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Postmus I.,Leiden University | Verschuren J.J.W.,Leiden University | De Craen A.J.M.,Leiden University | Slagboom P.E.,Netherlands Consortium for Healthy Ageing | And 7 more authors.
Pharmacogenomics | Year: 2012

Statins are the most commonly prescribed class of drug worldwide and therapy is highly effective in reducing low-density lipoprotein cholesterol levels and cardiovascular events. However, there is large variability in clinical response to statin treatment. Recent research provides evidence that genetic variation contributes to this variable response to statin treatment. Until recently, pharmacogenetic studies have used mainly candidate gene approaches to investigate these effects. Since candidate gene studies explain only a small part of the observed variation and results have often been inconsistent, genome-wide association (GWA) studies may be a better approach. In this paper the most important candidate gene studies and the first published GWA studies assessing statin response are discussed. Moreover, we describe the PHASE study, an EU-funded GWA study that will investigate the genetic variation responsible for the variation in response to pravastatin in a large randomized clinical trial. © 2012 Future Medicine Ltd.


Talens R.P.,Leiden University | Jukema J.W.,Leiden University | Jukema J.W.,Interuniversity Cardiology Institute of the Netherlands | Jukema J.W.,Durrer Center for Cardiogenetic Research | And 9 more authors.
International Journal of Epidemiology | Year: 2012

Background: Human epidemiological studies suggest that small size at birth and food deprivation during gestation confer an excess risk of coronary heart diseases (CHD) in adulthood, frequently in a sex-specific manner. Prior epigenetic studies indicate that such prenatal conditions are marked by persistent and sometimes sex-specific changes in DNA methylation. Here, we have investigated the association between DNA methylation and myocardial infarction (MI) at six loci sensitive to prenatal nutrition, anticipating potential sex-specificity. Method: Within the placebo group of the PROSPER trial on pravastatin and the risk of CHD, we compared all individuals who were event free at baseline and developed MI during 3 years' follow-up (n = 122) with a similar-sized control group. Methylation at IL10, LEP, ABCA1, IGF2, INS and GNASAS was measured in DNA extracted from leucocytes using mass spectrometry. Results: DNA methylation at GNASAS was modestly higher in MI cases compared with controls (P = 0.030). A significant sex interaction was observed for INS (P = 0.014) and GNASAS (P = 0.031). Higher DNA methylation at these loci was associated with MI among women (INS: +2.5%, P = 0.002; GNASAS: +4.2%, P = 0.001). Hypermethylation at one locus and at both loci was associated with odds ratios (ORs) of 2.8 and 8.6, respectively (P trend = 3.0 × 10 -4). No association was observed among men. Conclusions: The risk of MI in women is associated with DNA methylation marks at specific loci previously shown to be sensitive to prenatal conditions. This observation may reflect a developmental component of MI. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2011; all rights reserved.


Stijntjes M.,Leiden University | Stijntjes M.,VU University Amsterdam | Pasma J.H.,Leiden University | Van Vuuren M.,Leiden University | And 4 more authors.
Gerontology | Year: 2015

Background: Evidence is emerging that cognitive performance is involved in maintaining balance and thereby involved in falls in the elderly. Objective: To investigate the association of cognitive status with measures of standing balance in elderly outpatients. Methods: In a cross-sectional study, 197 community-dwelling elderly [mean age (SD) 81.9 (7.1) years] referred to a geriatric outpatient clinic were included and subsequently dichotomized into a group with low and normal cognitive status based on cut-off values of the Mini-Mental State Examination, Montreal Cognitive Assessment and Visual Association Test. The ability to maintain standing balance as well as the center of pressure (CoP) movement were assessed during 10 s of side-by-side, semi-tandem and tandem stance with eyes open and eyes closed. Logistic and linear regression were used to examine the association between cognitive status and measures of standing balance adjusted for age, gender and highest completed education. Results: Low cognitive status in elderly outpatients was associated with a lower ability to maintain 10 s of balance in side-by-side stance with eyes closed [OR (95% CI): 3.57 (1.60; 7.97)] and in semi-tandem stance with eyes open and eyes closed [OR (95% CI): 3.93 (1.71; 9.00) and OR (95% CI): 2.32 (1.11; 4.82), respectively]. Cognitive status was not associated with CoP movement. Conclusion: Low cognitive status associates with a lower ability to maintain standing balance in more demanding standing conditions in elderly outpatients. This may have implications for routine geriatric screening strategies and interpretation of results of either standing balance or cognitive tests. © 2014 S. Karger AG, Basel.


Gonzalez-Covarrubias V.,Netherlands Metabolomics Center | Gonzalez-Covarrubias V.,Leiden University | Beekman M.,Leiden University | Uh H.-W.,Netherlands Consortium for Healthy Ageing | And 15 more authors.
Aging Cell | Year: 2013

Middle-aged offspring of nonagenarians, as compared to their spouses (controls), show a favorable lipid metabolism marked by larger LDL particle size in men and lower total triglyceride levels in women. To investigate which specific lipids associate with familial longevity, we explore the plasma lipidome by measuring 128 lipid species using liquid chromatography coupled to mass spectrometry in 1526 offspring of nonagenarians (59 years ± 6.6) and 675 (59 years ± 7.4) controls from the Leiden Longevity Study. In men, no significant differences were observed between offspring and controls. In women, however, 19 lipid species associated with familial longevity. Female offspring showed higher levels of ether phosphocholine (PC) and sphingomyelin (SM) species (3.5-8.7%) and lower levels of phosphoethanolamine PE (38:6) and long-chain triglycerides (TG) (9.4-12.4%). The association with familial longevity of two ether PC and four SM species was independent of total triglyceride levels. In addition, the longevity-associated lipid profile was characterized by a higher ratio of monounsaturated (MUFA) over polyunsaturated (PUFA) lipid species, suggesting that female offspring have a plasma lipidome less prone to oxidative stress. Ether PC and SM species were identified as novel longevity markers in females, independent of total triglycerides levels. Several longevity-associated lipids correlated with a lower risk of hypertension and diabetes in the Leiden Longevity Study cohort. This sex-specific lipid signature marks familial longevity and may suggest a plasma lipidome with a better antioxidant capacity, lower lipid peroxidation and inflammatory precursors, and an efficient beta-oxidation function. © 2013 John Wiley & Sons Ltd and the Anatomical Society.


Sala M.,Leiden University | De Roos A.,Leiden University | Van Den Berg A.,Leiden University | Altmann-Schneider I.,Leiden University | And 6 more authors.
Diabetes Care | Year: 2014

OBJECTIVE We investigated the association between metabolic syndrome risk factors and brain tissue integrity, as assessed by magnetic resonance imaging. RESEARCH DESIGN AND METHODS From the Leiden Longevity Study, which is a community-based study of long-lived subjects, their offspring, and partners thereof, 130 subjects (61men; mean age 66 years)were included. A metabolic syndrome scorewas computed by summing the individual number of components according to the Adult Treatment Panel III criteria. We performed linear and logistic regression analysis and used standardized b-values to assess the association between metabolic syndrome and brainmacrostructure (brain volume andwhitematter lesion load, lacunar infarcts, and cerebral microbleeds) and microstructure (mean magnetization transfer ratio [MTR], MTR histogram peak height, fractional anisotropy, and mean diffusivity [MD]). Linear and stepwise regression analysis was performed to identify the individual contribution of one metabolic syndrome parameter adjusting for the four other parameters. Models were adjusted for age, sex, and relation to longlived family. RESULTS Brain macrostructure was not associated with metabolic syndrome. In contrast, metabolic syndrome was associated with decreased gray (b =20.3 P = 0.001) and whitematter peak height (b =20.3, P = 0.002) and increased gray matter MD (b = 0.2, P = 0.01, P = 0.01). Serum HDL cholesterol (b = 0.22, P = 0.012), triglycerides (b =20.25, P = 0.002), BMI (b =20.2, P = 0.014), and diastolic blood pressure (b = 20.17, P = 0.047, and b=20.23, P = 0.009, for gray and white matter, respectively) were independent factors in these changes in brain microstructure.CONCLUSIONS In early manifestmetabolic syndrome, brain tissue decline can be detected. Serum HDL cholesterol, triglycerides, BMI, and diastolic blood pressure were independent factors in brain tissue integrity. © 2014 by the American Diabetes Association.

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