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2.
Blood ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420334

RESUMO

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30,234 VTE cases and 172,122 controls and assessed the association between 12,923,718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new, independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for both novel and previously known regions co-localized with eQTL signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

3.
Laryngoscope ; 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31424564

RESUMO

OBJECTIVES/HYPOTHESIS: To determine the 10-year incidence of hearing impairment (HI) and associated risk factors in the Beaver Dam Offspring Study (BOSS; 2004-present), a large middle-aged cohort followed for 10 years. STUDY DESIGN: Prospective cohort study. METHODS: Hearing thresholds were measured at baseline (2005-2008) and 5- (2010-2013) and 10-year (2015-2017) follow-up examinations. HI was defined as a pure-tone average >25 dB HL in either ear. BOSS participants free of HI at baseline with at least one follow-up examination (N = 2,065) were included. Potential risk factors evaluated included cardiovascular measures, health history, lifestyle factors, inflammatory markers, vitamins D and B12, lead, and cadmium. RESULTS: Participants were 21 to 79 years (mean age = 47.9 years) at baseline. The 10-year cumulative HI incidence was 17.4% (95% confidence interval [CI]: 15.7-19.2) and was twice as likely in men (24.4%, 95% CI: 21.5-27.7) than in women (12.2%, 95% CI: 10.3-14.3). In a multivariable adjusted model, age (hazard ratio [HR] = 1.48, 95% CI: 1.38-1.59, per 5 years), male sex (HR = 2.47, 95% CI: 1.91-3.18), less than a college education (HR = 1.35, 95% CI: 1.02-1.79), body mass index (HR = 1.03, 95% CI: 1.01-1.05, per kg/m2 ), and higher cadmium levels (HR = 1.42, 95% CI: 1.05-1.92, quintile 5 vs. quintiles 1-4) were associated with the 10-year cumulative incidence of HI. There was no association between high lead levels, vitamins D or B12, and 10-year incidence of HI. CONCLUSIONS: In addition to age and sex, obesity, education, and blood cadmium levels were associated with increased incidence of HI. These prospective results add to evidence that age-related HI is a multifactorial preventable disorder. LEVEL OF EVIDENCE: 2b Laryngoscope, 2019.

4.
Otolaryngol Head Neck Surg ; : 194599819868145, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31382849

RESUMO

OBJECTIVE: To investigate the association of midlife hypertension with late-life hearing impairment. STUDY DESIGN: Data from the Atherosclerosis Risk in Communities study, an ongoing prospective longitudinal population-based study (baseline, 1987-1989). SETTING: Washington County, Maryland, research field site. SUBJECTS AND METHODS: Subjects included 248 community-dwelling men and women aged 67 to 89 years in 2013. Systolic blood pressure (SBP) and diastolic blood pressure were measured at each of 5 study visits from 1987-1989 to 2013. Hypertension was defined by elevated systolic or diastolic blood pressure or antihypertensive medication use. A 4-frequency (0.5-4 kHz) better-hearing ear pure tone average in decibels hearing loss (dB HL) was calculated from pure tone audiometry measured in 2013. A cutoff of 40 dB HL was used to indicate clinically significant moderate to severe hearing impairment. Hearing thresholds at 5 frequencies (0.5-8 kHz) were also considered separately. RESULTS: Forty-seven participants (19%) had hypertension at baseline (1987-1989), as opposed to 183 (74%) in 2013. The SBP association with late-life pure tone average differed by the time of measurement, with SBP measured at earlier visits associated with poorer hearing; the difference in pure tone average per 10-mm Hg SBP measured was 1.43 dB HL (95% CI, 0.32-2.53) at baseline versus -0.43 dB HL (95% CI, -1.41 to 0.55) in 2013. Baseline hypertension was associated with higher thresholds (poorer hearing) at 4 frequencies (1, 2, 4, 8 kHz). CONCLUSION: Midlife SBP was associated with poorer hearing measured 25 years later. Further analysis into the longitudinal relationship between hypertension and hearing impairment is warranted.

5.
Genet Epidemiol ; 43(7): 776-785, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31218750

RESUMO

Nontraditional glycemic biomarkers, including fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) are potential alternatives or complement to traditional measures of hyperglycemia. Genetic variants are associated with these biomarkers, but the heritability, or extent to which genetics control their variation, is not known. We estimated pedigree-based, SNP-based, and bivariate heritabilities for traditional glycemic biomarkers (fasting glucose, HbA1c), and nontraditional biomarkers (fructosamine, glycated albumin, 1,5-AG) among white participants in the Atherosclerosis Risk in Communities (ARIC) Study (N = 400 first-degree relatives from sibships, N = 5,575 unrelated individuals). Pedigree-based heritabilities (representing heritability from the entire genome) for nontraditional biomarkers were substantial (0.44-0.55) and comparable to HbA1c (0.34); the fasting glucose estimate was nonsignificant. SNP-based heritabilities (representing heritability from common variants) were lower than pedigree-based heritabilities for all biomarkers. Bivariate heritabilities showed shared genetics between fructosamine and glycated albumin (0.46 pedigree-based, 1.00 SNP-based) and glycated albumin and 1,5-AG (0.50 pedigree-based, 0.47 SNP-based). Genetic factors contribute to a considerable proportion of the variance of fructosamine, glycated albumin, and 1,5-AG and a portion of this heritability likely comes from common variants.

6.
Clin Transl Gastroenterol ; 10(7): e00057, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31232720

RESUMO

INTRODUCTION: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM. We approached this question from a unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM. METHODS: We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin. RESULTS: The mean GRS was identical between 321 subjects with CP-DM and 423 subjects with T2DM (66.53 vs 66.42, P = 0.95), and the GRS of both diabetic groups was significantly higher than that of nondiabetic controls (n = 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreas-specific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM. DISCUSSION: Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.

7.
Environ Int ; 132: 104723, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31208937

RESUMO

BACKGROUND: DNA methylation (DNAm) may contribute to processes that underlie associations between air pollution and poor health. Therefore, our objective was to evaluate associations between DNAm and ambient concentrations of particulate matter (PM) ≤2.5, ≤10, and 2.5-10 µm in diameter (PM2.5; PM10; PM2.5-10). METHODS: We conducted a methylome-wide association study among twelve cohort- and race/ethnicity-stratified subpopulations from the Women's Health Initiative and the Atherosclerosis Risk in Communities study (n = 8397; mean age: 61.5 years; 83% female; 45% African American; 9% Hispanic/Latino American). We averaged geocoded address-specific estimates of daily and monthly mean PM concentrations over 2, 7, 28, and 365 days and 1 and 12 months before exams at which we measured leukocyte DNAm in whole blood. We estimated subpopulation-specific, DNAm-PM associations at approximately 485,000 Cytosine-phosphate-Guanine (CpG) sites in multi-level, linear, mixed-effects models. We combined subpopulation- and site-specific estimates in fixed-effects, inverse variance-weighted meta-analyses, then for associations that exceeded methylome-wide significance and were not heterogeneous across subpopulations (P < 1.0 × 10-7; PCochran's Q > 0.10), we characterized associations using publicly accessible genomic databases and attempted replication in the Cooperative Health Research in the Region of Augsburg (KORA) study. RESULTS: Analyses identified significant DNAm-PM associations at three CpG sites. Twenty-eight-day mean PM10 was positively associated with DNAm at cg19004594 (chromosome 20; MATN4; P = 3.33 × 10-8). One-month mean PM10 and PM2.5-10 were positively associated with DNAm at cg24102420 (chromosome 10; ARPP21; P = 5.84 × 10-8) and inversely associated with DNAm at cg12124767 (chromosome 7; CFTR; P = 9.86 × 10-8). The PM-sensitive CpG sites mapped to neurological, pulmonary, endocrine, and cardiovascular disease-related genes, but DNAm at those sites was not associated with gene expression in blood cells and did not replicate in KORA. CONCLUSIONS: Ambient PM concentrations were associated with DNAm at genomic regions potentially related to poor health among racially, ethnically and environmentally diverse populations of U.S. women and men. Further investigation is warranted to uncover mechanisms through which PM-induced epigenomic changes may cause disease.

