Biology subjects

Tikkanen, E.

Publications and source records attributed to Tikkanen, E..

4 recordsLinked to original sources

bioRxiv2018

Metabolomic signature of angiopoietin-like protein 3 deficiency in fasting and postprandial state

ObjectiveLoss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with low levels of plasma lipoproteins and decreased coronary artery disease risk. We aimed to determine detailed metabolic effects of genetically-induced ANGPTL3 deficiency in fasting and postprandial state.\n\nApproach and ResultsWe studied individuals carrying S17X loss-of-function mutation in ANGPTL3 (6 homozygous and 32 heterozygous carriers) and 38 noncarriers. Nuclear magnetic resonance metabolomics was used to quantify 225 circulating metabolic measures. We compared metabolic differences between loss-of-function carriers and noncarriers in fasting state and after a high fat meal. In fasting, ANGPTL3 deficiency was characterized by similar extent of reductions in low-density lipoprotein cholesterol (0.74 SD-units lower concentration per loss-of-function allele [95%CI 0.42-1.06]) as observed for many triglyceride-rich lipoprotein measures, including very-low-density lipoprotein cholesterol (0.75 [0.45-1.05]). Within most lipoprotein subclasses, absolute levels of cholesterol were decreased more than triglycerides, resulting in the relative proportion of cholesterol being reduced within triglyceride-rich lipoproteins and their remnants. Further, beta-hydroxybutyrate was elevated (0.55 [0.21-0.89]). Homozygous ANGPTL3 loss-of-function carriers showed essentially no postprandial increase in triglyceride-rich lipoproteins and fatty acids, without evidence for adverse compensatory metabolic effects.\n\nConclusionsIn addition to overall triglyceride and low-density lipoprotein cholesterol lowering effects, ANGPTL3 deficiency results in reduction of cholesterol proportion within triglyceride-rich lipoproteins and their remnants. Further, ANGPTL3 loss-of-function carriers had elevated ketone body production, suggesting enhanced hepatic fatty acid beta-oxidation. The detailed metabolic profile in human knockouts of ANGPTL3 reinforces inactivation of ANGPTL3 as a promising therapeutic target for decreasing cardiovascular risk.\n\nHIGHLIGHTSO_LIANGPTL3 deficiency results in similar reductions in LDL cholesterol and many triglyceride-rich lipoprotein lipids measures, such as VLDL cholesterol, with no evidence of substantial adverse effects on the comprehensive panel of circulating metabolite biomarkers tested here.\nC_LIO_LIIn particular, ANGPTL3 deficiency results in reduction of cholesterol content in triglyceride-rich lipoproteins and their remnants, which have been highlighted as risk factor for cardiovascular disease independently of LDL levels.\nC_LIO_LIHomozygous ANGPTL3 loss-of-function carriers show essentially no postprandial increase in triglyceride-rich lipoproteins and fatty acids in response to a fat challenge, and display consistently elevated postprandial levels of ketone bodies and lactate when compared to noncarriers, suggesting enhanced hepatic fatty acid beta-oxidation.\nC_LI

genetics↗

bioRxiv2017

Birthweight, Type 2 Diabetes and Cardiovascular Disease: Addressing the Barker Hypothesis with Mendelian randomization

BackgroundLow birthweight (BW) has been associated with a higher risk of hypertension, type 2 diabetes (T2D) and cardiovascular disease (CVD) in epidemiological studies. The Barker hypothesis posits that intrauterine growth restriction resulting in lower BW is causal for these diseases, but causality and mechanisms are difficult to infer from observational studies. Mendelian randomization (MR) is a new tool to address this important question.\n\nMethodsWe performed regression analyses to assess associations of self-reported BW with CVD and T2D in 237,631 individuals from the UK Biobank, a large population-based cohort study aged 40-69 years recruited across UK in 2006-2010. Further, we assessed the causal relationship of such associations using the two- sample MR approach, estimating the causal effect by contrasting the SNP effects on the exposure with the SNP effects on the outcome using independent publicly available genome-wide association datasets.\n\nResultsIn the observational analyses, BW showed strong inverse associations with systolic and diastolic blood pressure ({beta}, -0.83 and -0.26; per raw unit in outcomes and SD change in BW; 95% CI, -0.90, -0.75 and -0.31, -0.22, respectively), T2D (odds ratio [OR], 0.83; 95% CI, 0.79, 0.87), lipid-lowering treatment (OR, 0.84; 95% CI, 0.81, 0.86) and CAD (hazard ratio [HR] 0.85; 95% CI, 0.78, 0.94); while the associations with adult body mass index (BMI) and body fat ({beta}, 0.04 and 0.02; per SD change in outcomes and BW; 95% CI, 0.03, 0.04 and 0.01, 0.02, respectively) were positive. The MR analyses indicated inverse causal associations of BW with low density lipoprotein cholesterol, 2-hour glucose, CAD and T2D, and positive causal association with BMI; but no associations with blood pressure. Sensitivity analyses and robust MR methods provided consistent results and indicated no horizontal pleiotropy.\n\nConclusionOur study indicates that lower BW is causally and directly related with increased susceptibility to CAD and T2D in adulthood. This causal relationship is not mediated by adult obesity or hypertension.

genetics↗

bioRxiv2017

Biological Insights Into Muscular Strength: Genetic Findings in the UK Biobank

BackgroundHand grip strength, a simple indicator of muscular strength, has been associated with a range of health conditions, including fractures, disability, cardiovascular disease and premature death risk. Twin studies have suggested a high (50-60%) heritability, but genetic determinants are largely unknown.\n\nAimsIn this study, our aim was to study genetic variation associated with muscular strength in a large sample of 334,925 individuals of European descent from the UK Biobank, and to evaluate shared genetic aetiology with and causal effects of grip strength on physical and cognitive health.\n\nMethods and ResultsIn our discovery analysis of 223,315 individuals, we identified 101 loci associated with grip strength at genome-wide significance (P<5x10-8). Of these, 64 were associated (P<0.01 and consistent direction) also in the replication dataset (N=111,610). Many of the lead SNPs were located in or near genes known to have a function in developmental disorders (FTO, SLC39A8, TFAP2B, TGFA, CELF1, TCF4, BDNF, FOXP1, KIF1B, ANTXR2), and one of the most significant genes based on a gene-based analysis (ATP2A1) encodes SERCA1, the critical enzyme in calcium uptake to the sarcoplasmic reticulum, which plays a major role in muscle contraction and relaxation. Further, we demonstrated a significant enrichment of gene expression in brain-related transcripts among grip strength associations. Finally, we observed inverse genetic correlations of grip strength with cardiometabolic traits, and positive correlation with parents age of death and education; and showed that grip strength was causally related to fitness, physical activity and other indicators of frailty, including cognitive performance scores.\n\nConclusionsIn our study of over 330,000 individuals from the general population, the genetic findings for hand grip strength suggest an important role of the central nervous system in strength performance. Further, our results indicate that maintaining good muscular strength is important for physical and cognitive performance and healthy aging.

genomics↗

bioRxiv2017

Fitness, Physical Activity, And Cardiovascular Disease: Longitudinal And Genetic Analyses In The UK Biobank Study

BackgroundExercise is inversely related with cardiovascular disease (CVD), but large-scale studies of incident CVD events are lacking. Moreover, little is known about genetic determinants of fitness and physical activity, and modifiable effects of exercise in individuals with elevated genetic risk of CVD. Finally, causal analyses of exercise traits are limited.\n\nMethodsWe estimated associations of grip strength, physical activity, and cardiorespiratory fitness with CVD and all-cause death in up to 502,635 individuals from the UK Biobank. We also examined these associations in individuals with different genetic burden on coronary heart disease (CHD) and atrial fibrillation (AF). Finally, we performed genome-wide association study (GWAS) of grip strength and physical activity, as well as Mendelian randomization analysis to assess the causal role of grip strength in CHD.\n\nFindingsGrip strength, physical activity, and cardiorespiratory fitness showed strong inverse associations with incident cardiovascular events and all-cause death (for composite CVD; HR, 0.78, 95% CI, 0.77-0.80; HR, 0.94, 95% CI, 0.93-0.95, and HR, 0.67, 95% CI, 0.63-0.71, per SD change, respectively). We observed stronger associations of grip strength with CHD and AF for individuals in the lowest tertile of genetic risk (Pinteraction = 0.006, Pinteraction = 0.03, respectively), but the inverse associations were present in each category of genetic risk. We report 27 novel genetic loci associated with grip strength and 2 loci with physical activity, with the strongest associations in FTO (rs56094641, P=3.8x10-24) and SMIM2 (rs9316077, P=1.4x10-8), respectively. By use of Mendelian randomization, we provide evidence that grip strength is causally related to CHD.\n\nInterpretationMaintaining physical strength is likely to prevent future cardiovascular events, also in individuals with elevated genetic risk for CVD.\n\nFundingNational Institutes of Health (1 R01 HL135313-01), Knut and Alice Wallenberg Foundation (2013.0126), and the Finnish Cultural Foundation.

epidemiology↗