Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 161
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
JMIR Mhealth Uhealth ; 7(9): e13238, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31573928

RESUMO

BACKGROUND: New electronic cohort (e-Cohort) study designs provide resource-effective methods for collecting participant data. It is unclear if implementing an e-Cohort study without direct, in-person participant contact can achieve successful participation rates. OBJECTIVE: The objective of this study was to compare 2 distinct enrollment methods for setting up mobile health (mHealth) devices and to assess the ongoing adherence to device use in an e-Cohort pilot study. METHODS: We coenrolled participants from the Framingham Heart Study (FHS) into the FHS-Health eHeart (HeH) pilot study, a digital cohort with infrastructure for collecting mHealth data. FHS participants who had an email address and smartphone were randomized to our FHS-HeH pilot study into 1 of 2 study arms: remote versus on-site support. We oversampled older adults (age ≥65 years), with a target of enrolling 20% of our sample as older adults. In the remote arm, participants received an email containing a link to enrollment website and, upon enrollment, were sent 4 smartphone-connectable sensor devices. Participants in the on-site arm were invited to visit an in-person FHS facility and were provided in-person support for enrollment and connecting the devices. Device data were tracked for at least 5 months. RESULTS: Compared with the individuals who declined, individuals who consented to our pilot study (on-site, n=101; remote, n=93) were more likely to be women, highly educated, and younger. In the on-site arm, the connection and initial use of devices was ≥20% higher than the remote arm (mean percent difference was 25% [95% CI 17-35] for activity monitor, 22% [95% CI 12-32] for blood pressure cuff, 20% [95% CI 10-30] for scale, and 43% [95% CI 30-55] for electrocardiogram), with device connection rates in the on-site arm of 99%, 95%, 95%, and 84%. Once connected, continued device use over the 5-month study period was similar between the study arms. CONCLUSIONS: Our pilot study demonstrated that the deployment of mobile devices among middle-aged and older adults in the context of an on-site clinic visit was associated with higher initial rates of device use as compared with offering only remote support. Once connected, the device use was similar in both groups.

2.
J Am Heart Assoc ; 8(16): e013011, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31390924

RESUMO

Background Previous studies assessing the association between body mass index (BMI) and atrial fibrillation (AF) did not account for time-varying covariates, which may be affected by previous BMI. We illustrate how the g-formula can account for time-varying confounding. Methods and Results We included 4392 participants from the Framingham Heart Study who were AF free at ages 45 to 55 years, and followed them for up to 20 years. We estimated hazard ratios (HRs) comparing time-varying nonobese versus obese with Cox models. We used the g-formula to compare nonobese versus obese and 10% annual decrease in BMI (until normal weight is reached) versus natural course. We estimated HRs and differences in restricted mean survival times, the mean difference in time alive and AF free. We adjusted for sex, age, and time-varying risk factors. Cox models indicated that nonobese participants had a decreased rate of AF versus obese participants (HR, 0.83; 95% CI, 0.72-0.97). G-formula analyses comparing everyone had they been nonobese versus obese yielded stronger associations (HR, 0.73; 95% CI, 0.58-0.91). The restricted mean survival time was 19.22 years had everyone been nonobese and 19.03 years had everyone been obese (difference, 2.25 months; 95% CI, -0.66 to 5.16). When assessing a 10% annual decrease in BMI, the association was weaker (HR 0.96; 95% CI, 0.86-1.08). Conclusions Decreased BMI was associated with a lower rate of AF after accounting for time-varying covariates that depend on previous exposure using the g-formula, which Cox models cannot accommodate. Absolute measures like the restricted mean survival time difference offer context to relative measures of association.

