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1.
BMC Med Genomics ; 12(1): 141, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640709

RESUMO

BACKGROUND: Epigenetic age acceleration, a measure of biological aging based on DNA methylation, is associated with cardiovascular mortality. However, little is known about its relationship with hypertensive target organ damage to the heart, kidneys, brain, and peripheral arteries. METHODS: We investigated associations between intrinsic (IEAA) or extrinsic (EEAA) epigenetic age acceleration, blood pressure, and six types of organ damage in a primarily hypertensive cohort of 1390 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. DNA methylation from peripheral blood leukocytes was collected at baseline (1996-2000), and measures of target organ damage were assessed in a follow-up visit (2000-2004). Linear regression with generalized estimating equations was used to test for associations between epigenetic age acceleration and target organ damage, as well as effect modification of epigenetic age by blood pressure or sex. Sequential Oligogenic Linkage Analysis Routines (SOLAR) was used to test for evidence of shared genetic and/or environmental effects between epigenetic age acceleration and organ damage pairs that were significantly associated. RESULTS: After adjustment for sex, chronological age, and time between methylation and organ damage measures, higher IEAA was associated with higher urine albumin to creatinine ratio (UACR, p = 0.004), relative wall thickness (RWT, p = 0.022), and left ventricular mass index (LVMI, p = 0.007), and with lower ankle-brachial index (ABI, p = 0.014). EEAA was associated with higher LVMI (p = 0.005). Target organ damage associations for all but IEAA with LVMI remained significant after further adjustment for blood pressure and antihypertensive use (p < 0.05). Further adjustment for diabetes attenuated the IEAA associations with UACR and RWT, and adjustment for smoking attenuated the IEAA association with ABI. No effect modification by age or sex was observed. CONCLUSIONS: Measures of epigenetic age acceleration may help to better characterize the functional mechanisms underlying organ damage from cellular aging and/or hypertension. These measures may act as subclinical biomarkers for damage to the kidney, heart, and peripheral vasculature; however more research is needed to determine whether these relationships remain independent of lifestyle factors and comorbidities.

2.
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.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31466396

RESUMO

DNA methylation (DNAm) clocks are important biomarkers of cellular aging and are associated with a variety of age-related chronic diseases and all-cause mortality. Examining the relationship between education and lifestyle risk factors for age-related diseases and multiple DNAm clocks can increase the understanding of how risk factors contribute to aging at the cellular level. This study explored the association between education or lifestyle risk factors for age-related diseases and the acceleration of four DNAm clocks, including intrinsic (IEAA) and extrinsic epigenetic age acceleration (EEAA), PhenoAge acceleration (PhenoAA), and GrimAge acceleration (GrimAA) in the African American participants of the Genetic Epidemiology Network of Arteriopathy. We performed both cross-sectional and longitudinal analyses. In cross-sectional analyses, gender, education, BMI, smoking, and alcohol consumption were all independently associated with GrimAA, whereas only some of them were associated with other clocks. The effect of smoking and education on GrimAA varied by gender. Longitudinal analyses suggest that age and BMI continued to increase GrimAA, and that age and current smoking continued to increase PhenoAA after controlling DNAm clocks at baseline. In conclusion, education and common lifestyle risk factors were associated with multiple DNAm clocks. However, the association with each risk factor varied by clock, which suggests that different clocks may capture adverse effects from different environmental stimuli.

4.
Nat Commun ; 10(1): 3669, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413261

RESUMO

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

5.
PLoS One ; 14(5): e0216222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075152

RESUMO

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies. METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models. CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

6.
Diabetes ; 68(5): 1073-1083, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936141

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 × 10-6) with replication at Bonferroni-corrected P < 8.6 × 10-4 Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 × 10-4). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.

7.
PLoS One ; 14(4): e0214061, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30973896

RESUMO

BACKGROUND: Gene expression may be an important biological mediator in associations between social factors and health. However, previous studies were limited by small sample sizes and use of differing cell types with heterogeneous expression patterns. We use a large population-based cohort with gene expression measured solely in monocytes to investigate associations between seven social factors and expression of genes previously found to be sensitive to social factors. METHODS: We employ three methodological approaches: 1) omnibus test for the entire gene set (Global ANCOVA), 2) assessment of each association individually (linear regression), and 3) machine learning method that performs variable selection with correlated predictors (elastic net). RESULTS: In global analyses, significant associations with the a priori defined socially sensitive gene set were detected for major or lifetime discrimination and chronic burden (p = 0.019 and p = 0.047, respectively). Marginally significant associations were detected for loneliness and adult socioeconomic status (p = 0.066, p = 0.093, respectively). No associations were significant in linear regression analyses after accounting for multiple testing. However, a small percentage of gene expressions (up to 11%) were associated with at least one social factor using elastic net. CONCLUSION: The Global ANCOVA and elastic net findings suggest that a small percentage of genes may be "socially sensitive," (i.e. demonstrate differential expression by social factor), yet single gene approaches such as linear regression may be ill powered to capture this relationship. Future research should further investigate the biological mechanisms through which social factors act to influence gene expression and how systemic changes in gene expression affect overall health.

8.
Epigenetics ; 14(4): 383-391, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30915882

RESUMO

INTRODUCTION: Cigarette smoking has been associated with adverse health outcomes for mothers and children and is a major contributor to heart disease. Although cigarette smoking is known to affect the epigenome, few studies have been done in African American populations. In this study, we investigated the association between cigarette smoking and DNA methylation (DNAm) among African Americans from the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure Study (InterGEN), and the Genetic Epidemiology Network of Arteriopathy (GENOA). METHODS: The InterGEN study aims to examine the effects of genetic and psychological factors on blood pressure among African American women and their children. Current cigarette smoking was assessed at baseline. DNAm of saliva was assessed using the 850K EPIC Illumina BeadChip for Epigenome-Wide Association analyses. A replication study was conducted among 1100 participants in the GENOA study using the same BeadChip. RESULTS: After controlling for age, body mass index, population structure and cell composition, 26 epigenome-wide significant sites (FDR q < 0.05) were identified, including the AHRR and PHF14 genes associated with atherosclerosis and lung disease, respectively. Six novel CpG sites were discovered in the InterGEN sample and replicated in the GENOA sample. Genes mapped include RARA, FSIP1, ALPP, PIK3R5, KIAA0087, and MGAT3, which were largely associated with cancer development. CONCLUSION: We observed significant epigenetic associations between smoking and disease-associated genes (e.g., cardiovascular disease, lung cancer). Six novel CpG sites were identified and replicated across saliva and blood samples.

9.
Hum Genet ; 138(4): 375-388, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30852652

RESUMO

Metabolic coherence (MC) is a network-based approach to dimensionality reduction that can be used, for example, to interpret the joint expression of genes linked to human metabolism. Computationally, the derivation of 'transcriptomic' MC involves mapping of an individual gene expression profile onto a gene-centric network derived beforehand from a metabolic network (currently Recon2), followed by the determination of the connectivity of a particular, profile-specific subnetwork. The biological significance of MC has been exemplified previously in the context of human inflammatory bowel disease, among others, but the genetic architecture of this quantitative cellular trait is still unclear. Therefore, we performed a genome-wide association study (GWAS) of MC in the 1000 Genomes/ GEUVADIS data (n = 457) and identified a solitary genome-wide significant association with single nucleotide polymorphisms (SNPs) in the intronic region of the cadherin 18 (CDH18) gene on chromosome 5 (lead SNP: rs11744487, p = 1.2 × 10- 8). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n = 2661; lead SNP), but failed in two additional studies (KORA, Germany, n = 711; GENOA, USA, n = 411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis.


Assuntos
Caderinas/genética , Loci Gênicos , Redes e Vias Metabólicas/genética , Metabolismo/genética , Transcriptoma , Estudos de Coortes , Feminino , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
10.
Biol Res Nurs ; 21(3): 279-285, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30781968

RESUMO

With the rapid advancement of omics-based research, particularly big data such as genome- and epigenome-wide association studies that include extensive environmental and clinical variables, data analytics have become increasingly complex. Researchers face significant challenges regarding how to analyze multifactorial data and make use of the findings for clinical translation. The purpose of this article is to provide a scientific exemplar for use of genetic burden scores as a data analysis method for studies with both genotype and DNA methylation data in which the goal is to evaluate associations with chronic conditions such as metabolic syndrome (MetS). This study included 739 African American men and women from the Genetic Epidemiology Network of Arteriopathy Study who met diagnostic criteria for MetS and had available genetic and epigenetic data. Genetic burden scores for evaluated genes were not significant after multiple testing corrections, but DNA methylation at 2 CpG sites (dihydroorotate dehydrogenase cg22381196 pFDR = .014; CTNNA3 cg00132141 pFDR = .043) was significantly associated with MetS after controlling for multiple comparisons. Interactions between the marginally significant CpG sites and burden scores, however, were not significant. More work is required in this area to identify intermediate biological pathways influenced by environmental, genetic, and epigenetic variation that may explain the high prevalence of MetS among African Americans. This study does serve, however, as an example of the use of the genetic burden score as an alternative data analysis approach for complex studies involving the analysis of genetic and epigenetic data simultaneously.


Assuntos
Afro-Americanos/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética , Síndrome Metabólica/genética , Síndrome Metabólica/fisiopatologia , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
11.
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
12.
Nat Genet ; 50(11): 1505-1513, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30297969

RESUMO

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

13.
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.

14.
Healthcare (Basel) ; 6(3)2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30081448

RESUMO

The United States Precision Medicine Initiative (PMI) was announced by then President Barack Obama in January 2015. It is a national effort designed to take into account genetic, environmental, and lifestyle differences in the development of individually tailored forms of treatment and prevention. This goal was implemented in March 2015 with the formation of an advisory committee working group to provide a framework for the proposed national research cohort of one million or more participants. The working group further held a public workshop on participant engagement and health equity, focusing on the design of an inclusive cohort, building public trust, and identifying active participant engagement features for the national cohort. Precision techniques offer medical and public health practitioners the opportunity to personally tailor preventive and therapeutic regimens based on informatics applied to large volume genotypic and phenotypic data. The PMI's (All of Us Research Program's) medical and public health promise, its balanced attention to technical and ethical issues, and its nuanced advisory structure made it a natural choice for inclusion in the University of Michigan course "Issues in Public Health Genetics" (HMP 517), offered each fall by the University's School of Public Health. In 2015, the instructors included the PMI as the recurrent case study introduced at the beginning and referred to throughout the course, and as a class exercise allowing students to translate issues into policy. In 2016, an entire class session was devoted to precision medicine and precision public health. In this article, we examine the dialogues that transpired in these three course components, evaluate session impact on student ability to formulate PMI policy, and share our vision for next-generation courses dealing with precision health. Methodology: Class materials (class notes, oral exercise transcripts, class exercise written hand-ins) from the three course components were inspected and analyzed for issues and policy content. The purpose of the analysis was to assess the extent to which course components have enabled our students to formulate policy in the precision public health area. Analysis of student comments responding to questions posed during the initial case study comprised the initial or "pre-" categories. Analysis of student responses to the class exercise assignment, which included the same set of questions, formed the "post-" categories. Categories were validated by cross-comparison among the three authors, and inspected for frequency with which they appeared in student responses. Frequencies steered the selection of illustrative quotations, revealing the extent to which students were able to convert issue areas into actual policies. Lecture content and student comments in the precision health didactic session were inspected for degree to which they reinforced and extended the derived categories. Results: The case study inspection yielded four overarching categories: (1) assurance (access, equity, disparities); (2) participation (involvement, representativeness); (3) ethics (consent, privacy, benefit sharing); and (4) treatment of people (stigmatization, discrimination). Class exercise inspection and analysis yielded three additional categories: (5) financial; (6) educational; and (7) trust-building. The first three categories exceeded the others in terms of number of student mentions (8⁻14 vs. 4⁻6 mentions). Three other categories were considered and excluded because of infrequent mention. Students suggested several means of trust-building, including PMI personnel working with community leaders, stakeholder consultation, networking, and use of social media. Student representatives prioritized participant and research institution access to PMI information over commercial access. Multiple schemes were proposed for participant consent and return of results. Both pricing policy and Medicaid coverage were touched on. During the didactic session, students commented on the importance of provider training in precision health. Course evaluation highlighted the need for clarity on the organizations involved in the PMI, and leaving time for student-student interaction. Conclusions: While some student responses during the exercise were terse, an evolution was detectable over the three course components in student ability to suggest tangible policies and steps for implementation. Students also gained surety in presenting policy positions to a peer audience. Students came up with some very creative suggestions, such as use of an electronic platform to assure participant involvement in the disposition of their biological sample and personal health information, and alternate examples of ways to manage large volumes of data. An examination of socio-ethical issues and policies can strengthen student understanding of the directions the Precision Medicine Initiative is taking, and aid in training for the application of more varied precision medicine and public health techniques, such as tier 1 genetic testing and whole genome and exome sequencing. Future course development may reflect additional features of the ongoing All of Us Research Program, and further articulate precision public health approaches applying to populations as opposed to single individuals.

15.
Blood ; 132(17): 1842-1850, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30042098

RESUMO

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10-5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

16.
Am J Public Health ; 108(5): 611-613, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29565671

RESUMO

OBJECTIVES: To compare population-based sterilization rates between Latinas/os and non-Latinas/os sterilized under California's eugenics law. METHODS: We used data from 17 362 forms recommending institutionalized patients for sterilization between 1920 and 1945. We abstracted patient gender, age, and institution of residence into a data set. We extracted data on institution populations from US Census microdata from 1920, 1930, and 1940 and interpolated between census years. We used Spanish surnames to identify Latinas/os in the absence of data on race/ethnicity. We used Poisson regression with a random effect for each patient's institution of residence to estimate incidence rate ratios (IRRs) and compare sterilization rates between Latinas/os and non-Latinas/os, stratifying on gender and adjusting for differences in age and year of sterilization. RESULTS: Latino men were more likely to be sterilized than were non-Latino men (IRR = 1.23; 95% confidence interval [CI] = 1.15, 1.31), and Latina women experienced an even more disproportionate risk of sterilization relative to non-Latinas (IRR = 1.59; 95% CI = 1.48, 1.70). CONCLUSIONS: Eugenic sterilization laws were disproportionately applied to Latina/o patients, particularly Latina women and girls. Understanding historical injustices in public health can inform contemporary public health practice.

17.
Genet Epidemiol ; 42(4): 320-332, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29601641

RESUMO

Many gene mapping studies of complex traits have identified genes or variants that influence multiple phenotypes. With the advent of next-generation sequencing technology, there has been substantial interest in identifying rare variants in genes that possess cross-phenotype effects. In the presence of such effects, modeling both the phenotypes and rare variants collectively using multivariate models can achieve higher statistical power compared to univariate methods that either model each phenotype separately or perform separate tests for each variant. Several studies collect phenotypic data over time and using such longitudinal data can further increase the power to detect genetic associations. Although rare-variant approaches exist for testing cross-phenotype effects at a single time point, there is no analogous method for performing such analyses using longitudinal outcomes. In order to fill this important gap, we propose an extension of Gene Association with Multiple Traits (GAMuT) test, a method for cross-phenotype analysis of rare variants using a framework based on the distance covariance. The approach allows for both binary and continuous phenotypes and can also adjust for covariates. Our simple adjustment to the GAMuT test allows it to handle longitudinal data and to gain power by exploiting temporal correlation. The approach is computationally efficient and applicable on a genome-wide scale due to the use of a closed-form test whose significance can be evaluated analytically. We use simulated data to demonstrate that our method has favorable power over competing approaches and also apply our approach to exome chip data from the Genetic Epidemiology Network of Arteriopathy.


Assuntos
Variação Genética , Característica Quantitativa Herdável , Simulação por Computador , Bases de Dados Genéticas , Exoma , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Modelos Genéticos , Fenótipo
18.
Mol Psychiatry ; 23(11): 2133-2144, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29311653

RESUMO

Cognitive functions are important correlates of health outcomes across the life-course. Individual differences in cognitive functions are partly heritable. Epigenetic modifications, such as DNA methylation, are susceptible to both genetic and environmental factors and may provide insights into individual differences in cognitive functions. Epigenome-wide meta-analyses for blood-based DNA methylation levels at ~420,000 CpG sites were performed for seven measures of cognitive functioning using data from 11 cohorts. CpGs that passed a Bonferroni correction, adjusting for the number of CpGs and cognitive tests, were assessed for: longitudinal change; being under genetic control (methylation QTLs); and associations with brain health (structural MRI), brain methylation and Alzheimer's disease pathology. Across the seven measures of cognitive functioning (meta-analysis n range: 2557-6809), there were epigenome-wide significant (P < 1.7 × 10-8) associations for global cognitive function (cg21450381, P = 1.6 × 10-8), and phonemic verbal fluency (cg12507869, P = 2.5 × 10-9). The CpGs are located in an intergenic region on chromosome 12 and the INPP5A gene on chromosome 10, respectively. Both probes have moderate correlations (~0.4) with brain methylation in Brodmann area 20 (ventral temporal cortex). Neither probe showed evidence of longitudinal change in late-life or associations with white matter brain MRI measures in one cohort with these data. A methylation QTL analysis suggested that rs113565688 was a cis methylation QTL for cg12507869 (P = 5 × 10-5 and 4 × 10-13 in two lookup cohorts). We demonstrate a link between blood-based DNA methylation and measures of phonemic verbal fluency and global cognitive ability. Further research is warranted to understand the mechanisms linking genomic regulatory changes with cognitive function to health and disease.

19.
Menopause ; 25(6): 625-634, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29381664

RESUMO

OBJECTIVE: Experimental models suggest estrogen has a renoprotective effect, but human studies show variable results. Our objective was to study the association of hormone therapy (HT) and albuminuria in postmenopausal women and to synthesize the results with outcomes from prior studies. METHODS: We analyzed data from postmenopausal women who participated in the second study visit (2000-2004) of the Genetic Epidemiology Network of Arteriopathy (GENOA) study. The exposure was self-reported HT use and the outcome was albuminuria (urine albumin-to-creatinine ratio >25 mg/g creatinine). We also conducted a systematic review and meta-analysis on the association of HT and urine protein in postmenopausal women. Continuous and dichotomous measures of protein excretion were converted to a standardized mean difference (SMD) for each study. RESULTS: In the GENOA cohort (n = 2,217), there were fewer women with albuminuria among HT users than nonusers (9% vs 19%, P < 0.001). HT use was associated with decreased odds of albuminuria (odds ratio 0.65, 95% confidence interval (CI), 0.45-0.95), after adjusting for significant differences in age, race, education, comorbidities, and the age at and cause of menopause. The SMD of the effect of HT on urine proteinuria/albuminuria in the randomized control trials (n = 3) was 0.02 (95% CI, -0.29 to 0.33) and -0.13 (95% CI, -0.31 to 0.05) in the observational studies (n = 9). There was significantly less albuminuria among HT users (SMD -0.15, 95% CI, -0.27 to -0.04) in the 9 studies that only reported albuminuria as an outcome and in the 10 studies with a comparator arm (SMD -0.15, 95% CI, -0.26 to -0.04). CONCLUSIONS: HT is associated with decreased odds of albuminuria, but some of the observed benefits may be related to reported outcomes, the presence of a comparator arm, and the type of study design.

20.
Biol Res Nurs ; 20(2): 161-167, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29338330

RESUMO

INTRODUCTION: Plasma concentrations of lipids (i.e., total cholesterol, high-density cholesterol, low-density cholesterol, and triglycerides) are amenable to therapeutic intervention and remain important factors for assessing risk of cardiovascular diseases. Some of the observed variability in serum lipid concentrations has been associated with genetic and epigenetic variants among cohorts with European ancestry (EA). Serum lipid levels have also been associated with genetic variants in multiethnic populations. METHODS: The purpose of this study was to determine whether single-nucleotide polymorphisms (SNPs) and DNA methylation (DNAm) differences contribute to lipid variation among African Americans ([AAs], N = 739) in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. RESULTS: Previous meta-analyses identified 161 SNPs that are associated with lipid traits in populations of EA. We evaluated these SNPs and 66 DNAm sites within the genes containing the SNPs in the GENOA cohort using linear mixed-effects modeling. We did not identify any significant associations of SNPs or DNAm with serum lipid levels. These results suggest that the SNPs identified as being significant for lipid levels through the EA genome-wide association studies may not be significant across AA populations. CONCLUSIONS: Reductions in morbidity and mortality due to variation in lipids among AAs may be achieved through a better understanding of the genetic and epigenetic factors associated with serum lipid levels for early and appropriate screening. Further large-scale studies specifically within AA and other non-EA populations are warranted.

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