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1.
Alzheimers Dement ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33155766

RESUMO

INTRODUCTION: Apolipoprotein E (APOE) alleles are associated with cognitive decline, mild cognitive impairment (MCI), and Alzheimer's disease in Whites, but have weaker and inconsistent effects reported in Latinos. We hypothesized that this heterogeneity is due to ancestry-specific genetic effects. METHODS: We investigated the associations of the APOE alleles with significant cognitive decline and MCI in 4183 Latinos, stratified by six Latino backgrounds, and explored whether the proportion of continental genetic ancestry (European, African, and Amerindian) modifies these associations. RESULTS: APOE ε4 was associated with an increased risk of significant cognitive decline (odds ratio [OR] = 1.15, P-value = 0.03), with the strongest association in Cubans (OR = 1.46, P-value = 0.007). APOE-ε2 was associated with decreased risk of MCI (OR = 0.37, P-value = 0.04) in Puerto Ricans. Amerindian genetic ancestry was found to protect from the risk conferred by APOE ε4 on significant cognitive decline. DISCUSSION: Results suggest that APOE alleles' effects on cognitive outcomes differ across six Latino backgrounds and are modified by continental genetic ancestry.

2.
Nat Commun ; 11(1): 5182, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057025

RESUMO

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.


Assuntos
Afro-Americanos/genética , Loci Gênicos , Doença Pulmonar Obstrutiva Crônica/genética , Fenômenos Fisiológicos Respiratórios/genética , Sequenciamento Completo do Genoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Proteínas de Ligação ao Cálcio/genética , Estudos de Viabilidade , Feminino , Seguimentos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteínas Inibidoras de STAT Ativados/genética , Doença Pulmonar Obstrutiva Crônica/etnologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética
3.
Nat Commun ; 11(1): 5236, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067431

RESUMO

The etiology of major neurodevelopmental disorders such as schizophrenia and autism is unclear, with evidence supporting a combination of genetic factors and environmental insults, including viral infection during pregnancy. Here we utilized a mouse model of maternal immune activation (MIA) with the viral mimic PolyI:C infection during early gestation. We investigated the transcriptional changes in the brains of mouse fetuses following MIA during the prenatal period, and evaluated the behavioral and biochemical changes in the adult brain. The results reveal an increase in RNA editing levels and dysregulation in brain development-related gene pathways in the fetal brains of MIA mice. These MIA-induced brain editing changes are not observed in adulthood, although MIA-induced behavioral deficits are observed. Taken together, our findings suggest that MIA induces transient dysregulation of RNA editing at a critical time in brain development.


Assuntos
Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/genética , Complicações na Gravidez/imunologia , Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/genética , Edição de RNA , Animais , Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Encéfalo/imunologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Imunidade Materno-Adquirida , Camundongos , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/psicologia , Poli I-C/efeitos adversos , Poli I-C/imunologia , Complicações na Gravidez/etiologia , Complicações na Gravidez/genética , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/psicologia
4.
Genet Epidemiol ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33094516

RESUMO

Whole genome sequencing (WGS) and whole exome sequencing studies are used to test the association of rare genetic variants with health traits. Many existing WGS efforts now aggregate data from heterogeneous groups, for example, combining sets of individuals of European and African ancestries. We here investigate the statistical implications on rare variant association testing with a binary trait when combining together heterogeneous studies, defined as studies with potentially different disease proportion and different frequency of variant carriers. We study and compare in simulations the Type 1 error control and power of the naïve score test, the saddlepoint approximation to the score test, and the BinomiRare test in a range of settings, focusing on low numbers of variant carriers. We show that Type 1 error control and power patterns depend on both the number of carriers of the rare allele and on disease prevalence in each of the studies. We develop recommendations for association analysis of rare genetic variants. (1) The Score test is preferred when the case proportion in the sample is 50%. (2) Do not down-sample controls to balance case-control ratio, because it reduces power. Rather, use a test that controls the Type 1 error. (3) Conduct stratified analysis in parallel with combined analysis. Aggregated testing may have lower power when the variant effect size differs between strata.