3.
JAMA Neurol ; 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31180460

RESUMO

Importance: Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles. Objective: To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing. Design, Setting, and Participants: The discovery stage included 10 441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures: Score, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE ε4 carriers and noncarriers. Results with P ≤ 1 × 10-5 were further evaluated in the replication data sets and combined by meta-analysis. Results: Among 3145 patients with AD and 4213 controls lacking ε4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%] women), novel genome-wide significant associations were obtained in the discovery sample with rs536940594 in AC099552 (odds ratio [OR], 88.0; 95% CI, 9.08-852.0; P = 2.22 × 10-7) and rs138412600 in GPAA1 (OR, 1.78; 95% CI, 1.44-2.2; meta-P = 7.81 × 10-8). GPAA1 was also associated with expression in the brain of GPAA1 (ß = -0.08; P = .03) and its repressive transcription factor, FOXG1 (ß = 0.13; P = .003), and global cognition function (ß = -0.53; P = .009). Significant gene-wide associations (threshold P ≤ 6.35 × 10-7) were observed for OR8G5 (P = 4.67 × 10-7), IGHV3-7 (P = 9.75 × 10-16), and SLC24A3 (P = 2.67 × 10-12) in 2377 patients with AD and 706 controls with ε4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women). Conclusions and Relevance: The study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE ε4 alleles that reinforce known and suggest additional pathways leading to AD.

4.
Am J Clin Nutr ; 110(3): 742-749, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31187853

RESUMO

BACKGROUND: Genes in metabolic and nutrient signaling pathways play important roles in lifespan in model organisms and human longevity. OBJECTIVE: The aim of this study was to examine the relation of a quantitative measure of healthy diet to gene expression in a community-based cohort. METHODS: We used the 2015 Dietary Guidelines for Americans Adherence Index (DGAI) score to quantify key dietary recommendations of an overall healthy diet. Our current analyses included 2220 Offspring participants (mean age 66 ± 9 y, 55.4% women) and 2941 Third-Generation participants (mean age 46 ± 9 y, 54.5% women) from the Framingham Heart Study. Gene expression was profiled in blood through the use of the Affymetrix Human Exon 1.0 ST Array. We conducted a transcriptome-wide association study of DGAI adjusting for age, sex, smoking, cell counts, and technical covariates. We also constructed a combined gene score from genes significantly associated with DGAI. RESULTS: The DGAI was significantly associated with the expression of 19 genes (false discovery rate <0.05). The most significant gene, ARRDC3, is a member of the arrestin family of proteins, and evidence in animal models and human data suggests that this gene is a regulator of obesity and energy expenditure. The DGAI gene score was associated with body mass index (P = 1.4 × 10-50), fasting glucose concentration (P = 2.5 × 10-11), type 2 diabetes (P = 1.1 × 10-5), and metabolic syndrome (P = 1.8 × 10-32). CONCLUSIONS: Healthier diet was associated with genes involved in metabolic function. Further work is needed to replicate our findings and investigate the relation of a healthy diet to altered gene regulation.

5.
Epigenomics ; 11(9): 1089-1105, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31240951

RESUMO

Aim: We compared the performance of multiple testing corrections for candidate gene methylation studies, namely Sidak (accurate Bonferroni), false-discovery rate and three adjustments that incorporate the correlation between CpGs: extreme tail theory (ETT), Gao et al. (GEA), and Li and Ji methods. Materials & methods: The experiment-wide type 1 error rate was examined in simulations based on Illumina EPIC and 450K data. Results: For high-correlation genes, Sidak and false-discovery rate corrections were conservative while the Li and Ji method was liberal. The GEA method tended to be conservative unless a threshold parameter was adjusted. The ETT yielded an appropriate type 1 error rate. Conclusion: For genes with substantial correlation across measured CpGs, GEA and ETT can appropriately correct for multiple testing in candidate gene methylation studies.

6.
Menopause ; 26(10): 1204-1212, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31188284

RESUMO

OBJECTIVE: We hypothesize that mechanisms associated with extended reproductive age may overlap with mechanisms for the selection of genetic variants that slow aging and decrease risk for age-related diseases. Therefore, the goal of this analysis is to search for genetic variants associated with delayed age of menopause (AOM) among women in a study of familial longevity. METHODS: We performed a meta-analysis of genome-wide association studies for AOM in 1,286 women in the Long Life Family Study (LLFS) and 3,151 women in the Health and Retirement Study, and then sought replication in the Framingham Heart Study (FHS). We used Cox proportional hazard regression of AOM to account for censoring, with a robust variance estimator to adjust for within familial relations. RESULTS: In the meta-analysis, a single nucleotide polymorphism (SNP) previously associated with AOM reached genome-wide significance (rs16991615; HR = 0.74, P = 6.99 × 10). A total of 35 variants reached >10 level of significance and replicated in the FHS and in a 2015 large meta-analysis (ReproGen Consortium). We also identified several novel SNPs associated with AOM including rs3094005: MICB, rs13196892: TXNDC5 | MUTED, rs72774935: SSBP2 | ATG10, rs9447453: COL12A1, rs114298934: FHL2 | NCK2, rs6467223: TNPO3, rs9666274 and rs10766593: NAV2, and rs7281846: HSPA13. CONCLUSIONS: This work indicates novel associations and replicates known associations between genetic variants and AOM. A number of these associations make sense for their roles in aging. VIDEO SUMMARY: Supplemental Digital Content 1, http://links.lww.com/MENO/A420.

