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Berlin Brandenburg

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  • 1
    In: Circulation, 2018, Vol.137(24), pp.2583-2591
    Description: BACKGROUND:: Observational studies have shown inverse associations among fitness, physical activity, and cardiovascular disease. However, little is known about these associations in individuals with elevated genetic susceptibility for these diseases. METHODS:: We estimated associations of grip strength, objective and subjective physical activity, and cardiorespiratory fitness with cardiovascular events and all-cause death in a large cohort of 502 635 individuals from the UK Biobank (median follow-up, 6.1 years; interquartile range, 5.4–6.8 years). Then we further examined these associations in individuals with different genetic burden by stratifying individuals based on their genetic risk scores for coronary heart disease and atrial fibrillation. We compared disease risk among individuals in different tertiles of fitness, physical activity, and genetic risk using lowest tertiles as reference. RESULTS:: Grip strength, physical activity, and cardiorespiratory fitness showed inverse associations with incident cardiovascular events (coronary heart disease: hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.77–0.81; HR, 0.95; 95% CI, 0.93–0.97; and HR, 0.68; 95% CI, 0.63–0.74, per SD change, respectively; atrial fibrillation: HR, 0.75; 95% CI, 0.73–0.76; HR, 0.93; 95% CI, 0.91–0.95; and HR, 0.60; 95% CI, 0.56–0.65, per SD change, respectively). Higher grip strength and cardiorespiratory fitness were associated with lower risk of incident coronary heart disease and atrial fibrillation in each genetic risk score group (Ptrend 〈0.001 in each genetic risk category). In particular, high levels of cardiorespiratory fitness were associated with 49% lower risk for coronary heart disease (HR, 0.51; 95% CI, 0.38–0.69) and 60% lower risk for atrial fibrillation (HR, 0.40; 95%, CI 0.30–0.55) among individuals at high genetic risk for these diseases. CONCLUSIONS:: Fitness and physical activity demonstrated inverse associations with incident cardiovascular disease in the general population, as well as in individuals with elevated genetic risk for these diseases.
    Keywords: Adult–Epidemiology ; Aged–Physiopathology ; Atrial Fibrillation–Epidemiology ; Biological Specimen Banks–Physiopathology ; Cardiorespiratory Fitness–Physiopathology ; Coronary Disease–Physiopathology ; Exercise–Physiopathology ; Female–Physiopathology ; Follow-Up Studies–Physiopathology ; Humans–Physiopathology ; Male–Physiopathology ; Middle Aged–Physiopathology ; Risk Factors–Physiopathology ; United Kingdom–Physiopathology ; Cardiovascular Disease ; Epidemiology ; Fitness ; Genetics ; Physical Activity;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 2
    In: Circulation, 2018, Vol.138(Suppl_1 Suppl 1), pp.A12970-A12970
    Description: ANGPTL3 is a promising therapeutic target for lowering atherogenic blood lipid levels and decreasing cardiovascular disease risk with no apparent adverse effects. However, detailed metabolic effects of ANGPTL3 deficiency are unclear. In this study, we aimed to determine detailed metabolic effects of ANGPTL3 deficiency in fasting and postprandial state. The study population consisted of cases with familial combined hypolipidemia (FHBL2) caused by a loss-of-function (LoF) mutation in ANGPTL3 gene (N=6 homozygous and N=32 heterozygous carriers) and their controls (N=38). We used nuclear magnetic resonance (NMR) profiling to quantify a wide range of metabolic measures, including lipid concentrations in lipoprotein subclasses, fatty acids, amino acids, and ketone bodies. We compared metabolic signatures of cases and controls in fasting state and after an energy-rich meal. In addition, we used genetic association data from up to 24,925 individuals to compare the metabolic signature of ANGPTL3 LoF mutation with a common variant (rs2131925) in ANGPTL3, and a major triglyceride-rich lipoproteins -associated genetic variant (rs964184) in the APOC3-APOA5-APOA4-APOA1 gene cluster. We found that individuals with ANGPTL3 deficiency (FHBL2) had markedly reduced levels of triglycerides, total cholesterol, free cholesterol and cholesterol esters in all major lipoproteins and their subclasses. They also showed reduced levels of most fatty acids, citrate and acetate, and elevated 3-beta-hydroxybutyrate, a surrogate biomarker of fatty acid beta-oxidation. Homozygous ANGPTL3 LoF variant carriers showed a significant postprandial reduction of cholesterol in large, medium and small VLDL particles as well as in circulating fatty acids, whereas the postprandial response in heterozygous carriers resembled that of controls. ANGPTL3 LoF, ANGPTL3 rs2131925 G- and rs964184 C-allele carriers displayed similar alterations in VLDL and LDL associated lipid parameters, but the common variant -associated HDL levels differed from those of ANGPTL3 LoF carriers. We conclude that in addition to reductions in all major lipoprotein subclasses, ANGPTL3 deficiency results in elevated 3-beta-hydroxybutyrate suggesting enhanced fatty acid beta-oxidation as well as reduced circulating fatty acids putatively alleviating ectopic fat deposition.
    ISSN: 0009-7322
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  • 3
    Language: English
    In: The Lancet, 2011, Vol.377(9763), pp.379-380
    Description: The fact that noninvasive, easily available, and often inexpensive traditional risk factors for CHD such as age, gender, or blood pressure out perform by a large margin a genetic risk score reaffirms the importance of comprehensive physical examination and medical history as the cornerstones of the diagnostic...
    Keywords: Medicine
    ISSN: 0140-6736
    E-ISSN: 1474-547X
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  • 4
    Language: English
    In: Diabetologia, 2016, Vol.59(11), pp.2369-2377
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s00125-016-4081-6 Byline: Emmi Tikkanen (1,2), Matti Pirinen (2), Antti-Pekka Sarin (2), Aki S. Havulinna (3), Satu Mannisto (3), Juha Saltevo (4), Marja-Liisa Lokki (5), Juha Sinisalo (6), Annamari Lundqvist (3), Antti Jula (3), Veikko Salomaa (3), Samuli Ripatti (1,2,7) Keywords: Epidemiology; Genetics; Insulin resistance; Insulin sensitivity Abstract: Aims/hypothesis Epidemiological studies have identified several traits associated with CHD, but few of these have been shown to be causal risk factors and thus suitable targets for treatment. Our aim was to evaluate the causal role of a large set of known CHD risk factors using single-nucleotide polymorphisms (SNPs) as instrumental variables. Methods Based on published genome-wide association studies (GWASs), we estimated the associations between the established risk factors (blood lipids, obesity, glycaemic traits and BP) and CHD with two complementary approaches: (1) using summary statistics from GWASs to analyse the accordance of SNP effects on risk factors and on CHD and (2) individual-level analysis where we constructed genetic risk scores (GRSs) in a large Finnish dataset (N=26,554, CHD events n=4016). We used a weighted regression-based method for summary-level data to evaluate the causality of risk factors. The associations between the GRSs and CHD in the Finnish dataset were evaluated with logistic and conditional logistic regression models. Results The summary-level data analysis revealed causal effects between glycaemic traits (insulin and glucose) and CHD. The individual-level data analysis supported the causal role of insulin, but not of glucose, on CHD. The GRS for insulin was associated with CHD in the Finnish cohort (OR 1.06 per SD in GRS, 95% CI 1.02, 1.10, p=0.002). Conclusions/interpretation These results support the causal role of insulin in the pathogenesis of CHD. Efficient treatment and prevention of insulin resistance is essential to prevent future CHD events. Author Affiliation: (1) Department of Public Health, University of Helsinki, PO Box 20, Tukholmankatu 8 B, FIN-00014, Helsinki, Finland (2) Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland (3) Department of Health, National Institute for Health and Welfare, Helsinki, Finland (4) Department of Medicine, Central Finland Central Hospital, Jyvaskyla, Finland (5) Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland (6) Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (7) Wellcome Trust Sanger Institute, Hinxton, UK Article History: Registration Date: 12/08/2016 Received Date: 27/04/2016 Accepted Date: 04/08/2016 Online Date: 26/08/2016 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00125-016-4081-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
    Keywords: Epidemiology ; Genetics ; Insulin resistance ; Insulin sensitivity
    ISSN: 0012-186X
    E-ISSN: 1432-0428
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  • 5
    Language: English
    In: Journal of the American College of Cardiology, 05 April 2016, Vol.67(13), pp.602-602
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/S0735-1097(16)30603-9 Byline: Satu Vaara, Emmi Tikkanen, Olavi Parkkonen, Marja-Liisa Lokki, Samuli Ripatti, Markus Perola, Markku S. Nieminen, Juha Sinisalo Author Affiliation: Heart and Lung Center HUCH, Helsinki University Central Hospital, Helsinki, Finland Article Note: (footnote) Poster Contributions Poster Area, South Hall A1 Sunday, April 03, 2016, 3:45 p.m.-4:30 p.m. Session Title: Acute Coronary Syndromes: Going One Step More Basic Abstract Category: 13. Acute Coronary Syndromes: Basic Presentation Number: 1214-036
    Keywords: Medicine
    ISSN: 0735-1097
    E-ISSN: 1558-3597
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  • 6
    In: Anesthesiology, 2013, Vol.119(6), pp.1422-1433
    Description: BACKGROUND:: Catechol-O-methyltransferase (COMT) metabolizes catecholamines in different tissues. Polymorphisms in COMT gene can attenuate COMT activity and increase sensitivity to pain. Human studies exploring the effect of COMT polymorphisms on pain sensitivity have mostly included small, heterogeneous samples and have ignored several important single nucleotide polymorphisms (SNPs). This study examines the effect of COMT polymorphisms on experimental and postoperative pain phenotypes in a large ethnically homogeneous female patient cohort. METHODS:: Intensity of cold (+2-4°C) and heat (+48°C) pain and tolerance to cold pain were assessed in 1,000 patients scheduled for breast cancer surgery. Acute postoperative pain and oxycodone requirements were recorded. Twenty-two COMT SNPs were genotyped and their association with six pain phenotypes analyzed with linear regression. RESULTS:: There was no association between any of the tested pain phenotypes and SNP rs4680. The strongest association signals were seen between rs165774 and heat pain intensity as well as rs887200 and cold pain intensity. In both cases, minor allele carriers reported less pain. Neither of these results remained significant after strict multiple testing corrections. When analyzed further, the effect of rs887200 was, however, shown to be significant and consistent throughout the cold pressure test. No evidence of association between the SNPs and postoperative oxycodone consumption was found. CONCLUSIONS:: SNPs rs887200 and rs165774 located in the untranslated regions of the gene had the strongest effects on pain sensitivity. Their effect on pain is described here for the first time. These results should be confirmed in further studies and the potential functional mechanisms of the variants studied.
    Keywords: Acute Pain–Epidemiology ; Adult–Genetics ; Aged–Therapeutic Use ; Analgesics, Opioid–Genetics ; Anesthesia–Surgery ; Breast Neoplasms–Genetics ; Catechol O-Methyltransferase–Therapeutic Use ; Cold Temperature–Epidemiology ; Databases, Genetic–Genetics ; Female–Genetics ; Follow-Up Studies–Genetics ; Genetic Variation–Genetics ; Genome-Wide Association Study–Genetics ; Genotype–Genetics ; Haplotypes–Genetics ; Hot Temperature–Genetics ; Humans–Genetics ; Middle Aged–Genetics ; Oxycodone–Genetics ; Pain Measurement–Genetics ; Pain, Postoperative–Genetics ; Polymorphism, Single Nucleotide–Genetics ; Abridged ; Analgesics, Opioid ; Oxycodone ; Catechol O-Methyltransferase;
    ISSN: 0003-3022
    ISSN: 15281175
    E-ISSN: 15281175
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  • 7
    Language: English
    In: Diabetes, February 2017, Vol.66(2), pp.543-550
    Description: Observational studies have shown that elevated systolic blood pressure (SBP) is associated with future onset of type 2 diabetes, but whether this association is causal is not known. We applied the Mendelian randomization framework to evaluate the causal hypothesis that elevated SBP increases risk for type 2 diabetes. We used 28 genetic variants associated with SBP and evaluated their impact on type 2 diabetes using a European-centric meta-analysis comprising 37,293 case and 125,686 control subjects. We found that elevation of SBP levels by 1 mmHg due to our genetic score was associated with a 2% increase in risk of type 2 diabetes (odds ratio 1.02, 95% CI 1.01-1.03, P = 9.05 × 10). To limit confounding, we constructed a second score based on 13 variants exclusively associated with SBP and found a similar increase in type 2 diabetes risk per 1 mmHg of genetic elevation in SBP (odds ratio 1.02, 95% CI 1.01-1.03, P = 1.48 × 10). Sensitivity analyses using multiple, alternative causal inference measures and simulation studies demonstrated consistent association, suggesting robustness of our primary observation. In line with previous reports from observational studies, we found that genetically elevated SBP was associated with increased risk for type 2 diabetes. Further work will be required to elucidate the biological mechanism and translational implications.
    Keywords: Blood Pressure -- Genetics ; Diabetes Mellitus, Type 2 -- Genetics
    ISSN: 00121797
    E-ISSN: 1939-327X
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  • 8
    In: International Journal of Epidemiology, 2017, Vol. 46(4), pp.1223-1229
    Description: Background: Familial factors play an important role in the variation of risk factors of cardiovascular diseases (CVD), but less is known about how they affect the risk of death from CVD. We estimated familial aggregation of CVD mortality for twins offering the maximum level of risk due to genetic and other familial factors.Methods: Altogether, 132 771 twin individuals, including 65 196 complete pairs from Denmark, Finland and Sweden born in 1958 or earlier, participated in this study. During the register-based follow-up, 11 641 deaths occurred from coronary heart disease (CHD), including 6280 deaths from myocardial infarct and 4855 deaths occurred from stroke, with 1092 deaths from ischaemic stroke and 1159 deaths from haemorrhagic stroke. Relative recurrence risk ratios (RRRs) with 95% confidence intervals (95% CIs) for monozygotic and dizygotic twins were calculated.Results: In the analyses pooling men and women, the RRR for monozygotic twins was 1.49 (95% CI 1.40-1.57) for CHD and 1.81 for any stroke (95% CI 1.54-2.09). The highest RRR was found for haemorrhagic stroke (3.53 95% CI 2.01-5.04). For dizygotic twins, the RRRs were generally lower.Conclusions: Family aggregation was found for CHD and haemorrhagic stroke. Clustering of risk factors in families increases the risk of CVD.
    Keywords: Coronary Heart Disease ; Stroke ; Genetics ; Twins ; Family History
    ISSN: 0300-5771
    E-ISSN: 1464-3685
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  • 9
    In: Anesthesiology, 2013, Vol.119(6), pp.1410-1421
    Description: BACKGROUND:: This article describes the methods and results of the early part (experimental pain tests and postoperative analgesia) of a study that assesses genetic and other factors related to acute pain and persistent pain after treatment of breast cancer in a prospective cohort of 1,000 women. METHODS:: One thousand consenting patients were recruited to the study. Before surgery (breast resection or mastectomy with axillary surgery), the patients filled in questionnaires about health, life style, depression (Beck Depression Inventory), and anxiety (State-Trait Anxiety Inventory). They were also exposed to experimental tests measuring heat (43° and 48°C, 5 s) and cold (2-4°C) pain intensity and tolerance. Anesthesia was standardized with propofol and remifentanil, and postoperative analgesia was optimized with i.v. oxycodone. RESULTS:: The patients showed significant interindividual variation in heat and cold pain sensitivity and cold pain tolerance. There was a strong correlation between the experimental pain measures across the tests. Presence of chronic pain, the number of previous operations, and particularly state anxiety were related to increased pain sensitivity. Previous smoking correlated with decreased heat pain sensitivity. These factors explained 4–5% of the total variance in pain sensitivity in these tests. Oxycodone consumption during 20 h was significantly higher in patients who had axillary clearance. Oxycodone consumption had only a weak correlation with the experimental pain measures. CONCLUSIONS:: Contact heat and cold pressure tests identify variability in pain sensitivity which is modified by factors such as anxiety, chronic pain, previous surgery, and smoking. High levels of anxiety are connected to increased pain sensitivity in experimental and acute postoperative pain.In a study of 1,000 women undergoing breast surgery for cancer, a small portion of the variance in preoperative response to noxious heat and cold testing could be explained by anxiety, the presence of chronic pain, and the number of previous operations. There was a weak correlation between response to experimental pain testing and acute postoperative pain, with largely similar predictive factors across both.
    Keywords: Adult–Administration & Dosage ; Aged–Therapeutic Use ; Analgesics, Opioid–Complications ; Anesthesia–Epidemiology ; Breast Neoplasms–Genetics ; Cohort Studies–Administration & Dosage ; Cold Temperature–Therapeutic Use ; Female–Epidemiology ; Follow-Up Studies–Etiology ; Hot Temperature–Genetics ; Humans–Drug Effects ; Mastectomy–Epidemiology ; Middle Aged–Genetics ; Oxycodone–Genetics ; Pain–Genetics ; Pain Measurement–Genetics ; Pain, Postoperative–Genetics ; Prospective Studies–Genetics ; Young Adult–Genetics ; Abridged ; Analgesics, Opioid ; Oxycodone;
    ISSN: 0003-3022
    ISSN: 15281175
    E-ISSN: 15281175
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  • 10
    Language: English
    In: The Lancet, 2010, Vol.376(9750), pp.1393-1400
    Description: Comparison of patients with coronary heart disease and controls in genome-wide association studies has revealed several single nucleotide polymorphisms (SNPs) associated with coronary heart disease. We aimed to establish the external validity of these findings and to obtain more precise risk estimates using a prospective cohort design. We tested 13 recently discovered SNPs for association with coronary heart disease in a case-control design including participants differing from those in the discovery samples (3829 participants with prevalent coronary heart disease and 48 897 controls free of the disease) and a prospective cohort design including 30 725 participants free of cardiovascular disease from Finland and Sweden. We modelled the 13 SNPs as a multilocus genetic risk score and used Cox proportional hazards models to estimate the association of genetic risk score with incident coronary heart disease. For case-control analyses we analysed associations between individual SNPs and quintiles of genetic risk score using logistic regression. In prospective cohort analyses, 1264 participants had a first coronary heart disease event during a median 10·7 years' follow-up (IQR 6·7–13·6). Genetic risk score was associated with a first coronary heart disease event. When compared with the bottom quintile of genetic risk score, participants in the top quintile were at 1·66-times increased risk of coronary heart disease in a model adjusting for traditional risk factors (95% CI 1·35–2·04, p value for linear trend=7·3×10 ). Adjustment for family history did not change these estimates. Genetic risk score did not improve C index over traditional risk factors and family history (p=0·19), nor did it have a significant effect on net reclassification improvement (2·2%, p=0·18); however, it did have a small effect on integrated discrimination index (0·004, p=0·0006). Results of the case-control analyses were similar to those of the prospective cohort analyses. Using a genetic risk score based on 13 SNPs associated with coronary heart disease, we can identify the 20% of individuals of European ancestry who are at roughly 70% increased risk of a first coronary heart disease event. The potential clinical use of this panel of SNPs remains to be defined. The Wellcome Trust; Academy of Finland Center of Excellence for Complex Disease Genetics; US National Institutes of Health; the Donovan Family Foundation.
    Keywords: Medicine
    ISSN: 0140-6736
    E-ISSN: 1474-547X
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