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1.
Sci Rep ; 11(1): 6662, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33758211

RESUMO

The sensitivity of electrocardiogram (ECG) criteria to detect left ventricular hypertrophy (LVH) is low, especially in women. We determined sex-specific sensitivities of ECG-LVH criteria, and developed new criteria, using cardiovascular magnetic resonance imaging (CMR). Sensitivities of ECG-LVH criteria were determined in participants of the UK Biobank (N = 3632). LVH was defined when left ventricular mass was > 95% confidence interval (CI) according to age and sex. In a training cohort (75%, N = 2724), sex-specific ECG-LVH criteria were developed by investigating all possible sums of QRS-amplitudes in all 12 leads, and selecting the sum with the highest pseudo-R2 and area under the curve to detect LVH. Performance was assessed in a validation cohort (25%, N = 908), and association with blood pressure change was investigated in an independent cohort. Sensitivities of ECG-LVH criteria were low, especially in women. Newly developed Groningen-LVH criterion for women (QV2 + RI + RV5 + RV6 + SV2 + SV4 + SV5 + SV6) outperformed all ECG-LVH criteria with a sensitivity of 42% (95% CI 35-49%). In men, newly developed criterion ((RI + RV5 + SII + SV2 + SV6) × QRS duration) was equally sensitive as 12-lead sum with a sensitivity of 44% (95% CI 37-51%) and outperformed the other criteria. In an independent cohort, the Groningen-LVH criteria were strongest associated with change in systolic blood pressure. Our proposed CMR sex-specific Groningen-LVH criteria improve the sensitivity to detect LVH, especially in women. Further validation and its association with clinical outcomes is warranted.

3.
Sci Rep ; 11(1): 2794, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531528

RESUMO

Underlying genetic determinants contribute to developing type 2 diabetes (T2D) future diseases. The present study aimed to identify which genetic variants are associated with the incident of the major T2D co-morbid disease. First, we conducted a discovery study by investigating the genetic associations of comorbid diseases within the framework of the Utrecht Cardiovascular Pharmacogenetic studies by turning information of > 25 years follow-up data of 1237 subjects whom were genotyped and included in the discovery study. We performed Cox proportional-hazards regression to examine associations between genetic variants and comorbid diseases including cardiovascular diseases (CVD), chronic eye disease, cancer, neurologic diseases and chronic kidney disease. Secondly, we replicated our findings in two independent cohorts consisting of 1041 subjects. Finally, we performed a meta-analysis by combining the discovery and two replication cohorts. We ascertained 390 (39.7%) incident cases of CVD, 182 (16.2%) of chronic eye disease, 155 (13.8%) of cancer, 31 (2.7%) of neurologic disease and 13 (1.1%) of chronic kidney disease during a median follow-up of 10.2 years. In the discovery study, we identified a total of 39 Single Nucleotide Polymorphisms (SNPs) associated with comorbid diseases. The replication study, confirmed that rs1870849 and rs8051326 may play a role in the incidence of chronic eye disease in T2D patients. Half of patients developed at least one comorbid disease, with CVD occurring most often and earliest followed by chronic eye disease. Further research is needed to confirm the associations of two associated SNPs with chronic eye disease in T2D.

4.
Ocul Surf ; 20: 13-19, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33421635

RESUMO

PURPOSE: Sleep is an important determinant of health and quality of life. This study aimed to clarify the association between dry eye and sleep quality using a large population-based cohort. METHODS: 71,761 participants (19-94 yrs, 59.4% female) from the Lifelines cohort in the Netherlands were assessed for dry eye using the Women's Health Study Dry Eye Questionnaire. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Logistic regression was used to examine the relationship between poor sleep quality (PSQI score >5) and dry eye, while correcting for age, sex, BMI, education, income, and 51 possible confounding comorbidities, including autoimmune diseases and psychiatric disorders. RESULTS: Overall, 8.9% of participants had dry eye. Of these, 36.4% had poor sleep quality compared to 24.8% of controls (OR 1.52 (95%CI 1.44-1.60), P < 0.0001, corrected for age and sex). After correcting for all comorbidities, dry eye was still associated with poor sleep (OR 1.20 (95%CI 1.11-1.28), P < 0.0001). This relationship was seen across all ages and sexes. Patients with dry eye scored worse on all subcomponents of the PSQI. Almost one-in-two (44.9%) persons with dry eye symptoms "often" or "constantly" had poor sleep quality. This proportion was similar to participants with sleep apnea and osteoarthritis. Additionally, increasing symptom frequency was tied to increased prevalence of poor sleep quality. CONCLUSIONS: All components of sleep quality were significantly reduced in participants with dry eye, even after correcting for comorbidities. These results indicate the substantial impact of dry eye on patients' lives, especially for those with frequent symptoms.