5.
Sleep ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33034629

RESUMO

Poor sleep quality can have harmful health consequences. Although many aspects of sleep are heritable, the understandings of genetic factors involved in its physiology remain limited. Here, we performed a genome-wide association study (GWAS) using the Pittsburgh Sleep Quality Index (PSQI) in a multi-ethnic discovery cohort (n=2,868) and found two novel genome-wide loci on chromosomes 2 and 7 associated with global sleep quality. A meta-analysis in 12 independent cohorts (100,000 individuals) replicated the association on chromosome 7 between NPY and MPP6. While NPY is an important sleep gene, we tested for an independent functional role of MPP6. Expression data showed an association of this locus with both NPY and MPP6 mRNA levels in brain tissues. Moreover, knockdown of an orthologue of MPP6 in Drosophila melanogaster sleep center neurons resulted in decreased sleep duration. With convergent evidence, we describe a new locus impacting human variability in sleep quality through known NPY and novel MPP6 sleep genes.

6.
Transl Psychiatry ; 10(1): 305, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873780

RESUMO

Schizophrenia is a debilitating psychiatric disorder with a significant number of patients not adequately responding to treatment. Phencyclidine (PCP) is used as a validated model for schizophrenia, shown to reliably induce positive, negative and cognitive-like behaviors in rodents. It was previously shown in our lab that behavioral phenotypes of PCP-treated mice can be alleviated after intracranial transplantation of mesenchymal stem cells (MSC). Here, we assessed the feasibility of intranasal delivery of MSCs-derived-extracellular vesicles (EVs) to alleviate schizophrenia-like behaviors in a PCP model of schizophrenia. As MSCs-derived EVs were already shown to concentrate at the site of lesion in the brain, we determined that in PCP induced injury the EVs migrate to the prefrontal cortex (PFC) of treated mice, a most involved area of the brain in schizophrenia. We show that intranasal delivery of MSC-EVs improve social interaction and disruption in prepulse inhibition (PPI) seen in PCP-treated mice. In addition, immunohistochemical studies demonstrate that the EVs preserve the number of parvalbumin-positive GABAergic interneurons in the PFC of treated mice. Finally, MSCs-EVs reduced glutamate levels in the CSF of PCP-treated mice, which might explain the reduction of toxicity. In conclusion, we show that MSCs-EVs improve the core schizophrenia-like behavior and biochemical markers of schizophrenia and might be used as a novel treatment for this incurable disorder.

7.
Transl Psychiatry ; 10(1): 327, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963225

RESUMO

In the original Article, Dr. Angela Ruban's name was misspelled as "Aangela Ruban". This has been corrected in the PDF, HTML, and XML versions of this Article.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32758008

RESUMO

RATIONALE: Sleep disorders are associated with hypertension and diabetes, primary risk factors for cardiovascular diseases and mortality. It is important to understand these associations in Hispanics/Latinos, in whom cardiovascular death is the leading cause of mortality. OBJECTIVES: To investigate the prospective associations of sleep disordered breathing (SDB) and insomnia with incident hypertension and diabetes among US Hispanics/Latinos over 6 years of follow-up and to assess potential gender differences in these associations. METHODS: Data from 11,623 Hispanic/Latino participants in the Hispanic Community Health Study/Study of Latinos (Visit 1: 2008-2011; Visit 2: 2014-2017) were analyzed using survey logistic regression models, adjusting for potential confounders. MEASUREMENTS AND MAIN RESULTS: SDB (apnea-hypopnea index ≥ 5) and insomnia (Women's Health Initiative Insomnia Rating Scale ≥ 9) were measured at baseline. Incident hypertension (≥ Stage 2) and diabetes were defined according to national guidelines. In the target population, 52.6% were female with mean age 41.1 ± 14.9 years at baseline. SDB was associated with a 1.54 higher adjusted odds of incident hypertension (95% confidence interval (CI) [1.18, 2.00]) and 1.37 higher odds of incident diabetes (95% CI [1.07, 1.75]) compared to no SDB. Insomnia was associated with incident hypertension (Odds Ratio (OR) = 1.37; 95% CI [1.11, 1.69]), but not diabetes. The association between insomnia and incident hypertension was stronger among men than women. CONCLUSIONS: SDB was associated with incident hypertension and diabetes. Insomnia was associated with incident hypertension. These findings support the importance of sleep disorders as modifiable targets for disease prevention and reduction.

