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Nanchen D.,Leiden University | Nanchen D.,University of Lausanne | Westendorp R.G.J.,Leiden University | Westendorp R.G.J.,Netherlands Consortium for Healthy Aging | And 12 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Subclinical thyroid dysfunction is common in older people. However, its clinical importance is uncertain. Objective: Our objective was to determine the extent to which subclinical hyperthyroidism and hypothyroidism influence the risk of heart failure and cardiovascular diseases in older people. Setting and Design: The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) is an prospective cohort study. Patients: Patients included men and women aged 70-82 yr (n = 5316) with known cardiovascular risk factors or previous cardiovascular disease. Main Outcome Measures: Incidence rate of heart failure hospitalization, atrial fibrillation, and cardiovascular events and mortality according to baseline thyroid status were evaluated. Euthyroid participants (TSH=0.45-4.5 mIU/liter) were compared with those with subclinical hyperthyroidism (TSH <0.45 mIU/liter) and those with subclinical hypothyroidism (TSH ≥4.5 mIU/liter, both with normal free T 4). Results: Subclinical hyperthyroidism was present in 71 participants and subclinical hypothyroidism in 199 participants. Over 3.2 yr follow-up, the rate of heart failure was higher for subclinical hyperthyroidism compared with euthyroidism [age- and sex-adjusted hazard ratio (HR) = 2.93, 95% confidence interval (CI) = 1.37-6.24, P = 0.005; multivariate-adjusted HR = 3.27, 95% CI = 1.52-7.02, P = 0.002). Subclinical hypothyroidism (only at threshold >10 mIU/liter) was associated with heart failure (age- and sex-adjusted HR = 3.01, 95% CI = 1.12-8.11, P = 0.029; multivariate HR = 2.28, 95% CI = 0.84-6.23). There were no strong evidence of an association between subclinical thyroid dysfunction and cardiovascular events or mortality, except in those with TSH below 0.1 or over 10 mIU/liter and not taking pravastatin. Conclusion: Older people at high cardiovascular risk with low or very high TSH along with normal free T4 appear at increased risk of incident heart failure. Copyright © 2012 by The Endocrine Society.


Sattar N.,University of Glasgow | Preiss D.,University of Glasgow | Murray H.M.,University of Glasgow | Welsh P.,University of Glasgow | And 27 more authors.
The Lancet | Year: 2010

Background: Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublished data whether any relation exists between statin use and development of diabetes. Methods: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009, for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ transplants or who needed haemodialysis. We used the I2 statistic to measure heterogeneity between trials and calculated risk estimates for incident diabetes with random-effect meta-analysis. Findings: We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1·09; 95% CI 1·02-1·17), with little heterogeneity (I2=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150-852) patients with statins for 4 years resulted in one extra case of diabetes. Interpretation: Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change. Funding: None. © 2010 Elsevier Ltd. All rights reserved.


Wang J.J.,University of Sydney | Wang J.J.,University of Melbourne | Buitendijk G.H.S.,Erasmus Medical Center | Rochtchina E.,University of Sydney | And 20 more authors.
Ophthalmology | Year: 2014