5.
Bioinformatics ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33416854

RESUMO

SUMMARY: Quality control (QC) of genome wide association study (GWAS) result files has become increasingly difficult due to advances in genomic technology. The main challenges include continuous increases in the number of polymorphic genetic variants contained in recent GWASs and reference panels, the rising number of cohorts participating in a GWAS consortium, and inclusion of new variant types. Here, we present GWASinspector, a flexible R package for comprehensive QC of GWAS results. This package is compatible with recent imputation reference panels, handles insertion/deletion and multi-allelic variants, provides extensive QC reports and efficiently processes big data files. Reference panels covering three human genome builds (NCBI36, GRCh37 and GRCh38) are available. GWASinspector has a user friendly design and allows easy set-up of the QC pipeline through a configuration file. In addition to checking and reporting on individual files, it can be used in preparation of a meta-analysis by testing for systemic differences between studies and generating cleaned, harmonized GWAS files. Comparison with existing GWAS QC tools shows that the main advantages of GWASinspector are its ability to more effectively deal with insertion/deletion and multi-allelic variants and its relatively low memory use. AVAILABILITY AND IMPLEMENTATION: Our package is available at The Comprehensive R Archive Network (CRAN): https://CRAN.R-project.org/package=GWASinspector. Reference datasets and a detailed tutorial can be found at the package website at http://gwasinspector.com/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

6.
BMC Ophthalmol ; 21(1): 18, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413217

RESUMO

BACKGROUND: Early detection of glaucoma is paramount to maintain patients' eyesight, however glaucomatous vision loss tends to begin in the periphery with up to 50% of patients unaware they are affected. Because glaucomatous vision loss is permanent, screening appears attractive, but currently is not cost-effective. Therefore we aim to investigate the utility of genetic pre-screening for glaucoma in a population-based setting, called EyeLife. METHODS: EyeLife adopts a double blind prospective design with contrasting groups. Selected participants (n = 1600) from the Lifelines cohort are 55 years of age or older, and of either the highest or lowest 20% of the genetic risk distribution for glaucoma. We obtained a highly curated list of genetic variants from the literature to obtain each participants' genetic risk for glaucoma. Participants will undergo comprehensive ophthalmic screening. The primary outcome is the relative risk of glaucoma given a high genetic risk compared to a low genetic risk. DISCUSSION: If genetic pre-screening is successful, it will increase the yield of a glaucoma screening program by focusing on high-risk individuals. This, in turn, may improve long-term visual health of middle-aged and elderly people. TRIAL REGISTRATION: Ethics approval was obtained on January 31, 2019, and the study was retrospectively registered with the Netherlands Trial Register ( NL8718 ) on the 17th of June, 2020.

7.
Environ Res ; 192: 110262, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33045228

RESUMO

The link between exposure to endocrine disrupting chemicals (EDCs) and the rapid increase in prevalence of obesity has recently been suggested. However, the magnitude and health impact of EDC exposure in at-risk populations remain largely unclear. In this study, we investigated the effect of a dietary intervention driven reduction in adipose tissue on the magnitude of urinary EDC exposure and mobilization, and whether higher EDC exposure leads to impaired weight loss in obese individuals. In this post-hoc analysis of the Lifestyle, OverWeight, Energy Restriction (LOWER) study from the Netherlands, 218 subjects were included. Five parabens, three bisphenols and thirteen metabolites of eight phthalates were measured in 24-h urine using LC-MS/MS, before and after three-months of a calory-restricted weight reduction intervention program. Associations between adiposity-related traits and EDCs were tested using multivariable linear regression and linear mixed effects models. A multiple testing correction based on the false discovery rate (FDR) was applied. After the 3-month intervention, urinary paraben and bisphenol excretions remained similar. Excretions of mono-butyl phthalates and most high-molecular-weight phthalates decreased, whereas mono-ethyl phthalate increased (all FDR<0.05). A reduction in adipose tissue was not associated with higher urinary EDC excretions. Higher baseline EDC excretions were associated with higher post-intervention body-mass index (methyl-, propylparaben), waist circumference (propylparaben, mono-n-butyl phthalate, mono-benzyl phthalate), and body fat percentage (mono-ethyl phthalate, mono-benzyl phthalate). Associations between parabens and body-mass index, and mono-benzyl phthalate and waist circumference and body fat percentage remained after multiple testing correction (all FDR<0.05). In a study of obese participants, we observed a reduction in most phthalates after a weight reduction intervention. A reduction in adipose tissue may not lead to mobilization and successively to higher urinary EDC excretions. Higher baseline paraben and phthalate exposures were associated with reduced weight loss, suggesting obesogenic properties.

8.
Am J Kidney Dis ; 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33359149

RESUMO

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) has a heritable component. We aimed to quantify familial aggregation of CKD in the general population and assess the extent to which kidney traits could be explained by genetic and environmental factors. STUDY DESIGN: Cross-sectional 3-generation family study. SETTING & PARTICIPANTS: Data were collected at entry into the Lifelines Cohort Study from a sample of the general population of the northern Netherlands, composed predominantly of individuals of European ancestry. EXPOSURE: Family history of CKD. OUTCOMES: The primary outcome was CKD, defined as estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2, where GFR was estimated using the CKD Epidemiology Collaboration creatinine equation. Among a subsample for which urinary albumin concentration was available (n=59,943), urinary albumin excretion was expressed as the rate of urinary albumin excretion (UAE) per 24 hours or urinary albumin-creatinine ratio (UACR). ANALYTICAL APPROACH: Familial aggregation of CKD was assessed by calculating the recurrence risk ratio (RRR), using adapted Cox proportional hazards models. Heritability of continuous kidney-related traits was estimated using linear mixed models and defined as the ratio of the additive genetic variance to total phenotypic variance. All models were adjusted for age, sex, and known risk factors for kidney disease. RESULTS: Among 155,911 participants with available eGFR data, the prevalence of CKD was 1.19% (1,862 cases per 155,911). The risk of CKD in those with an affected first-degree relative was 3 timeshigher than the risk in the total sample (RRR, 3.04 [95% CI, 2.26-4.09). In those with an affected spouse, risk of CKD was also higher (RRR, 1.56 [95% CI, 1.20-1.96]), indicative of shared environmental factors and/or assortative mating. Heritability estimates of eGFR, UAE, and UACR were 44%, 20%, and 18%, respectively. For serum urea, creatinine, and uric acid, estimates were 31%, 37%, and 48%, respectively, whereas estimates for serum electrolytes ranged from 22% to 28%. LIMITATIONS: Use of estimated rather than measured GFR. UAE data only available in a subsample. CONCLUSIONS: In this large population-based family study, a positive family history was strongly associated with increased risk of CKD. We observed moderate to high heritability of kidney traits and related biomarkers. These results indicate an important role of genetic factors in CKD risk.

9.
Nat Commun ; 11(1): 5980, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239672

RESUMO

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10-8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10-8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10-9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10-8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

10.
J Am Heart Assoc ; 9(22): e018089, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33167754

RESUMO

Background There is still uncertainty about the nature and relative impact of early determinants on childhood blood pressure. This study explored determinants of blood pressure at the age of 6 years in 2 Dutch birth cohorts. Methods and Results Results of hierarchical multiple linear regression analyses in GECKO (Groningen Expert Center for Kids With Obesity) Drenthe study (n=1613) were replicated in ABCD (Amsterdam Born Children and Their Development) study (n=2052). All analyses were adjusted for child's age, sex, height, and body mass index (BMI), and maternal education and subsequently performed in the combined sample. No associations were found between maternal smoking during pregnancy and childhood blood pressure. In the total sample, maternal prepregnancy BMI was positively associated with systolic blood pressure (SBP) (ß [95% CI], 0.09 [0.02-0.16] mm Hg) and diastolic blood pressure (ß [95% CI], 0.11 [0.04-0.17] mm Hg). Children of women with hypertension had higher SBP (ß [95% CI], 0.98 [0.17-1.79] mm Hg). Birth weight standardized for gestational age was inversely associated with SBP (ß [95% CI], -6.93 [-9.25 to -4.61] mm Hg) and diastolic blood pressure (ß [95% CI], -3.65 [-5.70 to -1.61] mm Hg). Longer gestational age was associated with lower SBP (ß [95% CI] per week, -0.25 [-0.42 to -0.08] mm Hg). Breastfeeding for 1 to 3 months was associated with lower SBP (ß [95% CI], -0.96 [-1.82 to -0.09] mm Hg) compared with no or <1 month of breastfeeding. Early BMI gain from the age of 2 to 6 years was positively associated with SBP (ß [95% CI], 0.41 [0.08-0.74] mm Hg) and diastolic blood pressure (ß [95% CI], 0.37 [0.07-0.66] mm Hg), but no effect modification by birth weight was found. Conclusions Higher maternal prepregnancy BMI, maternal hypertension, a relatively lower birth weight for gestational age, shorter gestational age, limited duration of breastfeeding, and more rapid early BMI gain contribute to higher childhood blood pressure at the age of 6 years.

11.
Am J Epidemiol ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33089864

RESUMO

Both genetic predisposition and low educational attainment (EA) are associated with higher risk of chronic kidney disease. We examined the interaction of EA and genetic risk in kidney function outcomes. We included 3,597 participants from the Prevention of REnal and Vascular ENd stage Disease Cohort Study, a longitudinal study in a community-based sample from Groningen, the Netherlands (median follow-up 11 years, 1997-2012). Kidney function was approximated by estimating glomerular filtration rate (eGFR) from serum creatinine and cystatin C. Individual longitudinal linear eGFR trajectories were derived from linear mixed models. Genotype data on 63 single nucleotide polymorphisms, with known associations to eGFR, were used to calculate an allele-weighted genetic score (WGS). EA was categorized into high, medium, and low. In ordinary least squares analysis, higher WGS and lower EA showed additive effects on reduced baseline eGFR; the interaction term was non-significant. In analysis of eGFR decline, the significant interaction term suggested amplification of genetic risk by low EA. Adjustment for known renal risk factors did not affect our results. This study presents the first evidence of gene-environment interaction between EA and a WGS on eGFR decline, and provides population-level insights into the mechanisms underlying socioeconomic disparities in chronic kidney disease.

12.
Environ Int ; 144: 106016, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32916427

RESUMO

BACKGROUND: Exposure to environmental endocrine disrupting chemicals (EDCs) may play an important role in the epidemic of metabolic diseases. Epigenetic alterations may functionally link EDCs with gene expression and metabolic traits. OBJECTIVES: We aimed to evaluate metabolic-related effects of the exposure to endocrine disruptors including five parabens, three bisphenols, and 13 metabolites of nine phthalates as measured in 24-hour urine on epigenome-wide DNA methylation. METHODS: A blood-based epigenome-wide association study was performed in 622 participants from the Lifelines DEEP cohort using Illumina Infinium HumanMethylation450 methylation data and EDC excretions in 24-hour urine. Out of the 21 EDCs, 13 compounds were detected in >75% of the samples and, together with bisphenol F, were included in these analyses. Furthermore, we explored the putative function of identified methylation markers and their correlations with metabolic traits. RESULTS: We found 20 differentially methylated cytosine-phosphate-guanines (CpGs) associated with 10 EDCs at suggestive p-value < 1 × 10-6, of which four, associated with MEHP and MEHHP, were genome-wide significant (Bonferroni-corrected p-value < 1.19 × 10-7). Nine out of 20 CpGs were significantly associated with at least one of the tested metabolic traits, such as fasting glucose, glycated hemoglobin, blood lipids, and/or blood pressure. 18 out of 20 EDC-associated CpGs were annotated to genes functionally related to metabolic syndrome, hypertension, obesity, type 2 diabetes, insulin resistance and glycemic traits. CONCLUSIONS: The identified DNA methylation markers for exposure to the most common EDCs provide suggestive mechanism underlying the contributions of EDCs to metabolic health. Follow-up studies are needed to unravel the causality of EDC-induced methylation changes in metabolic alterations.

13.
Invest Ophthalmol Vis Sci ; 61(11): 25, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931573

RESUMO

Purpose: We investigated relationship of glaucoma with measurements related to autonomic dysfunction, including heart rate variability (HRV) and blood pressure (BP). Methods: Glaucoma was defined using a questionnaire-based algorithm for 86,841 LifeLines Cohort Study participants. Baseline HRV (root mean square of successive differences [RMSSD]) was calculated from resting electrocardiograms; systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) were oscillometric-based measurements. We used a generalized linear mixed model, adjusted for age, age square, sex, body mass index, and familial relationships to assess the relationship of baseline HRV and BP (continuous and quartiles), hypertension, and antihypertensive medication with glaucoma at follow up (median, 3.8 years). Results: The odds ratio (OR) of glaucoma was 0.95 (95% confidence interval [CI], 0.92-0.99) per unit increase in log-transformed RMSSD (in ms), indicating that autonomous dysfunction (low HRV) is associated with a higher risk of glaucoma. Per 10-mm Hg increase in BP, we found ORs of 1.03 (95% CI, 1.01-1.05; P = 0.015) for SBP, 1.01 (95% CI, 0.97-1.05; P = 0.55) for DBP, 1.03 (95% CI, 1.00-1.06; P = 0.083) for MAP, and 1.04 (95% CI, 1.01-1.07; P = 0.006) for PP. The OR for the lowest versus highest RMSSD quartile was 1.15 (95% CI, 1.05-1.27; P = 0.003). The ORs for the highest versus second quartile were 1.09 (95% CI, 0.99-1.19; P = 0.091) for SBP and 1.13 (95% CI, 1.02-1.24; P = 0.015) for PP. Glaucoma was more common among hypertensives (OR, 1.25; 95% CI, 1.16-1.35; P < 0.001); among those using angiotensin-converting enzyme (ACE) inhibitors (OR, 1.35; 95% CI, 1.18-1.55; P < 0.001); and among those using calcium-channel blockers (OR, 1.19; 95% CI, 1.01-1.40; P = 0.039). Conclusions: Low HRV, high SBP, high PP, and hypertension were associated with glaucoma. Longitudinal studies may elucidate if autonomic dysregulation and high BP also predict glaucoma incidence.

14.
Hypertension ; 76(5): 1428-1434, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32981367

RESUMO

Blood pressure (BP) and obesity phenotypes may covary due to shared genetic or environmental factors or both. Furthermore, it is possible that the heritability of BP differs according to obesity status-a form of G×E interaction. This hypothesis has never been tested in White twins. The present study included 15 924 White male twin pairs aged between 15 and 33 years from the National Academy of Sciences-National Research Council World War II Veteran Twin Registry. Systolic and diastolic BPs, as well as height and weight, were measured at the induction physical examination. Body mass index (BMI) was used as the index of general obesity. Quantitative genetic modeling was performed using Mx software. Univariate analysis showed that narrow sense heritabilities (95% CI) for systolic BP, diastolic BP, height, and BMI were 0.401 (0.381-0.420), 0.297 (0.280-0.320), 0.866 (0.836-0.897), and 0.639 (0.614-0.664), respectively. Positive phenotypic correlations of BMI with systolic BP (r=0.13) and diastolic BP (r=0.08) were largely due to genetic factors (70% and 86%, respectively). The gene-BMI interaction analysis did not show any support for a modifying effect of BMI on genetic and environmental influences of systolic BP and diastolic BP. Our results suggest that correlations between BP and BMI are mainly explained by common genes influencing both. Higher BMI levels have no influence on the penetrance of genetic vulnerability to elevated BP. These conclusions may prove valuable for gene-finding studies.

15.
Hypertension ; 76(4): 1256-1262, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32829661

RESUMO

Dysregulation of the cardiac autonomic nervous system, as indexed by reduced heart rate variability (HRV), has been associated with the development of high blood pressure (BP). However, the underlying pathological mechanisms are not yet fully understood. This study aimed to estimate heritability of HRV and BP and to determine their genetic overlap. We used baseline data of the 3-generation Lifelines population-based cohort study (n=149 067; mean age, 44.5). In-house software was used to calculate root mean square of successive differences and SD of normal-to-normal intervals as indices of HRV based on 10-second resting ECGs. BP was recorded with an automatic BP monitor. We estimated heritabilities and genetic correlations with variance components methods in ASReml software. We additionally estimated genetic correlations with bivariate linkage disequilibrium score regression using publicly available genome-wide association study data. The heritability (SE) estimates were 15.6% (0.90%) for SD of normal-to-normal intervals and 17.9% (0.90%) for root mean square of successive differences. For BP measures, they ranged from 24.4% (0.90%) for pulse pressure to 30.3% (0.90%) for diastolic BP. Significant negative genetic correlations (all P<0.0001) of root mean square of successive differences/SD of normal-to-normal intervals with systolic BP (-0.20/-0.16) and with diastolic BP (-0.15/-0.13) were observed. LD score regression showed largely consistent genetic correlation estimates of root mean square of successive differences/SD of normal-to-normal intervals with systolic BP (range, -0.08 to -0.23) and diastolic BP (range, -0.20 to -0.27). Our study shows a substantial contribution of genetic factors in explaining the variance of HRV and BP measures in the general population. The significant negative genetic correlations between HRV and BP indicate that genetic pathways for HRV and BP partially overlap.

16.
Sci Rep ; 10(1): 11831, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678143

RESUMO

A meta-analysis of genome-wide association studies (GWAS) identified eight loci that are associated with heart rate variability (HRV), but candidate genes in these loci remain uncharacterized. We developed an image- and CRISPR/Cas9-based pipeline to systematically characterize candidate genes for HRV in live zebrafish embryos. Nine zebrafish orthologues of six human candidate genes were targeted simultaneously in eggs from fish that transgenically express GFP on smooth muscle cells (Tg[acta2:GFP]), to visualize the beating heart. An automated analysis of repeated 30 s recordings of beating atria in 381 live, intact zebrafish embryos at 2 and 5 days post-fertilization highlighted genes that influence HRV (hcn4 and si:dkey-65j6.2 [KIAA1755]); heart rate (rgs6 and hcn4); and the risk of sinoatrial pauses and arrests (hcn4). Exposure to 10 or 25 µM ivabradine-an open channel blocker of HCNs-for 24 h resulted in a dose-dependent higher HRV and lower heart rate at 5 days post-fertilization. Hence, our screen confirmed the role of established genes for heart rate and rhythm (RGS6 and HCN4); showed that ivabradine reduces heart rate and increases HRV in zebrafish embryos, as it does in humans; and highlighted a novel gene that plays a role in HRV (KIAA1755).

17.
Hypertension ; 76(1): 195-205, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32520614

RESUMO

We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P<1×10-5. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (P<1×10-7) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P<0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 (TXNIP) and cg00716257 (JDP2) determined by environmental effects acting on both systolic BP and methylation levels.

18.
Genet Epidemiol ; 44(6): 589-600, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32537749

RESUMO

As many cases of type 2 diabetes (T2D) are likely to remain undiagnosed, better tools for early detection of high-risk individuals are needed to prevent or postpone the disease. We investigated the value of the doubly weighted genetic risk score (dwGRS) for the prediction of incident T2D in the Lifelines and Estonian Biobank (EstBB) cohorts. The dwGRS uses an additional weight for each single nucleotide polymorphism in the risk score, to correct for "Winner's curse" bias in the effect size estimates. The traditional (single-weighted genetic risk score; swGRS) and dwGRS were calculated for participants in Lifelines (n = 12,018) and EstBB (n = 34,129). The dwGRS was found to have stronger association with incident T2D (hazard ratio [HR] = 1.26 [95% confidence interval: 1.10-1.43] and HR = 1.35 [1.28-1.42]) compared to the swGRS (HR = 1.21 [1.07-1.38] and HR = 1.25 [1.19-1.32]) in Lifelines and EstBB, respectively. Comparing the 5-year predicted risks from the models with and without the dwGRS, the continuous net reclassification index was 0.140 (0.034-0.243; p = .009 Lifelines), and 0.257 (0.194-0.319; p < 2 × 10-16 EstBB). The dwGRS provided incremental value to the T2D prediction model with established phenotypic predictors. It clearly distinguished the risk groups for incident T2D in both biobanks thereby showing its clinical relevance.

19.
J Am Heart Assoc ; 9(13): e015519, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32573316

RESUMO

Background Myocardial infarction is an important cause of morbidity and mortality in both men and women. Atypical or the absence of symptoms, more prevalent among women, may contribute to unrecognized myocardial infarctions and missed opportunities for preventive therapies. The aim of this research is to investigate sex-based differences of undiagnosed myocardial infarction in the general population. Methods and Results In the Lifelines Cohort Study, all individuals ≥18 years with a normal baseline ECG were followed from baseline visit till first follow-up visit (≈5 years, n=97 203). Individuals with infarct-related changes between baseline and follow-up ECGs were identified. The age- and sex-specific incidence rates were calculated and sex-specific cardiac symptoms and predictors of unrecognized myocardial infarction were determined. Follow-up ECG was available after a median of 3.8 (25th and 75th percentile: 3.0-4.6) years. During follow-up, 198 women experienced myocardial infarction (incidence rate 1.92 per 1000 persons-years) compared with 365 men (incidence rate 3.30; P<0.001 versus women). In 59 (30%) women, myocardial infarction was unrecognized compared with 60 (16%) men (P<0.001 versus women). Individuals with unrecognized myocardial infarction less often reported specific cardiac symptoms compared with individuals with recognized myocardial infarction. Predictors of unrecognized myocardial infarction were mainly hypertension, smoking, and higher blood glucose level. Conclusions A substantial proportion of myocardial infarctions are unrecognized, especially in women. Opportunities for secondary preventive therapies remain underutilized if myocardial infarction is unrecognized.

20.
Eye (Lond) ; 2020 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-32555517

RESUMO

PURPOSE: To improve upon self-reported glaucoma status in population-based cohorts by developing a questionnaire-based proxy incorporating self-reported status in conjunction with glaucoma-specific visual complaints. METHODS: A vision specific questionnaire, including questions from the National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) was administered to 79,866 Lifelines participants, a population-based cohort study in the Northern Netherlands. We compared NEI-VFQ-25 responses between 'definite' glaucoma cases (n = 90; self-reported surgical cases) and an age- and gender-matched subset of controls (n = 1,800) to uncover glaucoma-specific visual complaints, using a case-control logistic regression. We defined 'probable glaucoma' as both self-reported disease status and visual complaints, and 'possible glaucoma' as either. To evaluate the resulting proxy, we determined age-stratified glaucoma prevalences in the remaining cohort and compared the result to the literature. RESULTS: Per unit increase in the vision subscales (range 0-100) distance, peripheral and low luminance, we observed significantly increased odds of definite glaucoma (2% [P = 0.03], 4% [P = 1.2 × 10-8] and 2% [P = 0.02], respectively); the associated area under the curve was 0.73. We identified 300 probable and 3,015 (1,434 by self-report) possible glaucoma cases. Standardised prevalences of definite, probable and possible glaucoma for 55+ were 0.4%, 1.1% and 7.3%, respectively. For self-reported glaucoma (combining definite, probable and possible by self-report), this was 5.2%. CONCLUSIONS: The combination of self-reported glaucoma status and visual complaints can be used to capture glaucoma cases in population-based settings. The resulting prevalence of combined definite and probable glaucoma (1.5%) appears to be more consistent with previous reports than the prevalence estimate of 5.2% based only on self-report.

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