuntos
Previsões/métodos , Metaboloma/genética , Metaboloma/fisiologia , Adulto , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Mapeamento Cromossômico/métodos , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética
18.
Hypertension ; 73(1): 68-74, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30571559

RESUMO

H63D has been identified as a novel locus associated with the development of hypertension. The quantitative risks for hypertension, cardiac remodeling, and adverse events are not well studied. We analyzed white participants from the ARIC study (Atherosclerosis Risk in Communities) with H63D genotyping (N=10 902). We related genotype status to prevalence of hypertension at each of 5 study visits and risk for adverse cardiovascular events. Among visit 5 participants (N=4507), we related genotype status to echocardiographic features. Frequencies of wild type (WT)/WT, H63D/WT, and H63D/H63D were 73%, 24.6%, and 2.4%. The average age at baseline was 54.9±5.7 years and 47% were men. Participants carrying the H63D variant had higher systolic blood pressure ( P=0.004), diastolic blood pressure (0.012), and more frequently had hypertension ( P<0.001). Compared with WT/WT, H63D/WT and H63D/H63D participants had a 2% to 4% and 4% to 7% absolute increase in hypertension risk at each visit, respectively. The population attributable risk of H63D for hypertension among individuals aged 45 to 64 was 3.2% (95% CI, 1.3-5.1%) and 1.3% (95% CI, 0.0-2.4%) among individuals >65 years. After 25 years of follow-up, there was no relationship between genotype status and any outcome ( P>0.05). H63D/WT and H63D/H63D genotypes were associated with small differences in cardiac remodeling. In conclusion, the HFE H63D variant confers an increased risk for hypertension per allele and, given its frequency, accounts for a significant number of cases of hypertension. However, there was no increased risk for adverse cardiovascular events or substantial left ventricular remodeling.


Assuntos
Doenças Cardiovasculares , Proteína da Hemocromatose/genética , Hipertensão , Remodelação Ventricular/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Ecocardiografia/estatística & dados numéricos , Feminino , Predisposição Genética para Doença , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Estados Unidos/epidemiologia
19.
Wellcome Open Res ; 3: 4, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30175238

RESUMO

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

20.
Medicine (Baltimore) ; 97(33): e11865, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30113482

RESUMO

Rare variants, in particular renal salt handling genes, contribute to monogenic forms of hypertension and hypotension syndromes with electrolyte abnormalities. A study by Ji et al (2008) demonstrated this effect for rare loss-of-function coding variants in SLC12A3 (NCCT), SLC12A1 (NKCC2), and KCNJ1 (ROMK) that led to reduction of ∼6 mm Hg for SBP and ∼3 mm Hg for DBP among carriers in 2492 European ancestry Framingham Heart Study (FHS) subjects. These findings support a potentially large role for these variants in interindividual variation in systolic and diastolic blood pressure (SBP, DBP) in the population. The present study focuses on replicating the analyses completed by Ji et al to identify effects of rare variants in the population-based Atherosclerosis Risk in Communities (ARIC) study.We attempted to replicate the findings by Ji et al by applying their criteria to identify putative loss-of-function variants with allele frequency <0.001 and complete conservation across a set of orthologs, to exome sequencing data from 7444 European ancestry participants of the ARIC study.Although we failed to replicate the previous findings when applying their methods to the ARIC study data, we observed a similar effect when we restricted analyses to the subset of variants they observed.These results simultaneously support the utility of exome sequencing data for studying extremely rare coding variants in hypertension and underscore the need for improved filtering methods for identifying functional variants in human sequences.


Assuntos
Hipertensão/genética , Hipotensão/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Membro 1 da Família 12 de Carreador de Soluto/genética , Grupo com Ancestrais do Continente Africano/genética , Pressão Sanguínea/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de Risco , Membro 3 da Família 12 de Carreador de Soluto/genética , Sequenciamento Completo do Exoma
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA