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1.
J Am Heart Assoc ; 8(19): e014060, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31566055

RESUMO

See Article DuBose-Briski et al.

2.
Am J Hypertens ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31545351

RESUMO

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

3.
Mol Genet Genomic Med ; 7(10): e00788, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31407531

RESUMO

BACKGROUND: Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography. METHODS: We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)-by-drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community-based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE-Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta-analyses of main effects of drugs and 2.5 million SNP-by-drug interaction estimates. RESULTS: We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE-Is with consistent effects across cohorts (smallest p = 4.7 × 10-8 , minor allele frequency range 0.09-0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population. CONCLUSIONS: Our study identified one locus having genome-wide significant SNP-by-drug interaction effect on RWT among dCCB users in comparison to ACE-I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.

5.
Hypertension ; 74(3): 614-622, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31327267

RESUMO

Selection of antihypertensive treatment according to self-defined ethnicity is recommended by some guidelines but might be better guided by individual genotype rather than ethnicity or race. We compared the extent to which variation in blood pressure response across different ethnicities may be explained by genetic factors: genetically defined ancestry and gene variants at loci known to be associated with blood pressure. We analyzed data from 5 trials in which genotyping had been performed (n=4696) and in which treatment responses to ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, thiazide or thiazide-like diuretic and calcium channel blocker were available. Genetically defined ancestry for proportion of African ancestry was computed using the 1000 genomes population database as a reference. Differences in response to the thiazide diuretic hydrochlorothiazide, the ß-blockers atenolol and metoprolol, the angiotensin-converting enzyme inhibitor lisinopril, and the angiotensin receptor blocker candesartan were more closely associated to genetically defined ancestry than self-defined ethnicity in admixed subjects. A relatively small number of gene variants related to loci associated with drug-signaling pathways (KCNK3, SULT1C3, AMH, PDE3A, PLCE1, PRKAG2) with large effect size (-3.5 to +3.5 mm Hg difference in response per allele) and differing allele frequencies in black versus white individuals explained a large proportion of the difference in response to candesartan and hydrochlorothiazide between these groups. These findings suggest that a genomic precision medicine approach can be used to individualize antihypertensive treatment within and across populations without recourse to surrogates of genetic structure such as self-defined ethnicity.

6.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
7.
Am J Clin Nutr ; 110(2): 437-450, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31165884

RESUMO

BACKGROUND: Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans. OBJECTIVE: The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes. METHODS: A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes. RESULTS: The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs. CONCLUSIONS: We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.

12.
BMC Med Genomics ; 12(Suppl 1): 26, 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30704471

RESUMO

BACKGROUND: Cardiovascular disease, diabetes, and kidney disease are among the leading causes of death and disability worldwide. However, knowledge of genetic determinants of those diseases in African Americans remains limited. RESULTS: In our study, associations between 4956 GWAS catalog reported SNPs and 67 traits were examined among 7726 African Americans from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, which is focused on identifying factors that increase stroke risk. The prevalent and incident phenotypes studied included inflammation, kidney traits, cardiovascular traits and cognition. Our results validated 29 known associations, of which eight associations were reported for the first time in African Americans. CONCLUSION: Our cross-racial validation of GWAS findings provide additional evidence for the important roles of these loci in the disease process and may help identify genes especially important for future functional validation.

13.
Anal Chem ; 91(5): 3590-3596, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30758187

RESUMO

Large-scale untargeted lipidomics experiments involve the measurement of hundreds to thousands of samples. Such data sets are usually acquired on one instrument over days or weeks of analysis time. Such extensive data acquisition processes introduce a variety of systematic errors, including batch differences, longitudinal drifts, or even instrument-to-instrument variation. Technical data variance can obscure the true biological signal and hinder biological discoveries. To combat this issue, we present a novel normalization approach based on using quality control pool samples (QC). This method is called systematic error removal using random forest (SERRF) for eliminating the unwanted systematic variations in large sample sets. We compared SERRF with 15 other commonly used normalization methods using six lipidomics data sets from three large cohort studies (832, 1162, and 2696 samples). SERRF reduced the average technical errors for these data sets to 5% relative standard deviation. We conclude that SERRF outperforms other existing methods and can significantly reduce the unwanted systematic variation, revealing biological variance of interest.

14.
Sci Rep ; 9(1): 843, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696834

RESUMO

Five sequence variants in SLC16A11 (rs117767867, rs13342692, rs13342232, rs75418188, and rs75493593), which occur in two non-reference haplotypes, were recently shown to be associated with diabetes in Mexicans from the SIGMA consortium. We aimed to determine whether these previous findings would replicate in the HCHS/SOL Mexican origin group and whether genotypic effects were similar in other HCHS/SOL groups. We analyzed these five variants in 2492 diabetes cases and 5236 controls from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), which includes U.S. participants from six diverse background groups (Mainland groups: Mexican, Central American, and South American; and Caribbean groups: Puerto Rican, Cuban, and Dominican). We estimated the SNP-diabetes association in the six groups and in the combined sample. We found that the risk alleles occur in two non-reference haplotypes in HCHS/SOL, as in the SIGMA Mexicans. The haplotype frequencies were very similar between SIGMA Mexicans and the HCHS/SOL Mainland groups, but different in the Caribbean groups. The SLC16A11 sequence variants were significantly associated with risk for diabetes in the Mexican origin group (P = 0.025), replicating the SIGMA findings. However, these variants were not significantly associated with diabetes in a combined analysis of all groups, although the power to detect such effects was 85% (assuming homogeneity of effects among the groups). Additional analyses performed separately in each of the five non-Mexican origin groups were not significant. We also analyzed (1) exclusion of young controls and, (2) SNP by BMI interactions, but neither was significant in the HCHS/SOL data. The previously reported effects of SLC16A11 variants on diabetes in Mexican samples was replicated in a large Mexican-American sample, but these effects were not significant in five non-Mexican Hispanic/Latino groups sampled from U.S. populations. Lack of replication in the HCHS/SOL non-Mexicans, and in the entire HCHS/SOL sample combined may represent underlying genetic heterogeneity. These results indicate a need for future genetic research to consider heterogeneity of the Hispanic/Latino population in the assessment of disease risk, but add to the evidence suggesting SLC16A11 as a potential therapeutic target for type 2 diabetes.

15.
Int J Cardiol ; 274: 208-213, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30045819

RESUMO

BACKGROUND: Indices of cardiac mechanics are sensitive markers of subclinical myocardial dysfunction. Improved understanding of the clinical correlates and heritability of cardiac mechanics could result in novel insight into the acquired and genetic risk factors for myocardial dysfunction. Therefore, we sought to determine the clinical correlates and heritability of indices of cardiac mechanics in whites and African Americans (AAs). METHODS: We examined 2058 participants stratified by race (1104 whites, 954 AA) in the Hypertension Genetic Epidemiology Network (HyperGEN), a population- and family-based study, and performed digitization of analog echocardiograms with subsequent speckle-tracking analysis. We used linear mixed effects models to determine the clinical correlates of indices of cardiac mechanics (longitudinal, circumferential, radial strain; early diastolic strain rate; and early diastolic tissue velocities). Heritability estimates for cardiac mechanics were calculated using maximum-likelihood variance component analyses in Sequential Oligogenic Linkage Analysis Routine (SOLAR), with adjustment for clinical and echocardiographic covariates. RESULTS: Several clinical characteristics and conventional echocardiographic parameters were found to be associated with speckle-tracking traits of cardiac mechanics. Male sex, blood pressure, and fasting glucose were associated with worse longitudinal strain (LS) (P < 0.05 for all) after multivariable adjustment. After adjustment for covariates, LS, e' velocity, and early diastolic strain rate were found to be heritable; LS and e' velocity had higher heritability estimates in AAs compared to whites. CONCLUSIONS: Indices of cardiac mechanics are heritable traits even after adjustment for clinical and conventional echocardiographic correlates. These findings provide the basis for future studies of genetic determinants of these traits that may elucidate race-based differences in heart failure development.


Assuntos
Pressão Sanguínea/fisiologia , Ecocardiografia Doppler/métodos , Predisposição Genética para Doença , Ventrículos do Coração/fisiopatologia , Hipertensão/fisiopatologia , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Estudos Transversais , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hipertensão/epidemiologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Reprodutibilidade dos Testes , Processamento de Sinais Assistido por Computador , Estados Unidos/epidemiologia
16.
Am J Hypertens ; 32(4): 343-349, 2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30590387

RESUMO

BACKGROUND: Elevations of fasting glucose (FG) levels are frequently encountered in people treated with thiazide diuretics. The risk is lower in people treated with ACE inhibitors (ACEi). To determine if genetic factors play a role in FG elevation, we examined the interaction of a diabetes gene risk score (GRS) with the use of 3 different antihypertensive medications. METHODS: We examined 376 nondiabetic hypertensive individuals with baseline FG <100 mg/dl who were genotyped for 24 genes associated with risk of elevated glucose levels. All participants had ≥1 follow-up FG level over 6 years of follow-up. Participants were randomized to treatment with a thiazide-like diuretic (chlorthalidone), a calcium channel blocker (CCB; amlodipine), or an ACEi (lisinopril). Outcomes were an FG increase of ≥13 or ≥27 mg/dl, the upper 75% and 90% FG increase in the parent cohort from which the present cohort was obtained. Odds ratios were adjusted for factors that increase FG levels. RESULTS: For every 1 allele increase in GRS, the adjusted odds ratios (ORs) were 1.06 (95% confidence interval (CI): 0.99, 1.14; P = 0.06) and 1.09 (95% CI: 0.99, 1.20; P = 0.08). When results were examined by randomized medications, participants randomized to amlodipine had statistically significant odds for either outcome (OR: 1.23; 95% CI: 1.03, 1.48; P = 0.01 and OR: 1.31; 95% CI: 1.06, 1.62; P = 0.01). No such risk increase was found in participants randomized to the other 2 medications. CONCLUSIONS: A diabetes GRS predicts FG elevation in people treated with a CCB, but not with an ACEi or diuretic. These findings require confirmation. CLINICAL TRIALS REGISTRATION: Trial number NCT00000542.

17.
Hum Mol Genet ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30423114

RESUMO

Large meta-analyses of RA susceptibility in European and East Asian populations have identified >100 RA risk loci, but genome-wide studies of RA in African-Americans are absent. To address this disparity, we performed an analysis of 916 African-American RA patients and 1392 controls, and aggregated our data with genotyping data from >100,000 European and Asian RA patients and controls. We identified two novel risk loci that appear to be specific to African-Americans: GPC5 and RBFOX1 (pAA < 5 x 10-9). Most RA risk loci are shared across different ethnicities, but among discordant loci, we observed strong enrichment of variants having large effect sizes. We found strong evidence of effect concordance for only 3 of the 21 largest effect index variants in Europeans. We used the trans-ethnic fine-mapping algorithm PAINTOR3 to prioritize risk variants in >90 RA risk loci. Addition of African-American data to those of European and East Asian descent enabled identification of 7 novel high confidence candidate pathogenic variants (defined by posterior probability > 0.8). In summary, our trans-ethnic analyses are the first to include African-Americans, identified several new RA risk loci, and point to candidate pathogenic variants that may underlie this common autoimmune disease. These findings may lead to better ways to diagnose or stratify treatment approaches in RA.

18.
BMC Proc ; 12(Suppl 9): 35, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30275886

RESUMO

GAW20 provided participants with an opportunity to comprehensively examine genetic and epigenetic variation among related individuals in the context of drug treatment response. GAW20 used data from 188 families (N = 1105) participating in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (clinicaltrials.gov identifier NCT00083369), which included CD4+ T-cell DNA methylation at 463,995 cytosine-phosphate-guanine (CpG) sites measured before and after a 3-week treatment with fenofibrate, single-nucleotide variation at 906,600 loci, metabolic syndrome components ascertained before and after the drug intervention, and relevant covariates. All GOLDN participants were of European descent, with an average age of 48 years. In addition, approximately half were women and approximately 40% met the diagnostic criteria for metabolic syndrome. Unique advantages of the GAW20data set included longitudinal (3 weeks apart) measurements of DNA methylation, the opportunity to explore the contributions of both genotype and DNA methylation to the interindividual variability in drug treatment response, and the familial relationships between study participants. The principal disadvantage of GAW20/GOLDN data was the spurious correlation between batch effects and fenofibrate effects on methylation, which arose because the pre- and posttreatment methylation data were generated and normalized separately, and any attempts to remove time-dependent technical artifacts would also remove biologically meaningful changes brought on by fenofibrate. Despite this limitation, the GAW20 data set offered informative, multilayered omics data collected in a large population-based study of common disease traits, which resulted in creative approaches to integration and analysis of inherited human variation.

19.
Eur J Hum Genet ; 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30262922

RESUMO

High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) and is more prevalent in African Americans as compared to other US groups. Although large, population-based genome-wide association studies (GWAS) have identified over 300 common polymorphisms modulating inter-individual BP variation, largely in European ancestry subjects, most of them do not localize to regions previously identified through family-based linkage studies. This discrepancy has remained unexplained despite the statistical power differences between current GWAS and prior linkage studies. To address this issue, we performed genome-wide linkage analysis of BP traits in African-American families from the Family Blood Pressure Program (FBPP) and genotyped on the Illumina Human Exome BeadChip v1.1. We identified a genomic region on chromosome 1q31 with LOD score 3.8 for pulse pressure (PP), a region we previously implicated in DBP studies of European ancestry families. Although no reported GWAS variants map to this region, combined linkage and association analysis of PP identified 81 rare and low frequency exonic variants accounting for the linkage evidence. Replication analysis in eight independent African ancestry cohorts (N = 16,968) supports this specific association with PP (P = 0.0509). Additional association and network analyses identified multiple potential candidate genes in this region expressed in multiple tissues and with a strong biological support for a role in BP. In conclusion, multiple genes and rare variants on 1q31 contribute to PP variation. Beyond producing new insights into PP, we demonstrate how family-based linkage and association studies can implicate specific rare and low frequency variants for complex traits.

20.
Am J Clin Nutr ; 108(1): 188-200, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29901700

RESUMO

Background: The putative functional variant -265T>C (rs5082) within the APOA2 promoter has shown consistent interactions with saturated fatty acid (SFA) intake to influence the risk of obesity. Objective: The aim of this study was to implement an integrative approach to characterize the molecular basis of this interaction. Design: We conducted an epigenome-wide scan on 80 participants carrying either the rs5082 CC or TT genotypes and consuming either a low-SFA (<22 g/d) or high-SFA diet (≥22 g/d), matched for age, sex, BMI, and diabetes status in the Boston Puerto Rican Health Study (BPRHS). We then validated the findings in selected participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study (n = 379) and the Framingham Heart Study (FHS) (n = 243). Transcription and metabolomics analyses were conducted to determine the relation between epigenetic status, APOA2 mRNA expression, and blood metabolites. Results: In the BPRHS, we identified methylation site cg04436964 as exhibiting significant differences between CC and TT participants consuming a high-SFA diet, but not among those consuming low-SFA. Similar results were observed in the GOLDN Study and the FHS. Additionally, in the FHS, cg04436964 methylation was negatively correlated with APOA2 expression in the blood of participants consuming a high-SFA diet. Furthermore, when consuming a high-SFA diet, CC carriers had lower APOA2 expression than those with the TT genotype. Lastly, metabolomic analysis identified 4 pathways as overrepresented by metabolite differences between CC and TT genotypes with high-SFA intake, including tryptophan and branched-chain amino acid (BCAA) pathways. Interestingly, these pathways were linked to rs5082-specific cg04436964 methylation differences in high-SFA consumers. Conclusions: The epigenetic status of the APOA2 regulatory region is associated with SFA intake and APOA2 -265T>C genotype, promoting an APOA2 expression difference between APOA2 genotypes on a high-SFA diet, and modulating BCAA and tryptophan metabolic pathways. These findings identify potential mechanisms by which this highly reproducible gene-diet interaction influences obesity risk, and contribute new insights to ongoing investigations of the relation between SFA and human health. This study was registered at clinicaltrials.gov as NCT03452787.

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