Objective To examine effect modification between genetic susceptibility to age-related macular degeneration (AMD) and dietary antioxidant or fish consumption on AMD risk. Design Pooled data analysis of population-based cohorts. Participants Participants from the Blue Mountains Eye Study (BMES) and Rotterdam Study (RS). Methods Dietary intakes of antioxidants (lutein/zeaxanthin [LZ], β-carotene, and vitamin C), long-chain omega-3 polyunsaturated fatty acids, and zinc were estimated from food frequency questionnaires. The AMD genetic risk was classified according to the number of risk alleles of CFH (rs1061170) or ARMS2 (rs10490924) as low (no or 1 risk allele) or high (≥2 risk alleles). Interactions between dietary intake and genetic risk levels were assessed. Associations between dietary intake and AMD risk were assessed comparing the highest with the 2 lower intake tertiles by genetic risk subgroups using discrete logistic regression, conducted in each study separately and then using pooled data. Participants without AMD lesions at any visit were controls. We adjusted for age and sex in analyses of each cohort sample and for smoking status and study site in pooled-data analyses. Main Outcome Measures All 15-year incident late AMD cases were confirmed by chief investigators of the Beaver Dam Eye Study, BMES, and RS. Intergrader reproducibility was assessed in an early AMD subsample, with 86.4% agreement between BMES and RS graders, allowing for a 1-step difference on a 5-step AMD severity scale. Results In pooled data analyses, we found significant interaction between AMD genetic risk status and LZ intake (P = 0.0009) but nonsignificant interactions between genetic risk status and weekly fish consumption (P = 0.05) for risk of any AMD. Among participants with high genetic risk, the highest intake tertile of LZ was associated with a >20% reduced risk of early AMD, and weekly consumption of fish was associated with a 40% reduced risk of late AMD. No similar association was evident among participants with low genetic risk. No interaction was detected between β-carotene or vitamin C and genetic risk status. Conclusions Protection against AMD from greater LZ and fish consumption in persons with high genetic risk based on 2 major AMD genes raises the possibility of personalized preventive interventions. ©2014 by the American Academy of Ophthalmology.


Schol-Gelok S.,Erasmus University Rotterdam | Janssens A.C.J.W.,Erasmus University Rotterdam | Tiemeier H.,Erasmus University Rotterdam | Liu F.,Erasmus University Rotterdam | And 11 more authors.
Biological Psychiatry | Year: 2010

Background: Depression has a strong genetic component but candidate gene studies conducted to date have not shown consistent associations. Methods: We conducted a genome-wide parametric and nonparametric linkage analysis in a large-scale family-based study including 115 individuals with depression who were identified based on the Hospital Anxiety Depression Scale, Center for Epidemiologic Studies Depression Rating Scale, or use of antidepressive medication. Further, we investigated the most promising chromosomal regions found in the genome-wide linkage analysis with an association analysis in 734 individuals in the family-based study and 2373 individuals in the population-based study. Results: Our study demonstrated evidence for significant linkage of depression to chromosome 2p16.1-15 (logarithm of odds [LOD]= 5.13; parametric analysis) and suggestive evidence for linkage in nonparametric analysis to chromosome 5p15.33 (LOD=2.14), 11q25 (LOD=2.27), and 19p13.3 (LOD=2.66). The subsequent association analysis in the family-based study showed region-wide significant association in intron 1 of the OPCML gene on chromosome 11q25 (empirical p value=.04). The association analysis in the population-based study did not show any region-wide significant association, yet showed suggestive association in intron 1 of the APLP2 gene on chromosome 11q25. Conclusions: Our linkage and association studies suggest a locus for depression on chromosomes 2p16.1-15 and 11q25. The linkage to chromosome 11q25 may be, in part, explained by the OPCML or the APLP2 gene. Further, there is evidence for a role of the GNG7 gene (chromosome 19p13.3). © 2010 Society of Biological Psychiatry.


Mayerle J.,University of Greifswald | Den Hoed C.M.,Erasmus Medical Center | Schurmann C.,University of Greifswald | Stolk L.,Erasmus Medical Center | And 29 more authors.
JAMA - Journal of the American Medical Association | Year: 2013

Importance: Helicobacter pylori is a major cause of gastritis and gastroduodenal ulcer disease and can cause cancer. H pylori prevalence is as high as 90% in some developing countries but 10% of a given population is never colonized, regardless of exposure. Genetic factors are hypothesized to confer H pylori susceptibility. Objective: To identify genetic loci associated with H pylori seroprevalence in 2 independent population-based cohorts and to determine their putative pathophysiological role by whole-blood RNA gene expression profiling. Design, Setting, and Participants: Two independent genome-wide association studies (GWASs) and a subsequent meta-analysis were conducted for anti-H pylori IgG serology in the Study of Health in Pomerania (SHIP) (recruitment, 1997-2001 [n = 3830]) as well as the Rotterdam Study (RS-I) (recruitment, 1990-1993) and RS-II (recruitment, 2000-2001 [n = 7108]) populations. Whole-blood RNA gene expression profiles were analyzed in RS-III (recruitment, 2006-2008 [n = 762]) and SHIP-TREND (recruitment, 2008-2012 [n = 991]), and fecal H pylori antigen in SHIP-TREND (n = 961). Main Outcomes and Measures: H pylori seroprevalence. Results: Of 10 938 participants, 6160 (56.3%) were seropositive for H pylori. GWASs identified the toll-like receptor (TLR) locus (4p14; top-ranked single-nucleotide polymorphism (SNP), rs10004195; P = 1.4 × 10-18; odds ratio, 0.70 [95% CI, 0.65 to 0.76]) and the FCGR2A locus (1q23.3; top-ranked SNP, rs368433; P = 2.1 × 10-8; odds ratio, 0.73 [95% CI, 0.65 to 0.81]) as associated with H pylori seroprevalence. Among the 3 TLR genes at 4p14, only TLR1 was differentially expressed per copy number of the minor rs10004195-A allele (β = -0.23 [95% CI, -0.34 to -0.11]; P = 2.1 × 10-4). Individuals with high fecal H pylori antigen titers (optical density >1) also exhibited the highest 25% of TLR1 expression levels (P = .01 by χ2 test). Furthermore, TLR1 exhibited an Asn248Ser substitution in the extracellular domain strongly linked to the rs10004195 SNP. Conclusions and Relevance: GWAS meta-analysis identified an association between TLR1 and H pylori seroprevalence, a finding that requires replication in nonwhite populations. If confirmed, genetic variations in TLR1 may help explain some of the observed variation in individual risk for H pylori infection. ©2013 American Medical Association. All rights reserved.


Zhang L.,University of Iowa | Buitendijk G.H.S.,Erasmus Medical Center | Lee K.,University of Iowa | Sonka M.,University of Iowa | And 8 more authors.
Investigative Ophthalmology and Visual Science | Year: 2015

PURPOSE. To evaluate the validity of a novel fully automated three-dimensional (3D) method capable of segmenting the choroid from two different optical coherence tomography scanners: swept-source OCT (SS-OCT) and spectral-domain OCT (SD-OCT). METHODS. One hundred eight subjects were imaged using SS-OCT and SD-OCT. A 3D method was used to segment the choroid and quantify the choroidal thickness along each A-scan. The segmented choroidal posterior boundary was evaluated by comparing to manual segmentation. Differences were assessed to test the agreement between segmentation results of the same subject. Choroidal thickness was defined as the Euclidian distance between Bruch’s membrane and the choroidal posterior boundary, and reproducibility was analyzed using automatically and manually determined choroidal thicknesses. RESULTS. For SS-OCT, the average choroidal thickness of the entire 6-by 6-mm2 macular region was 219.5 lm (95% confidence interval [CI], 204.9–234.2 µm), and for SD-OCT it was 209.5 µm (95% CI, 197.9–221.0 µm). The agreement between automated and manual segmentations was high: Average relative difference was less than 5 lm, and average absolute difference was less than 15 µm. Reproducibility of choroidal thickness between repeated SS-OCT scans was high (coefficient of variation [CV] of 3.3%, intraclass correlation coefficient [ICC] of 0.98), and differences between SS-OCT and SD-OCT results were small (CV of 11.0%, ICC of 0.73). CONCLUSIONS. We have developed a fully automated 3D method for segmenting the choroid and quantifying choroidal thickness along each A-scan. The method yielded high validity. Our method can be used reliably to study local choroidal changes and may improve the diagnosis and management of patients with ocular diseases in which the choroid is affected. © 2015 The Association for Research in Vision and Ophthalmology, Inc.


Van Vliet P.,Leiden University | Oleksik A.M.,Leiden University | Van Heemst D.,Leiden University | De Craen A.J.M.,Leiden University | And 2 more authors.
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2010

Background.In contrast to middle age, higher body mass index (BMI), cholesterol levels, and blood pressures associate no longer with increased mortality in old age. With increasing age, these risk factors are prone to change over time. It is unclear whether dynamics of these traditional metabolic risk factors in late life associate with mortality and whether they occur in concert with each other.Methods.Within the Leiden 85-plus Study, a prospective population-based study of 599 participants aged 85 years, participants were annually assessed during a 5-year follow-up period and observed for mortality for 10 years.Results.BMI, total cholesterol levels, glucose levels, and blood pressures declined and HDL cholesterol levels increased between ages 85 and 90 years (all p <. 005). Participants who died at age 90 years had stronger annual declines in BMI, total cholesterol levels, and diastolic blood pressure and weaker increases in HDL cholesterol levels than participants who survived until the end of follow-up (all p ≤. 001). In a principal component analysis, annual changes in total, LDL, and HDL cholesterol levels; blood pressures; and glucose, albumin, hemoglobin, leukocyte, and C-reactive protein levels grouped together in one component (all correlation r with component >.40), which associated with all-cause and cancer mortality.Conclusions.In old age, larger declines in BMI, total cholesterol levels, and blood pressures and weaker increases in HDL cholesterol levels associate with mortality. We identified distinct clustering in the dynamics of these traditional metabolic risk factors and indicators of health and disease in a profile that is suggestive of underlying wasting disease. © 2010 The Author.


Slieker R.C.,Leiden University | Bos S.D.,Leiden University | Bos S.D.,Netherlands Consortium for Healthy Aging | Goeman J.J.,Leiden University | And 16 more authors.
Epigenetics and Chromatin | Year: 2013

Background: DNA methylation has been recognized as a key mechanism in cell differentiation. Various studies have compared tissues to characterize epigenetically regulated genomic regions, but due to differences in study design and focus there still is no consensus as to the annotation of genomic regions predominantly involved in tissue-specific methylation. We used a new algorithm to identify and annotate tissue-specific differentially methylated regions (tDMRs) from Illumina 450k chip data for four peripheral tissues (blood, saliva, buccal swabs and hair follicles) and six internal tissues (liver, muscle, pancreas, subcutaneous fat, omentum and spleen with matched blood samples). Results: The majority of tDMRs, in both relative and absolute terms, occurred in CpG-poor regions. Further analysis revealed that these regions were associated with alternative transcription events (alternative first exons, mutually exclusive exons and cassette exons). Only a minority of tDMRs mapped to gene-body CpG islands (13%) or CpG islands shores (25%) suggesting a less prominent role for these regions than indicated previously. Implementation of ENCODE annotations showed enrichment of tDMRs in DNase hypersensitive sites and transcription factor binding sites. Despite the predominance of tissue differences, inter-individual differences in DNA methylation in internal tissues were correlated with those for blood for a subset of CpG sites in a locus- and tissue-specific manner. Conclusions: We conclude that tDMRs preferentially occur in CpG-poor regions and are associated with alternative transcription. Furthermore, our data suggest the utility of creating an atlas cataloguing variably methylated regions in internal tissues that correlate to DNA methylation measured in easy accessible peripheral tissues. © 2013 Slieker et al.; licensee BioMed Central Ltd.


Verhaaren B.F.J.,Erasmus Medical Center | De Boer R.,Erasmus Medical Center | Vernooij M.W.,Erasmus Medical Center | Rivadeneira F.,Erasmus Medical Center | And 12 more authors.
Stroke | Year: 2011

BACKGROUND AND PURPOSE-: Recently, the first genomewide association study on cerebral white matter lesion burden identified chr17q25 to be significantly associated with white matter lesions. We report on the first independent replication study of this genetic association. METHODS-: In a population-based cohort study, we investigated the association between the 6 genomewide significant single nucleotide polymorphisms at that locus and cerebral white matter lesion volume on MRI, measured quantitatively, adjusted for age, sex, and intracranial volume. Adjustments for ApoE4 carriership and cardiovascular risk factors were evaluated separately. Finally, we performed a meta-analysis of all published data for the single most significant single nucleotide polymorphism, rs3744028. RESULTS-: The risk alleles of all the 6 single nucleotide polymorphisms were significantly associated with white matter lesion volume with P=1.1*10 for rs3744028, adjusted for age, sex, and intracranial volume. Additional adjustments only had minor influence on these associations. A meta-analysis with all published data for rs3744028 resulted in a probability value of 5.3*10. CONCLUSIONS-: This study further establishes chr17q25 as a novel genetic locus for WML volume. © 2011 American Heart Association, Inc.

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