7.
Aging Cell ; 18(4): e12964, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144443

RESUMO

CpG-related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation; however, their effects on Alzheimer disease (AD) risk have not been evaluated systematically. We conducted a genome-wide association study using a sliding-window approach to measure the combined effects of CGSes on AD risk in a discovery sample of 24 European ancestry cohorts (12,181 cases, 12,601 controls) from the Alzheimer's Disease Genetics Consortium (ADGC) and replication sample of seven European ancestry cohorts (7,554 cases, 27,382 controls) from the International Genomics of Alzheimer's Project (IGAP). The potential functional relevance of significant associations was evaluated by analysis of methylation and expression levels in brain tissue of the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), and in whole blood of Framingham Heart Study participants (FHS). Genome-wide significant (p < 5 × 10-8 ) associations were identified with 171 1.0 kb-length windows spanning 932 kb in the APOE region (top p < 2.2 × 10-308 ), five windows at BIN1 (top p = 1.3 × 10-13 ), two windows at MS4A6A (top p = 2.7 × 10-10 ), two windows near MS4A4A (top p = 6.4 × 10-10 ), and one window at PICALM (p = 6.3 × 10-9 ). The total number of CGS-derived CpG dinucleotides in the window near MS4A4A was associated with AD risk (p = 2.67 × 10-10 ), brain DNA methylation (p = 2.15 × 10-10 ), and gene expression in brain (p = 0.03) and blood (p = 2.53 × 10-4 ). Pathway analysis of the genes responsive to changes in the methylation quantitative trait locus signal at MS4A4A (cg14750746) showed an enrichment of methyltransferase functions. We confirm the importance of CGS in AD and the potential for creating a functional CpG dosage-derived genetic score to predict AD risk.

8.
JAMA Netw Open ; 2(3): e191350, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30924900

RESUMO

Importance: Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations. Objective: To identify genetic variants associated with AD risk using a nonstatistical approach. Design, Setting, and Participants: Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures: Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer's Disease Neuroimaging Initiative. Results: Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006). Conclusions and Relevance: Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets.

9.
Alzheimers Dement ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30503768

RESUMO

INTRODUCTION: The genetic architecture of Alzheimer's disease (AD) is only partially understood. METHODS: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome-sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families. RESULTS: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10-10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10-10). DISCUSSION: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.

10.
JAMA ; 320(22): 2354-2364, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30535219

RESUMO

Importance: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood. Objective: To perform large-scale whole-genome sequencing to identify genetic variants related to AF. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants). Exposures: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome. Main Outcomes and Measures: Early-onset AF (defined as AF onset in persons <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10-3. Results: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10-4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10-5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01). Conclusions and Relevance: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.


Assuntos
Fibrilação Atrial/genética , Conectina/genética , Mutação com Perda de Função , Adulto , Idade de Início , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Controle de Qualidade
11.
Front Neurosci ; 12: 592, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210277