9.
Transl Psychiatry ; 10(1): 245, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699239

RESUMO

Cognitive function such as reasoning, attention, memory, and language is strongly correlated with brain aging. Compared to non-Hispanic whites, Hispanics/Latinos have a higher risk of cognitive impairment and dementia. The genetic determinants of cognitive function have not been widely explored in this diverse and admixed population. We conducted a genome-wide association analysis of cognitive function in up to 7600 middle aged and older Hispanics/Latinos (mean = 55 years) from the Hispanic Community Health Study / Study of Latinos (HCHS/SOL). Four cognitive measures were examined: the Brief Spanish English Verbal Learning Test (B-SEVLT), the Word Fluency Test (WFT), the Digit Symbol Substitution Test (DSST), the Six-Item Screener (SIS). Four novel loci were identified: one for B-SEVLT at 4p14, two for WFT at 3p14.1 and 6p21.32, and one for DSST at 10p13. These loci implicate genes highly expressed in brain and previously connected to neurological diseases (UBE2K, FRMD4B, the HLA gene complex). By applying tissue-specific gene expression prediction models to our genotype data, additional genes highly expressed in brain showed suggestive associations with cognitive measures possibly indicating novel biological mechanisms, including IFT122 in the hippocampus for SIS, SNX31 in the basal ganglia for B-SEVLT, RPS6KB2 in the frontal cortex for WFT, and CSPG5 in the hypothalamus for DSST. These findings provide new information about the genetic determinants of cognitive function in this unique population. In addition, we derived a measure of general cognitive function based on these cognitive tests and generated genome-wide association summary results, providing a resource to the research community for comparison, replication, and meta-analysis in future genetic studies in Hispanics/Latinos.

10.
EBioMedicine ; 56: 102803, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32512511

RESUMO

BACKGROUND: Sleep Disordered Breathing (SDB) is associated with a wide range of pathophysiological changes due, in part, to hypoxemia during sleep. We sought to identify gene transcription associations with measures of SDB and hypoxemia during sleep, and study their response to treatment. METHODS: In two discovery cohorts, Framingham Offspring Study (FOS; N = 571) and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 580), we studied gene expression in peripheral blood mononuclear cells in association with three measures of SDB: Apnea Hypopnea Index (AHI); average oxyhemoglobin saturation (avgO2) during sleep; and minimum oxyhemoglobin saturation (minO2) during sleep. Associated genes were used for analysis of gene expression in the blood of 15 participants with moderate or severe obstructive sleep apnea (OSA) from the Heart Biomarkers In Apnea Treatment (HeartBEAT) trial. These genes were studied pre- and post-treatment (three months) with continuous positive airway pressure (CPAP). We also performed Gene Set Enrichment Analysis (GSEA) on all traits and cohort analyses. FINDINGS: Twenty-two genes were associated with SDB traits in both MESA and FOS. Of these, lower expression of CD1D and RAB20 was associated with lower avgO2 in MESA and FOS. CPAP treatment increased the expression of these genes in HeartBEAT participants. Immunity and inflammation pathways were up-regulated in subjects with lower avgO2; i.e., in those with a more severe SDB phenotype (MESA), whereas immuno-inflammatory processes were down-regulated following CPAP treatment (HeartBEAT). INTERPRETATION: Low oxygen saturation during sleep is associated with alterations in gene expression and transcriptional programs that are partially reversed by CPAP treatment.

11.
Chest ; 158(2): 739-750, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32298733

RESUMO

BACKGROUND: Heart failure (HF) is a leading cause of morbidity and mortality and although it is linked to sleep apnea, which physiological stressors most strongly associate with incident disease is unclear. We tested whether sleep apnea-specific hypoxic burden (SASHB) predicts incident HF in two independent cohort studies. RESEARCH QUESTION: In comparison with apnea-hypopnea index (AHI), how does sleep apnea-specific hypoxic burden predict incident HF? STUDY DESIGN AND METHODS: The samples were derived from two cohort studies: The Sleep Heart Health Study (SHHS), which included 4,881 middle-aged and older adults (54.4% women), age 63.6 ± 11.1 years; and the Outcomes of Sleep Disorders in Older Men (MrOS), which included 2,653 men, age 76.2 ± 5.4 years. We computed SASHB as the sleep apnea-specific area under the desaturation curve from pre-event baseline. We used Cox models for incident HF to estimate the adjusted hazard ratios (HRs) for natural log-transformed SASHB and AHI adjusting for multiple confounders. RESULTS: The SASHB predicted incident HF in men in both cohorts, whereas AHI did not. Men in SHHS and MrOS had adjusted HRs (per 1SD increase in SASHB) of 1.18 (95% CI, 1.02-1.37) and 1.22 (95% CI, 1.02-1.45), respectively. Associations with SASHB were observed in men with both low and high AHI levels. Associations were not significant in women. INTERPRETATION: In men, the hypoxic burden of sleep apnea was associated with incident HF after accounting for demographic factors, smoking, and co-morbidities. The findings Suggest that quantification of an easily measured index of sleep apnea-related hypoxias may be useful for identifying individuals at risk for heart disease, while also suggesting targets for intervention.

