Background and aims: The APOE epsilon 4 genotype has a higher risk for developing coronary artery disease (CAD), but there is preliminary evidence that antioxidative lifestyle factors interact with... Show moreBackground and aims: The APOE epsilon 4 genotype has a higher risk for developing coronary artery disease (CAD), but there is preliminary evidence that antioxidative lifestyle factors interact with APOE genotype on CAD risk. Here, we assessed the effect modification of physical activity, oily fish and polyunsaturated fatty acid (PUFA) intake with APOE genotype on risk of incident CAD. Methods: The present study comprised 345,659 white European participants from UK Biobank (mean age: 56.5 years, 45.7% men) without a history of CAD. Information regarding physical activity, oily fish intake and PUFA intake was collected through questionnaires, and information on incident CAD through linkage with hospital admission records. Analyses were performed using Cox proportional hazard models adjusted for age and sex. Results: Higher physical activity level and oily fish intake were both associated with a lower incidence of CAD. However, these associations were similar across the different APOE genotypes (p-values for interaction > 0.05). Most notable, higher PUFA intake was associated with a lower CAD risk in APOE epsilon 4 genotype carriers (hazard ratio: 0.76, 95% confidence interval: 0.63-0.92), and not in APOE epsilon 3/epsilon 3 genotype carriers (0.90; 0.79, 1.02), but without statistical evidence for effect modification (p-valueinteraction = 0.137). Conclusions: While higher physical activity and high fish and PUFA intake were associated with a lower risk of incident CAD, no evidence for interaction of these lifestyle factors with APOE genotype was observed in UK Biobank participants. Interventions intended to reduce cardiovascular risk might therefore be similarly effective across the APOE genotype carriers. Show less
Cardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the... Show moreCardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the interplay between genetic factors and lifestyle factors (eg sleep, nutrition, physical activity) with diseases such as cardiovascular disease and risk factors for cardiovascular disease (diabetes). For example, 12 blood biomarkers associated with insulin resistance have been identified, 5 of which are specifically much higher in subjects with diabetes. In addition, it appeared that a short sleep duration and poor sleep quality are associated with poorer lipids in the blood (eg cholesterol and LDL) and more insulin resistance. With regard to sleep, 59 new genetic variants have also been identified with regard to blood lipids (HDL, LDL, triglycerides). In addition, the results indicate that a better lifestyle can also help reduce the development of new cardiovascular diseases in people with an increased genetic risk. This is particularly interesting to prevent diseases in persons at high risk. All in all, this thesis has provided new insights into the various factors that are potentially important in the development of cardiovascular disease and diabetes. Show less
Bos, M.M.; Noordam, R.; Bennett, K.; Beekman, M.; Mook-Kanamori, D.O.; Dijk, K.W. van; ... ; Heemst, D. van 2020
Introduction Several plasma metabolites have been associated with insulin resistance and type 2 diabetes mellitus. Objectives We aimed to identify plasma metabolites associated with different... Show moreIntroduction Several plasma metabolites have been associated with insulin resistance and type 2 diabetes mellitus. Objectives We aimed to identify plasma metabolites associated with different indices of early disturbances in glucose metabolism and insulin sensitivity. Methods This cross-sectional study was conducted in a subsample of the Leiden Longevity Study comprising individuals without a history of diabetes mellitus (n = 233) with a mean age of 63.3 +/- 6.7 years of which 48.1% were men. We tested for associations of fasting glucose, fasting insulin, HOMA-IR, Matsuda Index, Insulinogenic Index and glycated hemoglobin with metabolites (Swedish Metabolomics Platform) using linear regression analysis adjusted for age, sex and BMI. Results were validated internally using an independent metabolomics platform (Biocrates platform) and replicated externally in the independent Netherlands Epidemiology of Obesity (NEO) study (Metabolon platform) (n = 545, mean age of 55.8 +/- 6.0 years of which 48.6% were men). Moreover, in the NEO study, we replicated our analyses in individuals with diabetes mellitus (cases: n = 36; controls = 561). Results Out of the 34 metabolites, a total of 12 plasma metabolites were associated with different indices of disturbances in glucose metabolism and insulin sensitivity in individuals without diabetes mellitus. These findings were validated using a different metabolomics platform as well as in an independent cohort of non-diabetics. Moreover, tyrosine, alanine, valine, tryptophan and alpha-ketoglutaric acid levels were higher in individuals with diabetes mellitus. Conclusion We found several plasma metabolites that are associated with early disturbances in glucose metabolism and insulin sensitivity of which five were also higher in individuals with diabetes mellitus. Show less
Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct... Show moreBoth short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles. Show less
Bos, M.M.; Heemst, D. van; Donga, E.; Mutsert, R. de; Rosendaal, F.R.; Blauw, G.J.; ... ; Noordam, R. 2019