RESUMO

The genetic architecture of late-onset Alzheimer disease (AD) in African Americans (AAs) differs from that in persons of European ancestry. In addition to APOE, genome-wide association studies (GWASs) of AD in AA samples have implicated ABCA7, COBL, and SLC10A2 as AA-AD risk genes. Previously, we identified by whole exome sequencing a small number of AA AD cases and subsequent genotyping in a large AA sample of AD cases and controls association of AD risk with a pair of rare missense variants in AKAP9. In this study, we performed targeted deep sequencing (including both introns and exons) of approximately 100 genes previously linked to AD or AD-related traits in an AA cohort of 489 AD cases and 472 controls to find novel AD risk variants. We observed association with an 11 base-pair frame-shift loss-of-function (LOF) variant in ABCA7 (rs567222111) for which the evidence was bolstered when combined with data from a replication AA cohort of 484 cases and 484 controls (OR = 2.42, p = 0.022). We also found association of AD with a rare 9 bp deletion (rs371245265) located very close to the AKAP9 transcription start site (rs371245265, OR = 10.75, p = 0.0053). The most significant findings were obtained with a rare protective variant in F5 (OR = 0.053, p = 6.40 × 10-5), a gene that was previously associated with a brain MRI measure of hippocampal atrophy, and two common variants in KIAA0196 (OR = 1.51, p<8.6 × 10-5). Gene-based tests of aggregated rare variants yielded several nominally significant associations with KANSL1, CNN2, and TRIM35. Although no associations passed multiple test correction, our study adds to a body of literature demonstrating the utility of examining sequence data from multiple ethnic populations for discovery of new and impactful risk variants. Larger sample sizes will be needed to generate well-powered epidemiological investigations of rare variation, and functional studies are essential for establishing the pathogenicity of variants identified by sequencing.

12.
Artigo em Inglês | MEDLINE | ID: mdl-30010802

RESUMO

Background: Biologic age may better reflect an individual's rate of aging than chronologic age. Methods: We conducted a transcriptome-wide association study with biologic age estimated with clinical biomarkers, which included: systolic blood pressure, forced expiratory volume at one second (FEV1), total cholesterol, fasting glucose, C-reactive protein, and serum creatinine. We assessed the association between the difference between biologic age and chronologic age (∆age) and gene expression in whole blood measured using the Affymetrix Human Exon 1.0st Array. Results: Our discovery sample included 2163 participants from the Framingham Offspring cohort (mean age 67±9 years, 55% women). A total of 481 genes were significantly associated with ∆age (P<2.8x10-6). Among them, 415 genes were validated (P<0.05/481=1.0x10-4) in 2946 participants from the Framingham Third Generation cohort (mean age 46± 9 years, 53% women). Many of significant genes were involved in the ubiquitin mediated proteolysis pathway. The replication in 414 Rotterdam Study participants (mean age 59±8, 52% women) found 104 of 415 validated genes reached nominal significance (P <0.05). Conclusion: We identified and validated 415 genes associated with ∆age in a community-based cohort. Future functional characterization of the biologic age-related gene network may identify targets to test for interventions to delay aging in older adults.

13.
Artigo em Inglês | MEDLINE | ID: mdl-29917058

RESUMO

Background: Frailty is a risk factor for cardiovascular disease. Underlying mechanisms to explain the connection between frailty and cardiovascular disease are unclear. We sought to examine the association between frailty and arterial stiffness, a precursor of hypertension and cardiovascular disease. Methods: We conducted a cross-sectional analysis of community-dwelling Framingham Heart Study Offspring and Omni participants ≥60 years of age examined in 2005-2008. Frailty was defined primarily according to the Fried physical phenotype definition, which identifies non-frail, pre-frail, and frail individuals. Arterial stiffness was assessed using carotid femoral pulse wave velocity (CFPWV). Generalized linear regression was used to examine the association between frailty level and CFPWV (modeled as -1000/CFPWV in msec/m, then transformed back to the original scale, m/s), adjusted for age, sex, cohort, mean arterial pressure, heart rate, height, and smoking. Results: Of 2,171 participants (55% women, 91% white), 45% were pre-frail and 7% frail. Mean ages were 67, 70, and 73 years and adjusted CFPWV least squares means were 10.0 (95% CI, 9.9-10.1), 10.3 (10.2-10.5), and 10.5m/s (10.1-11.0), P=0.0002 for non-frail, pre-frail and frail groups respectively. Results were similar using the Rockwood cumulative deficit model of frailty, and in a sensitivity analysis adjusting for prevalent coronary heart disease and diabetes. Conclusions: Pre-frailty and frailty were associated with higher arterial stiffness in a cohort of community-dwelling older adults. Arterial stiffness may help explain the relationship between frailty and cardiovascular disease.

14.
PLoS Genet ; 14(6): e1007368, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29879116

RESUMO

Selection pressure due to exposure to infectious pathogens endemic to Africa may explain distinct genetic variations in immune response genes. However, the impact of those genetic variations on human immunity remains understudied, especially within the context of modern lifestyles and living environments, which are drastically different from early humans in sub Saharan Africa. There are few data on population differences in constitutional immune environment, where genetic ancestry and environment are likely two primary sources of variation. In a study integrating genetic, molecular and epidemiologic data, we examined population differences in plasma levels of 14 cytokines involved in innate and adaptive immunity, including those implicated in chronic inflammation, and possible contributing factors to such differences, in 914 AA and 855 EA women. We observed significant differences in 7 cytokines, including higher plasma levels of CCL2, CCL11, IL4 and IL10 in EAs and higher levels of IL1RA and IFNα2 in AAs. Analyses of a wide range of demographic and lifestyle factors showed significant impact, with age, education level, obesity, smoking, and alcohol intake, accounting for some, but not all, observed population differences for the cytokines examined. Levels of two pro-inflammatory chemokines, CCL2 and CCL11, were strongly associated with percent of African ancestry among AAs. Through admixture mapping, the signal was pinpointed to local ancestry at 1q23, with fine-mapping analysis refined to the Duffy-null allele of rs2814778. In AA women, this variant was a major determinant of systemic levels of CCL2 (p = 1.1e-58) and CCL11 (p = 2.2e-110), accounting for 19% and 40% of the phenotypic variance, respectively. Our data reveal strong ancestral footprints in inflammatory chemokine regulation. The Duffy-null allele may indicate a loss of the buffering function for chemokine levels. The substantial immune differences by ancestry may have broad implications to health disparities between AA and EA populations.


Assuntos
Adaptação Biológica/genética , Citocinas/genética , Regulação da Expressão Gênica , Variação Genética , Seleção Genética , Imunidade Adaptativa/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Alelos , Evolução Biológica , Citocinas/sangue , Sistema do Grupo Sanguíneo Duffy/genética , Meio Ambiente , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Disparidades nos Níveis de Saúde , Voluntários Saudáveis , Humanos , Imunidade Inata/genética , Pessoa de Meia-Idade
15.
Breast Cancer Res ; 20(1): 45, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29871690

RESUMO

BACKGROUND: MicroRNAs (miRNAs) regulate gene expression and influence cancer. Primary transcripts of miRNAs (pri-miRNAs) are poorly annotated and little is known about the role of germline variation in miRNA genes and breast cancer (BC). We sought to identify germline miRNA variants associated with BC risk and tumor subtype among African-American (AA) women. METHODS: Under the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, genotyping and imputed data from four studies on BC in AA women were combined into a final dataset containing 224,188 miRNA gene single nucleotide polymorphisms (SNPs) for 8350 women: 3663 cases and 4687 controls. The primary miRNA sequence was identified for 566 miRNA genes expressed in Encyclopedia of DNA Elements (ENCODE) Tier 1 cell types and human pancreatic islets. Association analysis was conducted using logistic regression for BC status overall and by tumor subtype. RESULTS: A novel BC signal was localized to an 8.6-kb region of 17q25.3 by four SNPs (rs9913477, rs1428882938, rs28585511, and rs7502931) and remained statistically significant after multiple test correction (odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.26-1.65; p = 3.15 × 10-7; false discovery rate (FDR) = 0.03). These SNPs reside in a genomic location that includes both the predicted primary transcript of the noncoding miRNA gene MIR3065 and the first intron of the gene for brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2). Furthermore, miRNA-associated SNPs on chromosomes 1p32.3, 5q32, and 3p25.1 were the strongest signals for hormone receptor, luminal versus basal-like, and HER2 enrichment status, respectively. A second phase of genotyping (1397 BC cases, 2418 controls) that included two SNPs in the 8.6-kb region was used for validation and meta-analysis. While neither rs4969239 nor rs9913477 was validated, when meta-analyzed with the original dataset their association with BC remained directionally consistent (OR = 1.29, 95% CI = 1.16-1.44 (p = 4.18 × 10-6) and OR = 1.33, 95% CI = 1.17-1.51 (p = 1.6 × 10-5), respectively). CONCLUSION: Germline genetic variation indicates that MIR3065 may play an important role in BC development and heterogeneity among AA women. Further investigation to determine the potential functional effects of these SNPs is warranted. This study contributes to our understanding of BC risk in AA women and highlights the complexity in evaluating variation in gene-dense regions of the human genome.

