Prospective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring... Show moreProspective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring possible causality. We aimed to assess the causal associations of these cardiac blood biomarkers with dementia and cognition using two-sample Mendelian randomization (MR). Independent genetic instruments (p < 5e−7) for troponin T and I, N-terminal pro B-type natriuretic peptide (NT-proBNP) and growth-differentiation factor 15 (GDF15) were obtained from previously-performed genome-wide association studies of predominantly European ancestry. Summary statistics for gene-outcome associations in European-ancestry participants, for the two-sample MR analyses, were obtained for general cognitive performance (n = 257,842) and dementia (n = 111,326 clinically diagnosed and “proxy” AD cases, and 677,663 controls). Two-sample MR analyses were performed using inverse variance-weighted (IWV) analyses. Sensitivity analyses to evaluate horizontal pleiotropy included weighted median estimator, MR-Egger, and MR using cis-SNPs only. Using IVW, we did not find evidence for possible causal associations between genetically influenced cardiac biomarkers with cognition and dementia. For example, per standard deviation (SD) higher cardiac blood biomarker, the odds ratio for risk of dementia was 1.06 (95%CI 0.90; 1.21) for troponin T, 0.98 (95%CI 0.72; 1.23) for troponin I, 0.97 (95%CI 0.90; 1.06) for NT-proBNP and 1.07 (95%CI 0.93; 1.21) for GDF15. Sensitivity analyses showed higher GDF15 was significantly associated with higher dementia risk and worse cognitive function. We did not find strong evidence that cardiac biomarkers causally influence dementia risk. Future research should aim at elucidating the biological pathways through which cardiac blood biomarkers associate with dementia. Show less
Background and aims: Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles... Show moreBackground and aims: Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles have independent beneficial associations on cardiovascular disease (CVD) risk. We aimed to provide further insight into this observation by applying Mendelian randomization analyses of genetically-influenced TG and LDL-C levels on plasma metabolomic profiles Methods: We quantified over 100 lipoprotein metabolomic measures in the Netherlands Epidemiology of Obesity (NEO) study (N = 4838) and Oxford Biobank (OBB) (N = 6999) by nuclear magnetic resonance (NMR) spectroscopy. Weighted genetic scores for TG via five LPL alleles and LDL-C via 19 alleles were calculated and dichotomized by the median, resulting in four genotype combinations of high/low TG and high/low LDL-C. We performed linear regression analyses using a two & times; two design with the group with genetically-influenced high TG and LDL-C as a reference. Results: Compared to the individual groups with genetically-influenced lower TG or lower LDL-C only, the group with combined genetically-influenced lower TG and LDL-C showed an overall independent and additive pattern of changes in metabolomic measures. Over 100 measures were different (p < 1.35 & times; 10-3) compared to the reference, with effect sizes and directionality being similar in NEO and OBB. Most notably, levels of all very-low density lipoprotein (VLDL) and LDL sub-particles were lower. Conclusions: Our findings provide evidence that TG-lowering on top of LDL-C-lowering has additive beneficial effects on the lipoprotein profile compared to TG-lowering or LDL-C-lowering only, which is in accordance with reported additive genetic effects on CVD risk reduction. Show less
Zonneveld, M.H.; Noordam, R.; Grond, J. van der; Heemst, D. van; Mooijaart, S.P.; Sabayan, B.; ... ; Trompet, S. 2021
We aimed to investigate whether circulating leptin and body mass index (BMI) associate independently with cognitive function (decline) and brain volumes using magnetic resonance imaging (MRI) in... Show moreWe aimed to investigate whether circulating leptin and body mass index (BMI) associate independently with cognitive function (decline) and brain volumes using magnetic resonance imaging (MRI) in older individuals at risk of cardiovascular disease. We studied the cross-sectional and longitudinal associations in participants enrolled in the PROSPER study (Prospective Study of Pravastatin in the Elderly at Risk). Cognitive function was tested at baseline and repeated during a mean follow-up time of 3.2 years. Analyses were performed with multivariable (repeated) linear regression models and adjusted for demographics, cardiovascular risk-factors, and stratified by sex. We included 5623 dementia-free participants (52 % female, mean age 75 years) with a mean BMI of 26.9 (SD = 4.1). In a sub-study, 527 participants underwent brain MRI. At baseline, individuals with a BMI > 30 had a worse performance on the Stroop test (beta 5.0 s, 95 %CI 2.6;7.5) and larger volumes of the amygdala (beta 234 mm(3), 95 %CI 3;464) and hippocampus (beta 590 mm(3), 95 %CI 181;999), independent of intracranial volume and serum leptin levels, compared with individuals with the reference BMI (BMI 18-25 kg/m(2)). Per log ng/mL higher serum leptin, independent of BMI, a 135 mm(3) (95 %CI 2;268) higher volume of the amygdala was found, but no association was observed with cognitive tests nor with other brain volumes. Stratification for sex did not materially change the results. Whereas higher BMI associated with worse cognitive function independent of leptin levels, our study provided evidence that leptin and BMI independently associate with amygdala volume suggesting potential distinct biological associations. Show less