12.
J Clin Sleep Med ; 16(7): 1171-1178, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32248895

RESUMO

STUDY OBJECTIVES: African Americans have a high prevalence of severe sleep apnea that is often undiagnosed. We developed a prediction model for sleep apnea and compared the predictive values of that model to other prediction models among African Americans in the Jackson Heart Sleep Study. METHODS: Participants in the Jackson Heart Sleep Study underwent a type 3 home sleep apnea study and completed standardized measurements and questionnaires. We identified 26 candidate predictors from 17 preselected measures capturing information on demographics, anthropometry, sleep, and comorbidities. To develop the optimal prediction model, we fit logistic regression models using all possible combinations of candidate predictors. We then implemented a series of steps: comparisons of equivalent models based on the C-statistics, bootstrap to evaluate the finite sample properties of the C-statistics between models, and fivefold cross-validation to prevent overfitting. RESULTS: Of 719 participants, 38% had moderate or severe sleep apnea, 34% were male, and 38% reported habitual snoring. The average age and body mass index were 63.2 (standard deviation:10.7) years and 32.2 (standard deviation: 7.0) kg/m². The final prediction model included age, sex, body mass index, neck circumference, depressive symptoms, snoring, restless sleep, and witnessed apneas. The final model has an equal sensitivity and specificity of 0.72 and better predictive properties than commonly used prediction models. CONCLUSIONS: In comparing a prediction model developed for African Americans in the Jackson Heart Sleep Study to widely used screening tools, we found a model that included measures of demographics, anthropometry, depressive symptoms, and sleep patterns and symptoms better predicted sleep apnea.

13.
J Sleep Res ; : e13033, 2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32198950

RESUMO

Discrepancies between actigraphic and self-reported sleep measures are common. Studies of people with insomnia, in whom both sleep disturbances and discrepancy are common, suggest disturbances and discrepancy reflect differences in the sleeping brain's activity measurable using spectral electroencephalogram (EEG). Disentangling effects of discrepancy and disturbance on sleep EEG could help target research on the consequences and treatments of different sleep phenotypes. We therefore categorized participants in a cohort study including 2,850 men (average age = 76 years, standard deviation = 5.5) into four groups using median splits on actigraphic and self-reported sleep efficiency (SE). We compared spectral power between these groups in 1-Hz bins up to 24 Hz. Compared with the concordant-high SE group: (a) the group with high actigraphic and low self-reported SE had higher spectral power from 11-15 Hz across the night; (b) both groups with low actigraphic SE had higher power across the 15-24 Hz range, predominantly in early cycles, and greater slow frequency power in later cycles. These findings suggest that perceived wakefulness undetected by actigraphy may result from or drive activity corresponding to spindles. We also found, consistent with hyperarousal models, that low SE detectable via actigraphy was related to higher frequency power in the beta range; actigraph-measured inefficiency was also associated with later slow oscillations, potentially representing attempts to dissipate homeostatic drive elevated from earlier hyperarousal. These distinct spectral EEG markers (of low SE measured with actigraphy vs. low perceived SE that is not captured by actigraphy) may have different causes or consequences.

14.
Sci Rep ; 10(1): 189, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932708

RESUMO

Local ancestry, defined as the genetic ancestry at a genomic location of an admixed individual, is widely used as a genetic marker in genetic association and evolutionary genetics studies. Many methods have been developed to infer the local ancestries in a set of unrelated individuals, a few of them have been extended to small nuclear families, but none can be applied to large (e.g. three-generation) pedigrees. In this study, we developed a method, FamANC, that can improve the accuracy of local ancestry inference in large pedigrees by: (1) using an existing algorithm to infer local ancestries for all individuals in a family, assuming (contrary to fact) they are unrelated, and (2) improving its accuracy by correcting inference errors using pedigree structure. Applied on African-American pedigrees from the Cleveland Family Study, FamANC was able to correct all identified Mendelian errors and most of double crossovers.


Assuntos
Algoritmos , Grupos Étnicos/genética , Genética Populacional , Modelos Genéticos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Simulação por Computador , Genótipo , Haplótipos , Humanos , Linhagem
15.
Environ Res ; 182: 109095, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31927244

RESUMO

BACKGROUND: Although many studies have established significant associations between short-term air pollution and the risk of getting cardiovascular diseases, there is a lack of evidence based on causal distributed lag modeling. METHODS: Inverse probability weighting (ipw) propensity score models along with conditional logistic outcome regression models based on a case-crossover study design were applied to get the causal unconstrained distributed (lag0-lag5) as well as cumulative lag effect of short-term exposure to PM2.5/Ozone on hospital admissions of acute myocardial infarction (AMI), congestive heart failure (CHF) and ischemic stroke (IS) among New England Medicare participants during 2000-2012. Effect modification by gender, race, secondary diagnosis of Chronic Obstructive Pulmonary Diseases (COPD) and Diabetes (DM) was explored. RESULTS: Each 10 µg/m3 increase in lag0-lag5 cumulative PM2.5 exposure was associated with an increase of 4.3% (95% confidence interval: 2.2%, 6.4%, percentage change) in AMI hospital admission rate, an increase of 3.9% (2.4%, 5.5%) in CHF rate and an increase of 2.6% (0.4%, 4.7%) in IS rate. A weakened lagging effect of PM2.5 from lag0 to lag5 could be observed. No cumulative short-term effect of ozone on CVD was found. People with secondary diagnosis of COPD, diabetes, female gender and black race are sensitive population. CONCLUSIONS: Based on our causal distributed lag modeling, we found that short-term exposure to an increased ambient PM2.5 level had the potential to induce higher risk of CVD hospitalization in a causal way. More attention should be paid to population of COPD, diabetes, female gender and black race.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Doenças Cardiovasculares , Exposição Ambiental , Hospitalização , Ozônio , Material Particulado , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Grupos de Populações Continentais , Estudos Cross-Over , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Medicare , New England , Ozônio/toxicidade , Material Particulado/toxicidade , Estados Unidos
16.
Sleep ; 43(5)2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-31687772

RESUMO

STUDY OBJECTIVES: The bases for sex disparities in obstructive sleep apnea (OSA), is poorly understood. We quantified the influences of event definitions, sleep-state, and body position on apnea-hypopnea indices (AHIs) in men and women, and evaluated sex differences in pathophysiological endotypes. METHODS: Polysomnography (PSG) data were analyzed from 2057 participants from the multi-ethnic study of atherosclerosis. Alternative AHIs were compared using various desaturation and arousal criteria. Endotypes (loop gain, airway collapsibility, arousal threshold) were derived using breath-by-breath analysis of PSG signals. Regression models estimated the extent to which endotypes explained sex differences in AHI. RESULTS: The sample (mean 68.5 ± 9.2 years) included 54% women. OSA (AHI4P ≥15/h, defined by events with ≥4% desaturations) was found in 41.1% men and 21.8% women. Compared to AHI4P, male/female AHI ratios decreased by 5%-10% when using 3%-desaturation and/or arousal criteria; p < 0.05. REM-OSA (REM-AHI ≥15/h) was similar in men and women regardless of event desaturation criteria. REM-AHI4P ≥15/h was observed in 57% of men and women each. In NREM, AHI4P in men was 2.49 (CI95: 2.25, 2.76) of that in women. Women demonstrated lower loop gain, less airway collapsibility, and lower arousal threshold in NREM (ps < 0.0005). Endotypes explained 30% of the relative sex differences in NREM-AHI4P. CONCLUSIONS: There are significant sex differences in NREM-AHI levels and in physiological endotypes. Physiological endotypes explained a significant portion of the relative sex differences in NREM-AHI. Definitions that use 4%-desaturation criteria under-estimate AHI in women. Combining NREM and REM events obscures OSA prevalence in REM in women.

17.
EBioMedicine ; 50: 387-394, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31761615

RESUMO

BACKGROUND: Sleep disordered breathing (SDB) is a common disorder that results in oxidative stress and inflammation and is associated with multiple age-related health outcomes. Epigenetic age acceleration is a DNA methylation (DNAm)-based marker of fast biological aging. We examined the associations of SDB traits with epigenetic age acceleration. METHODS: A sample of 622 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) had blood DNAm measured and underwent Type 2 in-home polysomnography that assessed apnea-hypopnea index (AHI), percentage of sleep time with oxygen saturation lower than 90% (Per90), and arousal index. DNAm data provided measures of DNAm-Age acceleration and DNAm-PhenoAge acceleration. The association of each SDB trait with age acceleration was estimated using linear regression, controlling for covariates. In secondary analyses, we studied the associations of SDB traits with epigenetic age acceleration 2-10 years after sleep study in 530 individuals from the Framingham Heart Study (FHS). FINDINGS: In MESA, AHI was associated with greater DNAm-PhenoAge acceleration (ß = 0.03; 95% CI [0.001, 0.06]). Arousal index was associated with greater DNAm-Age acceleration (ß = 0.04; 95% CI [0.01, 0.07]). Both associations were stronger in women than men. In the secondary FHS analyses, Per90 was associated with greater DNAm-Age acceleration and this association was stronger in men. INTERPRETATION: More severe SDB was associated with epigenetic age acceleration in both cohorts. Future work should prospectively study short- and long-term effects of SDB, and whether treatment reduces epigenetic age acceleration among those individuals with SBD. FUNDING: National Institutes of Health.


Assuntos
Envelhecimento/genética , Suscetibilidade a Doenças , Epigênese Genética , Síndromes da Apneia do Sono/diagnóstico , Síndromes da Apneia do Sono/etiologia , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/diagnóstico , Aterosclerose/etiologia , Metilação de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Característica Quantitativa Herdável , Fatores de Risco
18.
Am J Hum Genet ; 105(5): 1057-1068, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31668705

RESUMO

Average arterial oxyhemoglobin saturation during sleep (AvSpO2S) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23,1,2 we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpO2S and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10-7). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpO2S variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpO2S. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpO2S.


Assuntos
Cromossomos Humanos Par 8/genética , Proteínas Ativadoras de GTPase/genética , Oxiemoglobinas/genética , Sono/genética , Proteínas Supressoras de Tumor/genética , Ligação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Sequenciamento Completo do Genoma/métodos
19.
Stat Med ; 38(24): 4841-4853, 2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31441522

RESUMO

It is increasingly of interest in statistical genetics to test for the presence of an additive interaction between genetic (G) and environmental (E) risk factors. In case-control studies involving a rare disease, a statistical test of no additive G×E interaction typically entails a test of no relative excess risk due to interaction (RERI). It has been shown that a likelihood ratio test of a null RERI incorporating the G-E independence assumption (RERI-LRT) outperforms the standard approach. The RERI-LRT relies on correct specification of a logistic model for the binary outcome, as a function of G, E, and auxiliary covariates. However, when at least one exposure is not categorical or auxiliary covariates are present, nonparametric estimation may not be feasible, while parametric logistic regression will a priori rule out the null hypothesis of no additive interaction in most practical situations, inflating type I error rate. In this paper, we present a general approach to test for G × E additive interaction exploiting G-E independence. Unlike the RERI-LRT, it allows the regression model for the binary outcome to remain unrestricted, and nonetheless still allows for covariate adjustment in order to ensure the G-E independence assumption or to rule out residual confounding. The methods are illustrated through extensive simulation studies and an ovarian cancer study.

20.
Sci Rep ; 9(1): 11410, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388106

RESUMO

Lower extremity peripheral artery disease (PAD) burden differs by race/ethnicity. Although familial aggregation and heritability studies suggest a genetic basis, little is known about the genetic susceptibility to PAD, especially in non-European descent populations. Genome-wide association studies (GWAS) of the ankle brachial index (ABI) and PAD (defined as an ABI < 0.90) have not been conducted in Hispanics/Latinos. We performed a GWAS of PAD and the ABI in 7,589 participants aged >45 years from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We also performed GWAS for ABI stratified by Hispanic/Latino ethnic subgroups: Central American, Mexican, and South American (Mainland group), and Cuban, Dominican, and Puerto Rican (Caribbean group). We detected two genome-wide significant associations for the ABI in COMMD10 in Puerto Ricans, and at SYBU in the Caribbean group. The lead SNP rs4466200 in the COMMD10 gene had a replication p = 0.02 for the ABI in Multi-Ethnic Study of Atherosclerosis (MESA) African Americans, but it did not replicate in African Americans from the Cardiovascular Health Study (CHS). In a regional look-up, a nearby SNP rs12520838 had Bonferroni adjusted p = 0.05 (unadjusted p = 7.5 × 10-5) for PAD in MESA Hispanics. Among three suggestive associations (p < 10-7) in subgroup-specific analyses, DMD on chromosome X, identified in Central Americans, replicated in MESA Hispanics (p = 2.2 × 10-4). None of the previously reported ABI and PAD associations in whites generalized to Hispanics/Latinos.

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