8.
Am Heart J ; 213: 30-34, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31085382

RESUMO

Hepatocyte growth factor (HGF) is associated with subclinical and clinical atherosclerosis. However, the significance of change in HGF and development of atherosclerotic disease is unknown. In a large and diverse population-based cohort, we report that change in the biomarker HGF is an independent predictor of incident CHD.

9.
Acta Diabetol ; 56(6): 619-629, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30888538

RESUMO

AIMS: It is unclear if the presence of type-2 diabetes in one spouse is associated with the development of diabetes in the other spouse. We studied the concordance of diabetes among black and white participants in the Atherosclerosis Risk in Communities (ARIC) study and summarized existing studies in a meta-analysis. METHODS: We conducted a prospective cohort analysis of ARIC data from 8077 married men and women (mean age 54 years) without diabetes at baseline (1987-1989). Complementary log-log models that accounted for interval censoring was used to model the hazard ratio (HR) for the association of spousal diabetes status with the incidence of diabetes. For the meta-analysis, we searched MEDLINE and EMBASE for observational studies published through December 2018 that evaluated spousal concordance for diabetes. RESULTS: During a median follow-up of 22 years, 2512 incident cases of diabetes were recorded. In models with adjustment for general adiposity, spousal cardiometabolic factors and other diabetes risk factors, adults who had a spouse with diabetes had elevated risk for incident diabetes compared to those without a spouse diagnosed with diabetes (HR 1.20, 95% confidence interval 1.02-1.41). This association did not differ by sex or race. Summarized estimates from the 17 studies (489,798 participants from 9 countries) included in the meta-analysis showed a positive association between spousal diabetes status and the development of diabetes (Pooled odds ratio 1.88, 95% CI 1.52-2.33). CONCLUSIONS: Results from this large prospective biracial cohort and meta-analysis provides evidence that spouses of persons with diabetes are a high-risk group for diabetes.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Cônjuges/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
10.
J Gerontol A Biol Sci Med Sci ; 74(11): 1786-1792, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30629132

RESUMO

BACKGROUND: Sensorineural impairments and cardiovascular risk factors (CVRF) and disease (CVD) in midlife may be important predictors of future cognitive health, but longitudinal studies that include multiple sensorineural measures in middle-aged adults are lacking. METHODS: Hearing, vision, and olfaction, and CVRF and CVD were measured at the Beaver Dam Offspring Study baseline (2005-2008) examination. The Mini-Mental State Examination and Trail Making Tests A and B were administered at all phases and additional cognitive function measures were obtained at 5 (2010-2013) and 10 years (2015-2017). Cox proportional hazards models were used to evaluate associations between baseline sensorineural impairments, CVRF, CVD, and 10-year cumulative incidence of cognitive impairment and decline. RESULTS: There were 2,556 participants (22-84 years) without cognitive impairment at baseline and data from at least one follow-up. In a multivariable model including age, sex, education, and head injury, visual impairment (hazard ratio = 2.59, 95% confidence interval = 1.34, 5.02), olfactory impairment (hazard ratio = 3.18, 95% confidence interval = 1.53, 6.59), CVD (hazard ratio = 2.37, 95% confidence interval = 1.24, 4.52), and not consuming alcohol in the past year (hazard ratio = 2.21, 95% confidence interval = 1.16, 4.19) were associated with the 10-year cumulative incidence of cognitive impairment. Current smoking and diabetes were associated with increased risk, and exercise with decreased risk, of 10-year decline in cognitive function. CONCLUSIONS: Visual and olfactory impairments, CVRF, and CVD were associated with the 10-year cumulative incidence of cognitive impairment and decline in middle-aged adults. Identifying modifiable factors associated with cognitive decline and impairment in midlife may provide opportunities for prevention or treatment and improve cognitive health later in life.

11.
J Am Heart Assoc ; 7(22): e009683, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30571501

RESUMO

Background Acute infections are known cardiovascular disease ( CVD ) triggers, but little is known regarding how CVD risk varies following inpatient versus outpatient infections. We hypothesized that in- and outpatient infections are associated with CVD risk and that the association is stronger for inpatient infections. Methods and Results Coronary heart disease (CHD) and ischemic stroke cases were identified and adjudicated in the ARIC (Atherosclerosis Risk in Communities Study). Hospital discharge diagnosis codes and Medicare claims data were used to identify infections diagnosed in in- and outpatient settings. A case-crossover design and conditional logistic regression were used to compare in- and outpatient infections among CHD and ischemic stroke cases (14, 30, 42, and 90 days before the event) with corresponding control periods 1 and 2 years previously. A total of 1312 incident CHD cases and 727 incident stroke cases were analyzed. Inpatient infections (14-day odds ratio [ OR ]=12.83 [5.74, 28.68], 30-day OR =8.39 [4.92, 14.31], 42-day OR =6.24 [4.02, 9.67], and 90-day OR =4.48 [3.18, 6.33]) and outpatient infections (14-day OR =3.29 [2.50, 4.32], 30-day OR =2.69 [2.14, 3.37], 42-day OR =2.45 [1.97, 3.05], and 90-day OR =1.99 [1.64, 2.42]) were more common in all CHD case periods compared with control periods and inpatient infection was a stronger CHD trigger for all time periods ( P<0.05). Inpatient infection was also a stronger stroke trigger with the difference borderline statistically significant ( P<0.10) for the 42- and 90-day time periods. Conclusions In- and outpatient infections are associated with CVD risk. Patients with an inpatient infection may be at particularly elevated CVD risk and should be considered potential candidates for CVD prophylaxis.

12.
J Am Acad Audiol ; 2018 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30461399

RESUMO

BACKGROUND: Associations between vascular health-related factors and hearing loss defined using audiometric pure-tone thresholds have been found. Studies have not focused on a potential relationship between vascular health-related factors and central auditory processing. PURPOSE: The aim of this study was to evaluate, on a population level, the relationship of vascular health-related factors with central auditory function. RESEARCH DESIGN: A cross-sectional, population study. STUDY SAMPLE: Subjects were participants in the Epidemiology of Hearing Loss Study (EHLS) or the Beaver Dam Offspring Study (BOSS)-prospective studies of aging and sensory loss. BOSS participants were the adult offspring of participants in the EHLS. Participants who completed the Dichotic Digits Test (DDT) during the fourth examination period of the EHLS (2008-2010) or the second examination period of the BOSS (2010-2013) were included (n = 3,655, mean age = 61.1 years). DATA COLLECTION AND ANALYSIS: The DDT-free recall test was conducted using 25 sets of triple-digit pairs at a 70 dB HL presentation level. The total number of correctly repeated digits from the right and left ears was converted to a percentage correct and used as an outcome. The percentage correct in the left ear was subtracted from the percentage correct in the right ear and used as an outcome. Vascular health-related measures obtained during the examination included blood pressure, mean carotid intima-media thickness, femoral pulse wave velocity (PWV), hemoglobin A1C, and non-high-density lipoprotein (HDL) cholesterol, and, in the EHLS participants, C-reactive protein and interleukin-6. Information on vascular health-related history and behaviors was self-reported. General linear modeling produced estimates of the age- and sex-adjusted least squares means for each vascular factor, and multiple linear regression was used for multivariable modeling of each outcome. RESULTS: After multivariable adjustment, participants with diabetes had a significantly lower (worse) mean DDT-free recall total score (-2.08 percentage points, p < 0.001) than those without diabetes. Participants who exercised at least once per week had a significantly higher (better) mean DDT-free recall total score (+1.07 percentage points, p < 0.01) than those who did not exercise at least once per week. Alcohol consumption was associated with a higher DDT-free recall total score (+0.15 percentage points per +25 g ethanol, p < 0.01). In multivariable modeling of the right-left ear difference in DDT-free recall scores, participants with a history of cardiovascular disease (CVD) or higher PWV demonstrated significantly larger differences (CVD: +3.11 percentage points, p = 0.02; PWV: +0.36 percentage points per 1 m/sec, p < 0.01). Higher levels of non-HDL cholesterol were associated with smaller right-left ear differences (-0.22 percentage points per 10 mg/dL, p = 0.01). Adjustment for handedness did not affect the results. CONCLUSIONS: Vascular health-related factors may play a role in central auditory function.

13.
J Clin Periodontol ; 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30362614

RESUMO

AIM: Periodontal disease is a cardiovascular disease (CVD) risk factor but few studies have considered the relationship between periodontal disease and venous thromboembolism (VTE). We hypothesized that periodontal disease is independently associated with increased risk of incident VTE. MATERIALS AND METHODS: We used data from 8,092 participants of the Atherosclerosis Risk in Communities (ARIC) study to examine periodontal disease in 1996-1998 and incident VTE through 2011. Periodontal disease was determined using self-reported tooth loss due to gum disease and dental examinations. Cox proportional hazards regression models were used to estimate hazard ratios for VTE and 95% confidence intervals adjusted for relevant confounders. RESULTS AND CONCLUSIONS: Participants were on average 62.7 years old at baseline and 13.9% self-reported tooth loss from gum disease. Over a mean of 12.9 years of follow-up, there were 313 incident VTE events. Self-reported tooth loss due to gum disease was associated with 30% higher VTE risk (HR = 1.29 (0.96, 1.73) after adjusting demographic factors, SES, periodontal risk factors, oral hygiene, and access to dental care variables. No statistically significant associations between clinical measures of periodontitis and VTE were observed after adjustment. Further research is needed to elucidate whether a relationship between periodontal disease and VTE exists.

14.
Alzheimers Dement (N Y) ; 4: 499-507, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364572

RESUMO

Introduction: Hearing impairment is highly prevalent and independently associated with cognitive decline. The Aging and Cognitive Health Evaluation in Elders study is a multicenter randomized controlled trial to determine efficacy of hearing treatment in reducing cognitive decline in older adults. Clinicaltrials.gov Identifier: NCT03243422. Methods: Eight hundred fifty participants without dementia aged 70 to 84 years with mild-to-moderate hearing impairment recruited from four United States field sites and randomized 1:1 to a best-practices hearing intervention or health education control. Primary study outcome is 3-year change in global cognitive function. Secondary outcomes include domain-specific cognitive decline, incident dementia, brain structural changes on magnetic resonance imaging, health-related quality of life, physical and social function, and physical activity. Results: Trial enrollment began January 4, 2018 and is ongoing. Discussion: When completed in 2022, Aging and Cognitive Health Evaluation in Elders study should provide definitive evidence of the effect of hearing treatment versus education control on cognitive decline in community-dwelling older adults with mild-to-moderate hearing impairment.

15.
Sleep ; 41(11)2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30184232

RESUMO

Study Objectives: To examine the associations of sleep measures with hemoglobin A1c (HbA1c) among individuals with and without type 2 diabetes. Methods: Data were from 2049 Multi-Ethnic Study of Atherosclerosis participants taking part in a sleep ancillary study. Cross-sectional linear regression models examined associations of actigraphy estimates of sleep (sleep duration, variability, and maintenance efficiency) and polysomnography measures (obstructive sleep apnea [OSA] and hypoxemia) with HbA1c, stratified by diabetes status. Primary models were adjusted for demographics, lifestyle behaviors, and obesity. Results: Among individuals with diabetes (20 per cent population), those who slept <5 hr/night had greater HbA1c than those who slept 7-8 hr/night (7.44 vs. 6.98 per cent, ptrend = 0.04), with no attenuation of associations after adjusting for OSA/hypoxemia. In women with diabetes, but not men, those in the lowest quartile of sleep maintenance efficiency had greater HbA1c than those in the highest quartile of sleep maintenance efficiency (7.60 vs. 6.97 per cent, ptrend < 0.01). Among those without diabetes, individuals with severe OSA or in the highest quartile of hypoxemia had significantly greater HbA1c than those without OSA or who were in the lowest quartile of hypoxemia (5.76 vs. 5.66 per cent, ptrend = 0.01; 5.75 vs. 5.66 per cent, ptrend < 0.01, respectively). Associations did not meaningfully differ by race/ethnicity. Conclusions: Among individuals with diabetes, HbA1c was significantly higher in men and women with short sleep duration and in women with poor sleep maintenance efficiency, suggesting a role for behavioral sleep interventions in the management of diabetes. Among individuals without diabetes, untreated severe OSA/hypoxemia may adversely influence HbA1c.

16.
Br J Nutr ; 120(10): 1159-1170, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30205856

RESUMO

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.

18.
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.

19.
Thromb Res ; 168: 53-59, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29902632

RESUMO

INTRODUCTION: Data from epidemiological studies and clinical trials suggest an influence of dietary and circulating polyunsaturated fatty acids (PUFAs) on the hemostasis profile. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) related to plasma PUFAs levels. We aimed to investigate whether the SNPs related to plasma PUFAs levels were also associated with plasma levels of hemostatic variables. MATERIALS AND METHODS: We tested the associations between 9 PUFA-related SNPs and 6 hemostatic variables in 9035 European Americans (EAs) and 2702 African Americans (AAs) in the Atherosclerosis Risk in Communities (ARIC) Study. We then conducted a replication study by looking-up our novel observed associations in three published GWAS for hemostatic factors in different EA populations. RESULTS: We observed a novel linoleic acid-related locus at the JMJD1C region associated with factor VII activity (FVIIc): rs10740118 and rs1935, Beta (p) = -1.31 (1 × 10-3) and 1.37 (5 × 10-4) in EAs, respectively, and - 1.24 (5 × 10-4) and 1.28 (3 × 10-4) in meta-analysis of EAs and AAs of ARIC. This novel association was replicated in two of three independent EA populations (p = 0.01 and 0.03 in meta-analyses). We confirmed previously reported associations at the docosapentaenoic acid-related GCKR locus with protein C and FVIIc and at JMJD1C with fibrinogen. Adjustment for plasma PUFAs did not abolish the associations between these loci and hemostatic variables. CONCLUSIONS: Our study identified a novel association for FVIIc at JMJD1C, a histone demethylase that plays a role in DNA repair and possibly transcription regulation and RNA processing.


Assuntos
Ácidos Graxos Ômega-3/genética , Ácidos Graxos Insaturados/genética , Pleiotropia Genética/genética , Variação Genética/genética , Feminino , Hemostáticos , Humanos , Masculino , Pessoa de Meia-Idade
20.
Comput Math Methods Med ; 2018: 2564531, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29743933

RESUMO

Multiple correlated traits are often collected in genetic studies. By jointly analyzing multiple traits, we can increase power by aggregating multiple weak effects and reveal additional insights into the genetic architecture of complex human diseases. In this article, we propose a multivariate linear regression-based method to test the joint association of multiple quantitative traits. It is flexible to accommodate any covariates, has very accurate control of type I errors, and offers very competitive performance. We also discuss fast and accurate significance p value computation especially for genome-wide association studies with small-to-medium sample sizes. We demonstrate through extensive numerical studies that the proposed method has competitive performance. Its usefulness is further illustrated with application to genome-wide association analysis of diabetes-related traits in the Atherosclerosis Risk in Communities (ARIC) study. We found some very interesting associations with diabetes traits which have not been reported before. We implemented the proposed methods in a publicly available R package.

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