16.
BMJ ; 361: k1453, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29699974

RESUMO

OBJECTIVE: To examine the association between risk factor burdens-categorized as optimal, borderline, or elevated-and the lifetime risk of atrial fibrillation. DESIGN: Community based cohort study. SETTING: Longitudinal data from the Framingham Heart Study. PARTICIPANTS: Individuals free of atrial fibrillation at index ages 55, 65, and 75 years were assessed. Smoking, alcohol consumption, body mass index, blood pressure, diabetes, and history of heart failure or myocardial infarction were assessed as being optimal (that is, all risk factors were optimal), borderline (presence of borderline risk factors and absence of any elevated risk factor), or elevated (presence of at least one elevated risk factor) at index age. MAIN OUTCOME MEASURE: Lifetime risk of atrial fibrillation at index age up to 95 years, accounting for the competing risk of death. RESULTS: At index age 55 years, the study sample comprised 5338 participants (2531 (47.4%) men). In this group, 247 (4.6%) had an optimal risk profile, 1415 (26.5%) had a borderline risk profile, and 3676 (68.9%) an elevated risk profile. The prevalence of elevated risk factors increased gradually when the index ages rose. For index age of 55 years, the lifetime risk of atrial fibrillation was 37.0% (95% confidence interval 34.3% to 39.6%). The lifetime risk of atrial fibrillation was 23.4% (12.8% to 34.5%) with an optimal risk profile, 33.4% (27.9% to 38.9%) with a borderline risk profile, and 38.4% (35.5% to 41.4%) with an elevated risk profile. Overall, participants with at least one elevated risk factor were associated with at least 37.8% lifetime risk of atrial fibrillation. The gradient in lifetime risk across risk factor burden was similar at index ages 65 and 75 years. CONCLUSIONS: Regardless of index ages at 55, 65, or 75 years, an optimal risk factor profile was associated with a lifetime risk of atrial fibrillation of about one in five; this risk rose to more than one in three a third in individuals with at least one elevated risk factor.


Assuntos
Fibrilação Atrial/epidemiologia , Complicações do Diabetes/epidemiologia , Hipertensão/epidemiologia , Fatores Etários , Idoso , Fibrilação Atrial/etiologia , Feminino , Inquéritos Epidemiológicos , Humanos , Hipertensão/complicações , Estilo de Vida , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco
17.
J Neuroimmune Pharmacol ; 13(2): 254-264, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29516269

RESUMO

We studied the effect of two rare mutations (rs144662445 and rs149979685) in the A-kinase anchoring protein 9 (AKAP9) gene, previously associated with Alzheimer disease (AD) in African Americans (AA), on post-translational modifications of AD-related pathogenic molecules, amyloid precursor protein (APP) and microtubule-associated protein Tau using lymphoblastoid cell lines (LCLs) from 11 AA subjects with at least one AKAP9 mutation and 17 AA subjects lacking these mutations. LCLs were transduced by viral vectors expressing causative AD mutations in APP or human full-length wild type Tau. Cell lysates were analyzed for total APP, Aß40, and total and T181 phospho-Tau (pTau). AKAP9 mutations had no effect on Aß40/APP, but significantly increased pTau/Tau ratio in LCLs treated with phosphodiesterase-4 inhibitor rolipram, which activates protein kinase A. Proteomic analysis of Tau interactome revealed enrichment of RNA binding proteins and decrease of proteasomal molecules in rolipram-treated cells with AKAP9 mutations. This study shows the impact of rare functional AKAP9 mutations on Tau, a central mechanism of AD pathogenesis, in LCLs derived from AD and control subjects.

18.
Alzheimers Res Ther ; 10(1): 22, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29458411

RESUMO

BACKGROUND: Simultaneous consideration of two neuropathological traits related to Alzheimer's disease (AD) has not been attempted in a genome-wide association study. METHODS: We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data. RESULTS: Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10-8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10-8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10-6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10-3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10-3) and visual (P = 5.6 × 10-4) cortices. CONCLUSIONS: Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.

19.
Dement Geriatr Cogn Disord ; 45(1-2): 1-17, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29486463

RESUMO

BACKGROUND/AIMS: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. METHODS: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. RESULTS/CONCLUSIONS: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.


Assuntos
Doença de Alzheimer/genética , Demência/genética , Proteínas do Tecido Nervoso/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Demência/epidemiologia , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Prevalência , Análise de Sequência de DNA
20.
Nat Commun ; 9(1): 387, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29374233

RESUMO

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10-11). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA