Rotterdam Study Research Articles

Sex-Specific Association of Cardiovascular Risk Factors With Migraine: The Population-Based Rotterdam Study.

Sex-Specific Association of Cardiovascular Risk Factors With Migraine: The Population-Based Rotterdam Study.

Association between thyroid function and osteoarthritis: a population-based cohort study

ObjectivesPrevious genetic and animal studies indicated a causal role of thyroid hormones in osteoarthritis (OA), which has not been observed in the general population. We aimed to investigate whether thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were associated with hand, hip, or knee OA. MethodsParticipants from the Rotterdam Study with baseline TSH, FT4, and joint radiographs were included. We used multivariable regression models to investigate the association of thyroid function with the prevalence, severity, incidence, and progression of OA. We conducted stratified analyses by sex, age, body mass index (BMI) and weight-bearing physical activity. ResultsAmong 9054 participants included (mean age 65 years, 56.3% women), higher FT4 concentrations were associated with an increased risk of prevalent knee OA (OR 1.04 per pmol/L, 95% CI 1.01-1.06, corresponding to an OR of 1.62 across the reference range [i.e., 14pmol/L changes] of FT4) and more severe knee OA. There was a positive association between FT4 and overall progression of knee OA (OR 1.03 per pmol/L, 1.00-1.07). No association of TSH with hand, hip, or knee OA was identified. Stratified analysis revealed an association between FT4 and prevalent knee OA among individuals with BMI≥30 kg/m2 (OR 1.05 per pmol/L, 1.01-1.08) and those with high levels of weight-bearing physical activity (OR 1.05 per pmol/L, 1.01-1.10). ConclusionsOur study indicated that higher FT4 concentrations may increase the risk of knee OA. This association might be greater in individuals with extra joint loading, such as those with obesity.

Defining high risk in the cardiovascular-kidney-metabolic syndrome and associated cardiovascular disease outcomes

Abstract Background The American Heart Association (AHA) recently developed the cardiovascular-kidney-metabolic (CKM) syndrome construct with stages 0-4 to comprehensively characterize the spectrum of cardiovascular disease (CVD) risk [1]. CKM Stage 3 is defined by subclinical CVD or high (≥20%) estimated 10-year CVD risk according to the newly-derived PREVENT models [2]. However, within CKM Stage 3, the burden of subclinical atherosclerosis equivalent to a ≥20% estimated CVD risk, and long-term CVD outcomes associated with CKM Stage 3, are not known. Purpose To (1) characterize the distribution of subclinical atherosclerosis by coronary artery calcium (CAC) according to PREVENT estimated CVD risk categories, and (2) quantify long-term CVD risk associated with CKM Stage 3, in two international cohorts of adults without prior CVD. Methods In participants of the Multi-Ethnic Study of Atherosclerosis (MESA, age 45-84 years) and the Rotterdam Study (age ≥55 years), the burden of CAC was calculated across estimated 10-year CVD risk (low, 0 to <5%; borderline 5 to <7.5%; intermediate, 7.5 to <20%; high, ≥20%). Participants were categorized into CKM stages according to CVD risk factors (body mass index, waist circumference, glycemic status, blood pressure, lipids, kidney function), estimated 10-year CVD risk (by AHA PREVENT model), and presence of CAC. The association of CKM syndrome stage with fatal or nonfatal CVD outcomes was evaluated with covariate-adjusted proportional hazards regression. Results Among 6,123 MESA participants (52% female, mean age 61.4 years) and 1,691 Rotterdam Study participants (46% female, mean age 67.1 years), the distribution of CAC across absolute 10-year CVD risk categories is shown in Figure 1. In high (≥20%) CVD risk adults, CAC score ≥100 was present in 50% of MESA participants and 48% of Rotterdam Study participants. Most participants were classified as CKM Stage 3 (53% in MESA, 83% in Rotterdam). Over a median follow-up of 17.5 years in MESA, CVD events occurred in 5% of CKM Stage 0, 6% of Stage 1, 9% of Stage 2, and 26% of Stage 3 participants. Over a median follow-up of 10.2 years in the Rotterdam Study, CVD events occurred in 0% of CKM Stage 0 and 1, 8% of Stage 2, and 17% of Stage 3 participants (Figure 2). The risk of total CVD was significantly higher in CKM Stage 3 participants relative to CKM Stage 0-2 (MESA: adjusted HR 2.74, 95% CI 2.32, 3.23; Rotterdam: adjusted HR 2.18, 95% CI 1.34, 3.54). Conclusions In an international, multi-ethnic sample of middle-aged adults, adults with high (≥20%) absolute 10-year CVD risk by PREVENT had substantial burden of CAC. Adults in CKM Stage 3 had approximately 2.2- to 2.7-times higher risk for CVD, compared with adults in lower CKM stages. Accounting for estimated CVD risk and burden of cardiovascular, kidney, and metabolic risk factors informs prevention of subclinical and clinical CVD.

A comprehensive study of genetic regulation and disease associations of plasma circulatory microRNAs using population-level data.

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Perturbations in plasma miRNA levels are known to impact disease risk and have potential as disease biomarkers. Exploring the genetic regulation of miRNAs may yield new insights into their important role in governing gene expression and disease mechanisms. We present genome-wide association studies of 2083 plasma circulating miRNAs in 2178 participants of the Rotterdam Study to identify miRNA-expression quantitative trait loci (miR-eQTLs). We identify 3292 associations between 1289 SNPs and 63 miRNAs, of which 65% are replicated in two independent cohorts. We demonstrate that plasma miR-eQTLs co-localise with gene expression, protein, and metabolite-QTLs, which help in identifying miRNA-regulated pathways. We investigate consequences of alteration in circulating miRNA levels on a wide range of clinical conditions in phenome-wide association studies and Mendelian randomisation using the UK Biobank data (N = 423,419), revealing the pleiotropic and causal effects of several miRNAs on various clinical conditions. In the Mendelian randomisation analysis, we find a protective causal effect of miR-1908-5p on the risk of benign colon neoplasm and show that this effect is independent of its host gene (FADS1). This study enriches our understanding of the genetic architecture of plasma miRNAs and explores the signatures of miRNAs across a wide range of clinical conditions. The integration of population-based genomics, other omics layers, and clinical data presents opportunities to unravel potential clinical significance of miRNAs and provides tools for novel miRNA-based therapeutic target discovery.

Hearing loss and its relation to longitudinal changes in white matter microstructure in older adults: The Rotterdam Study

Hearing loss is considered a potentially modifiable risk factor for dementia. The sensory deprivation theory postulates that hearing loss adversely affects cognition in older adults through structural brain changes, but longitudinal studies are scarce. To find evidence for a possible detrimental effect of hearing loss on white matter microstructure, we carried out a longitudinal study in the population-based Rotterdam Study. A total of 1877 participants with a median age at baseline of 56.4 years (IQR: [52.2–60.0]) underwent audiometry and had longitudinal diffusion imaging data available with a mean follow-up of 4.0 years. A lower level of hearing acuity was associated with worse white matter microstructure in the left uncinate fasciculus and superior longitudinal fasciculus at baseline. Poorer hearing acuity was also associated with faster microstructural deterioration over time in the left superior longitudinal fasciculus. The strongest effects were observed for low-frequency hearing thresholds, while the high-frequency thresholds showed the weakest associations. These results suggest that hearing loss may contribute to the age-related decline in brain structure, consistent with the sensory deprivation theory.

Cluster-Based White Matter Signatures and the Risk of Dementia, Stroke, and Mortality in Community-Dwelling Adults.

Markers of white matter (WM) injury on brain MRI are important indicators of brain health. Different patterns of WM atrophy, WM hyperintensities (WMHs), and microstructural integrity could reflect distinct pathologies and disease risks, but large-scale imaging studies investigating WM signatures are lacking. This study aims to identify distinct WM signatures using brain MRI in community-dwelling adults, determine underlying risk factor profiles, and assess risks of dementia, stroke, and mortality associated with each signature. Between 2005 and 2016, we measured WMH volume, WM volume, fractional anisotropy (FA), and mean diffusivity (MD) using automated pipelines on structural and diffusion MRI in community-dwelling adults aged older than 45 years of the Rotterdam study. Continuous surveillance was conducted for dementia, stroke, and mortality. We applied hierarchical clustering to identify separate WM injury clusters and Cox proportional hazard models to determine their risk of dementia, stroke, and mortality. We included 5,279 participants (mean age 65.0 years, 56.0% women) and identified 4 distinct data-driven WM signatures: (1) above-average microstructural integrity and little WM atrophy and WMH; (2) above-average microstructural integrity and little WMH, but substantial WM atrophy; (3) poor microstructural integrity and substantial WMH, but little WM atrophy; and (4) poor microstructural integrity with substantial WMH and WM atrophy. Prevalence of cardiovascular risk factors, lacunes, and cerebral microbleeds was higher in clusters 3 and 4 than in clusters 1 and 2. During a median 10.7 years of follow-up, 291 participants developed dementia, 220 had a stroke, and 910 died. Compared with cluster 1, dementia risk was increased for all clusters, notably cluster 3 (hazard ratio [HR] 3.06, 95% CI 2.12-4.42), followed by cluster 4 (HR 2.31, 95% CI 1.58-3.37) and cluster 2 (HR 1.67, 95% CI 1.17-2.38). Compared with cluster 1, risk of stroke was higher only for clusters 3 (HR 1.55, 95% CI 1.02-2.37) and 4 (HR 1.94, 95% CI 1.30-2.89), whereas mortality risk was increased in all clusters (cluster 2: HR 1.27, 95% CI 1.06-1.53, cluster 3: HR 1.65, 95% CI 1.35-2.03, cluster 4: HR 1.76, 95% CI 1.44-2.15), compared with cluster 1. Models including clusters instead of an individual imaging marker showed a superior goodness of fit for dementia and mortality, but not for stroke. Clustering can derive WM signatures that are differentially associated with dementia, stroke, and mortality risk. Future research should incorporate spatial information of imaging markers.

Effects and interaction of single nucleotide polymorphisms at the pharmacokinetic/pharmacodynamic site: insights from the Rotterdam study into metformin clinical response and dose titration.

Our study investigated the impact of genetic variations on metformin glycemic response in a cohort from the Rotterdam Study, comprising 14,926 individuals followed for up to 27 years. Among 1285 metformin users of European ancestry, using linear mixed models, we analyzed the association of single nucleotide polymorphisms (SNPs) and a Polygenic Risk Score (PRS) with glycemic response, measured by changes in metformin dosage or HbA1c levels. While individual genetic variants showed no significant association, rs622342 on SLC2A1 correlated with increased glycemic response only in metformin monotherapy patients (β = -2.09, P-value < 0.001). The collective effect of variants, as represented by PRS, weakly correlated with changes in metformin dosage (β = 0.023, P-value = 0.027). Synergistic interaction was observed between rs7124355 and rs8192675. Our findings suggest that while higher PRS correlates with increased metformin dosage, its modest effect size limits clinical utility, emphasizing the need for future research in diverse populations to refine genetic risk models.

Healthy and unhealthy plant-based diets and the risk of cardiovascular diseases: The Rotterdam study and updated meta-analysis

BackgroundConsumption of more plant-based foods is gaining popularity, but the role of healthy versus unhealthy plant-based diets in cardiovascular disease (CVD) risk remains inconclusive. ObjectivesWe investigated associations of plant-based diet indices (PDIs) with incident CVDs in a prospective cohort study and conducted an updated meta-analysis. MethodsWe included 3507 men and 5345 women of the population-based Rotterdam Study. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for CVD, coronary heart disease (CHD) and stroke with per SD increment of an overall PDI, healthy PDI (hPDI) and unhealthy PDI (uPDI), among men and women separately. We combined our findings with previously published effect estimates in an updated meta-analysis. ResultsWe documented 2015 CVD cases (1231 CHD and 952 stroke) during 107,290 person-years follow-up. Among men, the PDI and hPDI were associated with a 7 % (HR 0.93, 95 % CI 0.87–0.99) and 8 % (HR 0.92, 95 % CI 0.86–0.98) lower CVD risk. Among women, there was evidence suggesting a U-shaped association of the PDI with stroke (pnon-linearity < 0.01). In meta-analyses including up to 43,067 incident CVD cases among 359,740 participants from nine studies, the PDI and hPDI, were associated with a lower CVD risk, while uPDI with a higher CVD risk (pooled HRs [95 % CI], per SD, PDI: 0.94 [0.91–0.97], I2 = 50.4 %; hPDI: 0.94 [0.91–0.98], I2 = 74.7 %; uPDI: 1.03 [1.01–1.06], I2 = 49.0 %). ConclusionsOur findings support recommendations to consume relatively more healthy plant-based foods for CVD prevention. Potential differences by sex and non-linear associations warrant further investigation.

DXA images vs. pelvic radiographs: Reliability of hip morphology measurements

ObjectiveDual-energy x-ray absorptiometry (DXA) images are increasingly used to study hip morphology. Whether hip morphology measurements are consistent between DXA images and radiographs is unknown. Therefore, we investigated the agreement and reliability of the measurements performed on DXA images and radiographs. DesignWe included participants from the Rotterdam study, a population-based cohort study, who received a hip DXA image and pelvic radiograph on the same day. The acetabular depth-width ratio (ADR), modified acetabular index (mAI), alpha angle (AA), Wiberg and lateral center edge angle (WCEA, LCEA), extrusion index (EI) and triangular index ratio (TIR) were automatically determined on both imaging modalities. The intraobserver and intermethod agreement were studied using Bland-Altman methods, and the reliability was assessed using intraclass correlation coefficients (ICC). Secondly, the diagnostic agreement regarding dysplasia, cam, and pincer morphology was assessed using percent agreement and Cohen’s kappa. Results750 hips from 411 individuals, median age 67.3 years (range 52.2 – 90.6), 45.5% male, were included. The following intermethod ICCs (95% CI) were obtained: ADR 0.85 (0.74-0.91), mAI 0.75 (0.52-0.85), AA 0.72 (0.68-0.75), WCEA 0.81 (0.74-0.85), LCEA 0.93 (0.91-0.94), EI 0.88 (0.84-0.91), and TIR 0.81 (0.79-0.84). We found comparable intraobserver ICCs for each morphological measurement. ConclusionDXA images and pelvic radiographs could both reliably be used to study hip morphology. Due to the lower radiation burden, DXA images could be an excellent alternative to pelvic radiographs for research purposes.

Intracranial arteriosclerosis is not associated with cerebral amyloid deposition.

Intracranial arteriosclerosis and cerebral amyloid beta (Aβ) are both involved in the etiology of Alzheimer's disease (AD) dementia, but the direct link between these two pathologies remains elusive. In 633 participants (mean age 69 years, 51% women) from the population-based Rotterdam Study, we quantified cerebral Aβ accumulation on amyloid positron emission tomography (PET). We assessed calcification of the intracranial internal carotid (ICAC) and vertebrobasilar arteries (VBAC) as proxies of arteriosclerosis on non-enhanced computed tomography (CT). Using logistic and linear regression, we studied the relationship of presence, burden, and type of calcification with the presence and burden of Aβ. We found no associations of ICAC [odds ratio (OR): 0.85, 95% confidence interval (CI): 0.43, 1.72] or VBAC [OR: 0.59, CI: 0.26, 1.24] with cerebral Aβ. The results did not vary across ICAC subtypes. Intracranial arteriosclerosis was not associated with cerebral Aβ, underscoring their independence in the etiology of AD dementia. Comprehensive assessment of intracranial arteriosclerosis (e.g., including subtypes).Intracranial arteriosclerosis in different arteries and cerebral Aβ are not related.Arteriosclerosis and Aβ likely influence Alzheimer's disease dementia independently.

Serum phosphate in the general population: a need for sex-specific reference intervals.

Phosphate is important for several metabolic functions and essential for bone mineralization. Sex-differences exist in the relation between serum phosphate and certain diseases. The reference interval for phosphate is age-adjusted in infants, but most institutions use the same intervals for adult men and women despite increasing evidence for age and sex-differences. We aimed to study these differences in two large population-based cohorts in order to evaluate whether current reference intervals are adequate. 8837 participants from three cohorts of the Rotterdam Study (RS) and 422,443 participants from UK Biobank (UKBB), aged 40 and older and without chronic kidney disease, were analyzed for sex/differences in serum phosphate using standard reference values (0.8-1.45 mmol or 2.5-4.5 mg/dL). Analyses were further stratified in women by menopausal status. Women had higher serum phosphate concentrations and a higher population range compared to men in all cohorts. Hypophosphatemia was more prevalent in men and hyperphosphatemia was more prevalent in women. Sex-differences were present in all age-categories. Perimenopausal women had higher serum phosphate concentrations than men of the same age, but lower than postmenopausal women of the same age. This study in two population-based cohorts showed that women have higher serum phosphate concentrations than men and that women show a marked increase in serum phosphate during menopause. Moreover, the population range for serum phosphate was higher in women than in men. These findings indicate a need for sex-specific reference intervals for serum phosphate in adults older than 45 years.

Genome-wide association study meta-analysis of neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of genome-wide association studies (GWAS) of blood NfL levels from eleven cohorts of European ancestry, we identify two genome-wide significant loci at 16p12 (UMOD) and 17q24 (SLC39A11). We observe association of three loci at 1q43 (FMN2), 12q14, and 12q21 with blood NfL levels in the meta-analysis of African-American ancestry. In the trans-ethnic meta-analysis, we identify three additional genome-wide significant loci at 1p32 (FGGY), 6q14 (TBX18), and 4q21. In the post-GWAS analyses, we observe the association of higher NfL polygenic risk score with increased plasma levels of total-tau, Aβ-40, Aβ-42, and higher incidence of Alzheimer’s disease in the Rotterdam Study. Furthermore, Mendelian randomization analysis results suggest that a lower kidney function could cause higher blood NfL levels. This study uncovers multiple genetic loci of blood NfL levels, highlighting the genes related to molecular mechanism of neurodegeneration.

Metabolic syndrome, radiographic osteoarthritis progression and chronic pain of the knee among men and women from the general population: The Rotterdam study

ObjectiveAlthough a relationship between osteoarthritis and components of metabolic syndrome (MetS) has been suggested, most of the results have been cross-sectional. We, therefore, aimed to investigate the sex-specific longitudinal association of (components of) MetS with progression of radiographic osteoarthritis and chronic pain in the knee joints in a large prospective cohort. MethodIn the large population-based Rotterdam study of up to 6,138 individuals, median follow-up time 5.7 (IQR 5.5) years, we examined the relation between MetS and its components (abdominal obesity, high triglycerides, low high-density lipoprotein, elevated blood pressure, and type 2 diabetes) with the progression of osteoarthritis using generalized estimating equations, generalized linear models and competing risk analysis. Analyses were stratified for sex. Covariates adjusted for: age, smoking, alcohol use, education, sub-cohort, baseline K/L grade, months between radiographs and BMI. ResultsThe presence of MetS (37.6 % in men, 39 % in women) and elevated blood pressure was associated with an increased risk of knee osteoarthritis progression in both men and women. MetS was associated with an increased risk of incident chronic knee pain (CKP) in men. In addition, abdominal obesity and high triglycerides showed higher riskfor incidence of CKP in men,but not in women. The associations were attenuated and no longer significant after BMI-adjustment, except for the association of MetS and high triglycerides with incidence of CKP in men that stayed significant (OR 1.04, 95 %CI 1.00–1.07 for MetS and OR 1.04, 95 %CI 1.01–1.07 for high triglycerides). ConclusionMetabolic syndrome and individual metabolic components, such as abdominal obesity and elevated blood pressure, were associated with radiographic progression of knee OA in both men and women, but not independent of BMI. Metabolic syndrome and high triglycerides were associated with incidence of CKP only in men.

Arteriosclerotic Calcification and Atrial Fibrillation in the General Population: The Rotterdam Study

Limited population-based data on the gender differences and association between arteriosclerotic calcification at different sites and atrial fibrillation (AF) exist. We aimed to investigate the (gender-specific) associations between arteriosclerotic calcification at different sites with the risk of AF in the general population. Arteriosclerotic calcification was quantified using computed tomography examinations between 2003 and 2006 in 2,259 participants free of AF from the population-based Rotterdam Study. Cox proportional hazards models, adjusted for cardiovascular risk factors, were used to assess the associations of volumes of coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial and intracranial carotid arteries, vertebrobasilar arteries, and the aortic valve with incident AF. During a median follow-up of 8.6 years, 182 incident AF cases occurred. A larger CAC was associated with incident AF (hazard ratio [HR], 95% confidence interval [CI] 1.25 1.09 to 1.44, p = 0.0019). The gender-stratified analyses showed that larger CAC in men (HR 1.43, 95% CI 1.10 to 1.86, p = 0.0068) and larger AAC in women were associated with incident AF (HR1.44, 95% CI 1.04 to 2.01, p = 0.0299). In conclusion, CAC in the general population, especially in men, and AAC in women were significantly associated with new-onset AF. Our findings imply that interventions to lower arteriosclerotic calcification, particularly, CAC, carry potential for the prevention of AF in the general population, especially in men.

Circulating Metabolites Associated With Steatotic Liver Disease and Liver Enzymes: A Multiplatform Population-Based Study

Background & AimsSteatotic liver disease (SLD) is the most common chronic liver disease strongly associated with metabolic dysfunction, but its pathogenesis remains incompletely understood. Exploring circulating metabolites may help in elucidating underlying mechanisms and identifying new biomarkers for SLD. MethodsWe examined cross-sectionally the association between plasma metabolites and SLD as well as liver enzymes using data from four population-based cohort studies (Rotterdam study, ALSPAC, IRASFS, and SOL). Metabolites were assessed in the Nightingale platform (n=225 metabolites) by NMR spectroscopy and in the Metabolon platform (n=991 metabolites) by UHPLC-mass spectrometry. Serum levels of liver enzymes (ALT, AST, and GGT) were measured and SLD was diagnosed by ultrasound or CT-scan. Logistic and linear regression models were performed per cohort and meta-analyzed. A false discovery rate (-FDR) < 0.05 was considered as significant threshold. ResultsSeveral metabolites were significantly associated with SLD and liver enzymes, of which 21 metabolites were associated with both traits. The most significant associations were observed with phenylalanine, triglycerides in (HDL, IDL, and small-LDL), fatty acid (FA) ratios of (18:2 linoleic acid-to-total FA, omega 6 FA-to-total FA, and polyunsaturated FA-to-total FA) from the Nightingale and glutamate and sphingomyelin from the Metabolon platform. Other associated metabolites were mainly involved in lipid, amino acid, carbohydrates, and peptide metabolism. ConclusionsOur study indicates a landscape of circulating metabolites associated with SLD. The identified metabolites may contribute to a better understanding of the metabolic pathways underlying SLD and hold promising for potential biomarkers in early diagnosis and monitoring of the disease.

The NOS1AP gene rs10494366 common genetic variant does not modify the risk of sudden cardiac death in users of digoxin.

Common genetic variations in the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. In a previous study, we observed an association between the rs10494366 variant of this gene and an increased QT-interval shortening in digoxin users. As QT-interval shortening is a risk factor for sudden cardiac death (SCD), in this study, we investigated whether the association between digoxin use and risk of SCD differs in participants with different NOS1AP rs10494366 genotypes. We included 11 377 individuals from the prospective population-based cohort of the Rotterdam Study. We used Cox proportional hazard regression analysis with digoxin as time-dependent exposure to estimate the associations between current digoxin use and the risk of SCD among different rs10494366 genotype groups in the adjusted models. We also studied whether such an association was dose-dependent, comparing high dosage (≥ 0.250 mg), moderate dosage (0.125 mg ≤ dose< 0.250 mg) and low dosage (< 0.125 mg) digoxin users with non-users. The median baseline age of the total study population was 62 (interquartile range [IQR] 58-71) years. The cumulative incidence of SCD was 4.1% (469 cases), and among them, 74 (15.7%) individuals were current digoxin users at the time of death, during a median follow-up of 11.5 (IQR 6.5-17) years. Current digoxin users had an increased risk of SCD (multivariable adjusted model hazard ratio [HR]: 3.07; 95% confidence interval [CI]: 2.38-3.98), with no significant differences between the three genotype groups. The adjusted HRs were 4.03 [95% CI: 1.98-8.21] in the minor homozygous GG, 3.46 [95% CI: 2.37-5.04] in the heterozygous TG and 2.56 [95%CI: 1.70-3.86] in the homozygous TT genotype groups. Compared to low- and moderate-dose, high-dose digoxin users with GG genotype had the highest risk of SCD (HR: 5.61 [95% CI: 1.34-23.47]). Current use of digoxin is associated with a significantly increased risk of SCD. The NOS1AP gene rs10494366 variant did not modify the digoxin-associated risk of SCD in a population of European ancestry.

Sex-Specific Association of Cardiovascular Risk Factors With Migraine: The Population-Based Rotterdam Study.

Although several lines of evidence suggest a link between migraine and cardiovascular events, less is known about the association between cardiovascular risk factors (CVRFs) and migraine. This knowledge is clinically important to provide directions on mitigating the cardiovascular risk in patients with migraine. We hypothesized that CVRFs are associated with a higher migraine prevalence. Therefore, our primary objective was to investigate sex-specific associations between CVRFs and lifetime prevalence of migraine. We performed cross-sectional analyses within an ongoing population-based cohort study (Rotterdam Study), including middle-aged and elderly individuals. By means of (structured) interviews, physical examinations, and blood sampling, we obtained information on the lifetime prevalence of migraine and the following traditional CVRFs: current smoking, obesity, hypercholesterolemia, hypertension, and diabetes mellitus. Similarly, we obtained information on quantitative component data on these CVRFs, including pack-years of smoking, lipid levels, systolic and diastolic blood pressure (BP), body mass index, and fasting glucose levels. Patients with migraine were age-matched to individuals without migraine, and we performed conditional logistic regression analyses to investigate the sex-stratified association of CVRFs with migraine. In total, 7,266 community-dwelling middle-aged and elderly persons were included (median age 66.6 [IQR 56.4-74.8] years, 57.5% females). The lifetime prevalence of migraine was 14.9%. In females, current smoking (odds ratio (OR) 0.72, 95% CI 0.58-0.90), more pack-years (OR per SD increase 0.91, 95% CI 0.84-1.00), diabetes mellitus (OR 0.74, 95% CI 0.56-0.98), and higher fasting glucose levels (OR per SD increase in glucose 0.90, 95% CI 0.82 - 0.98) were all related to a lower migraine prevalence while a higher diastolic BP related to a higher migraine prevalence (OR per SD increase 1.16, 95% CI 1.04-1.29). In males, no significant associations between CVRFs and migraine were observed. Traditional CVRFs were either unrelated or inversely related to migraine in middle-aged and elderly individuals, but only in females. In males, we did not find any association between CVRFs and migraine. Because only an increased diastolic BP was related to a higher migraine prevalence in females, our study contributes to the hypothesis that migraine is not directly associated with traditional CVRFs. Future studies are warranted to extrapolate these findings to younger populations.

Dietary patterns, inflammatory biomarkers and cognition in older adults: An analysis of three population-based cohorts

BackgroundTargeting effective strategies to prevent cognitive decline is key in the aging population. Some diets have been linked to a slower cognitive decline, potentially through reducing inflammation. We aimed at determining the effect of inflammatory dietary patterns (IDPs) on cognitive function in three population-based cohorts. MethodsIn this longitudinal study, we analyzed data from the Canadian Longitudinal Study of Aging, CoLaus|PsyCoLaus and Rotterdam Study. Our analytical sample included participants over 55 years old with baseline data on cognition, dietary intake, and inflammatory markers. IDPs were derived for each cohort using reduced rank regression to reflect maximal variation in three inflammatory markers. We calculated scores of consumption of the IDPs, higher scores indicating more IDP consumption. We used inverse probability of treatment and censoring weights in the marginal structural models to estimate associations of higher versus lower quarters of consumption of an IDP on general cognition (Mini-Mental State Evaluation) and four cognitive domains (memory, verbal fluency, verbal learning and processing speed and executive function) during at least 3 years of follow-up. ResultsWe included 10,366 participants (mean age 68) followed-up for a mean of 5 years. Diet explained between 1 and 2% of the variation of the inflammatory markers. There were no mean differences in general cognition when comparing the highest to the lowest quarter of consumption of IDPs among the three cohorts. Mean differences for the four cognitive domains were of small magnitude across cohorts and not clinically relevant. ConclusionDiet explained low variation in inflammatory markers. Consuming IDPs was not associated with mean differences in general or domain-specific cognitive function.

Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylation

BackgroundThe plasma metabolome reflects the physiological state of various biological processes and can serve as a proxy for disease risk. Plasma metabolite variation, influenced by genetic and epigenetic mechanisms, can also affect the cellular microenvironment and blood cell epigenetics. The interplay between the plasma metabolome and the blood cell epigenome remains elusive. In this study, we performed an epigenome-wide association study (EWAS) of 1183 plasma metabolites in 693 participants from the LifeLines-DEEP cohort and investigated the causal relationships in DNA methylation–metabolite associations using bidirectional Mendelian randomization and mediation analysis.ResultsAfter rigorously adjusting for potential confounders, including genetics, we identified five robust associations between two plasma metabolites (l-serine and glycine) and three CpG sites located in two independent genomic regions (cg14476101 and cg16246545 in PHGDH and cg02711608 in SLC1A5) at a false discovery rate of less than 0.05. Further analysis revealed a complex bidirectional relationship between plasma glycine/serine levels and DNA methylation. Moreover, we observed a strong mediating role of DNA methylation in the effect of glycine/serine on the expression of their metabolism/transport genes, with the proportion of the mediated effect ranging from 11.8 to 54.3%. This result was also replicated in an independent population-based cohort, the Rotterdam Study. To validate our findings, we conducted in vitro cell studies which confirmed the mediating role of DNA methylation in the regulation of PHGDH gene expression.ConclusionsOur findings reveal a potential feedback mechanism in which glycine and serine regulate gene expression through DNA methylation.

The Clinical Usefulness of a Glaucoma Polygenic Risk Score in 4 Population-Based European Ancestry Cohorts

ObjectiveWe used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts. DesignSecondary analysis of four prospective population-based studies. ParticipantsWe included four European-ancestry cohorts: the United States (US) based Nurses’ Health Study (NHS), NHS2, and the Health Professionals Follow-up Study, and the Rotterdam Study (RS) in the Netherlands. The US cohorts included female nurses and male health professionals aged 55+ years. The RS included residents aged 45 years or older living in Rotterdam, the Netherlands. MethodsPRS weights were estimated by applying the Lassosum method on imputed genotype and phenotype data from the UK-Biobank. This resulted in 144,020 variants, single nucleotide polymorphism (SNPs) and indels, with non-zero betas that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models’ concordance (Harrell’s C-statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits. Main Outcome MeasuresThe relative risk for POAG and Harrell’s C-statistic (the equivalent of an area-under-the-curve for longitudinal models). ResultsAmong 1,046 cases and 38,809‬ controls, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08, 5.18) in the US cohorts, and 4.89 (2.93, 8.17) in the Rotterdam Study, compared with participants with median genetic risk (3rd quintile). In restricted cubic spline analyses, the relation between continuous PRS and POAG risk increased exponentially in the US and Rotterdam cohorts (Pspline<0.05). Combining age, sex, intraocular pressure >25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (0.73, 0.75). Adding the PRS to this model improved the concordance to 0.82 (0.80, 0.84). In a meta-analysis of all cohorts, cases in the highest tertile had a larger cup-disc ratio at diagnosis, by 0.11 (0.07, 0.15), and a 2.07-fold increased risk of requiring glaucoma surgery (1.19, 3.60). ConclusionsIncorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies.