Browsing by Subject "COHORT PROFILE"

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  • PRACTICAl Consortium; Law, Philip J.; Timofeeva, Maria; Fernandez-Rozadilla, Ceres; Palin, Kimmo; Hänninen, Ulrika A.; Cajuso, Tatiana; Tanskanen, Tomas; Kondelin, Johanna; Kaasinen, Eevi; Sarin, Antti-Pekka; Eriksson, Johan G.; Jousilahti, Pekka; Ripatti, Samuli; Palotie, Aarno; Renkonen-Sinisalo, Laura; Lepistö, Anna; Aaltonen, Lauri A.; Rissanen, Harri; Salomaa, Veikko; Böhm, Jan; Mecklin, Jukka-Pekka; Pukkala, Eero (2019)
    Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
  • Neumann, Alexander; Walton, Esther; Alemany, Silvia; Cecil, Charlotte; Gonzalez, Juan Ramon; Jima, Dereje D.; Lahti, Jari; Tuominen, Samuli T.; Barker, Edward D.; Binder, Elisabeth; Caramaschi, Doretta; Carracedo, Angel; Czamara, Darina; Evandt, Jorunn; Felix, Janine F.; Fuemmeler, Bernard F.; Gutzkow, Kristine B.; Hoyo, Cathrine; Julvez, Jordi; Kajantie, Eero; Laivuori, Hannele; Maguire, Rachel; Maitre, Lea; Murphy, Susan K.; Murcia, Mario; Villa, Pia M.; Sharp, Gemma; Sunyer, Jordi; Räikkönen, Katri; Bakermans-Kranenburg, Marian; van Ijzendoorn, Marinus; Guxens, Monica; Relton, Caroline L.; Tiemeier, Henning (2020)
    Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p <0.05) in either of the EWAS were correlated between timepoints (rho = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p <1 x 10(-7)), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p <1 x 10(-7). In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.
  • Lempainen, Johanna; Korhonen, Laura S.; Kantojärvi, Katri; Heinonen, Santtu; Toivonen, Laura; Räty, Panu; Ramilo, Octavio; Mejias, Asuncion; Vuorinen, Tytti; Waris, Matti; Karlsson, Linnea; Karlsson, Hasse; Laine, Antti-Pekka; Paunio, Tiina; Peltola, Ville (2021)
    Background. Genetic heterogeneity in type I interferon (IFN)-related gene IFI44L may account for variable susceptibility to respiratory tract infections (RTIs) in children. Methods. In 2 prospective, population-based birth cohorts, the STEPS Study and the FinnBrain Birth Cohort Study, IFI44L genotypes for rs273259 and rs1333969 were determined in relation to the development of RTIs until 1 or 2 years of age, respectively. At age 3 months, whole-blood transcriptional profiles were analyzed and nasal samples were tested for respiratory viruses in a subset of children. Results. In the STEPS Study (n=1135), IFI44L minor/minor gene variants were associated with lower rates of acute otitis media episodes (adjusted incidence rate ratio, 0.77 [95% confidence interval, .61-.96] for rs273259 and 0.74 [.55-.99] for rs1333969) and courses of antibiotics for RTIs (0.76 [.62-.95] and 0.73 [.56-.97], respectively. In the FinnBrain cohort (n=971), IFI44L variants were associated with lower rates of RTIs and courses of antibiotics for RTIs. In respiratory virus-positive 3-month-old children, IFI44L gene variants were associated with decreased expression levels of IFI44L and several other IFN-related genes. Conclusions. Variant forms of IFI44L gene were protective against early-childhood RTIs or acute otitis media, and they attenuated IFN pathway activation by respiratory viruses.
  • Stenholm, S.; Head, J.; Aalto, V.; Kivimaki, M.; Kawachi, I.; Zins, M.; Goldberg, M.; Platts, L. G.; Zaninotto, P.; Hanson, L. L. Magnusson; Westerlund, H.; Vahtera, J. (2017)
    BACKGROUND: While many studies have shown associations between obesity and increased risk of morbidity and mortality, little comparable information is available on how body mass index (BMI) impacts health expectancy. We examined associations of BMI with healthy and chronic disease-free life expectancy in four European cohort studies. METHODS: Data were drawn from repeated waves of cohort studies in England, Finland, France and Sweden. BMI was categorized into four groups from normal weight (18.5-24.9 kg m(-2)) to obesity class II (>= 35 kg m(-2)). Health expectancy was estimated with two health indicators: sub-optimal self-rated health and having a chronic disease (cardiovascular disease, cancer, respiratory disease and diabetes). Multistate life table models were used to estimate sex-specific healthy life expectancy and chronic disease-free life expectancy from ages 50 to 75 years for each BMI category. RESULTS: The proportion of life spent in good perceived health between ages 50 and 75 progressively decreased with increasing BMI from 81% in normal weight men and women to 53% in men and women with class II obesity which corresponds to an average 7-year difference in absolute terms. The proportion of life between ages 50 and 75 years without chronic diseases decreased from 62 and 65% in normal weight men and women and to 29 and 36% in men and women with class II obesity, respectively. This corresponds to an average 9 more years without chronic diseases in normal weight men and 7 more years in normal weight women between ages 50 and 75 years compared to class II obese men and women. No consistent differences were observed between cohorts. CONCLUSIONS: Excess BMI is associated with substantially shorter healthy and chronic disease-free life expectancy, suggesting that tackling obesity would increase years lived in good health in populations.
  • Koskinen, Juhani S.; Kytö, Ville; Juonala, Markus; Viikari, Jorma S. A.; Nevalainen, Jaakko; Kähönen, Mika; Lehtimäki, Terho; Hutri-Kähönen, Nina; Laitinen, Tomi; Tossavainen, Päivi; Jokinen, Eero; Magnussen, Costan G.; Raitakari, Olli T. (2020)
    Background and aims: Carotid plaque is a specific sign of atherosclerosis and adults with carotid plaque are at increased risk for cardiovascular outcomes. Atherosclerosis has roots in childhood and pediatric guidelines provide cut-off values for cardiovascular risk factors. However, it is unknown whether these cut-offs predict adulthood advanced atherosclerosis. Methods: The Cardiovascular Risk in Young Finns Study is a follow-up of children that begun in 1980 when 2653 participants with data for the present analyses were aged 3-18 years. In 2001 and 2007 follow-ups, in addition to adulthood cardiovascular risk factors, carotid ultrasound data was collected. Long-term burden, as the area under the curve, was evaluated for childhood (6-18 years) risk factors. To study the associations of guideline-based cut-offs with carotid plaque, both childhood and adult risk factors were classified according to clinical practice guidelines. Results: Carotid plaque, defined as a focal structure of the arterial wall protruding into lumen > 50% compared to adjacent intima-media thickness, was present in 88 (3.3%) participants. Relative risk for carotid plaque, when adjusted for age and sex, was 3.03 (95% CI, 1.76-5.21) for childhood dyslipidemia, 1.51 (95% CI, 0.99-2.32) for childhood elevated systolic blood pressure, and 1.93 (95% CI, 1.26-2.94) for childhood smoking. Childhood dyslipidemia and smoking remained independent predictors of carotid plaque in models additionally adjusted for adult risk factors and family history of coronary heart disease. Carotid plaque was present in less than 1% of adults with no childhood risk factors. Conclusions: Findings reinforce childhood prevention efforts and demonstrate the utility of guideline-based cutoffs in identifying children at increased risk for adulthood atherosclerosis.
  • Tukiainen, Taru; Pirinen, Matti; Sarin, Antti-Pekka; Ladenvall, Claes; Kettunen, Johannes; Lehtimaeki, Terho; Lokki, Marja-Liisa; Perola, Markus; Sinisalo, Juha; Vlachopoulou, Efthymia; Eriksson, Johan G.; Groop, Leif; Jula, Antti; Jaervelin, Marjo-Riitta; Raitakari, Olli T.; Salomaa, Veikko; Ripatti, Samuli (2014)
  • Barrios, Clara; Zierer, Jonas; Würtz, Peter; Haller, Toomas; Metspalu, Andres; Gieger, Christian; Thorand, Barbara; Meisinger, Christa; Waldenberger, Melanie; Raitakari, Olli; Lehtimäki, Terho; Otero, Sol; Rodriguez, Eva; Pedro-Botet, Juan; Kähönen, Mika; Ala-Korpela, Mika; Kastenmüller, Gabi; Spector, Tim D.; Pascual, Julio; Menni, Cristina (2018)
    Using targeted NMR spectroscopy of 227 fasting serum metabolic traits, we searched for novel metabolic signatures of renal function in 926 type 2 diabetics (T2D) and 4838 non-diabetic individuals from four independent cohorts. We furthermore investigated longitudinal changes of metabolic measures and renal function and associations with other T2D microvascular complications. 142 traits correlated with glomerular filtration rate (eGFR) after adjusting for confounders and multiple testing: 59 in diabetics, 109 in non-diabetics with 26 overlapping. The amino acids glycine and phenylalanine and the energy metabolites citrate and glycerol were negatively associated with eGFR in all the cohorts, while alanine, valine and pyruvate depicted opposite association in diabetics (positive) and nondiabetics (negative). Moreover, in all cohorts, the triglyceride content of different lipoprotein subclasses showed a negative association with eGFR, while cholesterol, cholesterol esters (CE), and phospholipids in HDL were associated with better renal function. In contrast, phospholipids and CEs in LDL showed positive associations with eGFR only in T2D, while phospholipid content in HDL was positively associated with eGFR both cross-sectionally and longitudinally only in non-diabetics. In conclusion, we provide a wide list of kidney function-associated metabolic traits and identified novel metabolic differences between diabetic and non-diabetic kidney disease.
  • Yeung, Edwina H.; Guan, Weihua; Zeng, Xuehuo; Salas, Lucas A.; Mumford, Sunni L.; de Prado Bert, Paula; van Meel, Evelien R.; Malmberg, Anni; Sunyer, Jordi; Duijts, Liesbeth; Felix, Janine F.; Czamara, Darina; Hämäläinen, Esa; Binder, Elisabeth B.; Räikkönen, Katri; Lahti, Jari; London, Stephanie J.; Silver, Robert M.; Schisterman, Enrique F. (2020)
    Background Prenatal inflammation has been proposed as an important mediating factor in several adverse pregnancy outcomes. C-reactive protein (CRP) is an inflammatory cytokine easily measured in blood. It has clinical value due to its reliability as a biomarker for systemic inflammation and can indicate cellular injury and disease severity. Elevated levels of CRP in adulthood are associated with alterations in DNA methylation. However, no studies have prospectively investigated the relationship between maternal CRP levels and newborn DNA methylation measured by microarray in cord blood with reasonable epigenome-wide coverage. Importantly, the timing of inflammation exposure during pregnancy may also result in different effects. Thus, our objective was to evaluate this prospective association of CRP levels measured during multiple periods of pregnancy and in cord blood at delivery which was available in one cohort (i.e., Effects of Aspirin in Gestation and Reproduction trial), and also to conduct a meta-analysis with available data at one point in pregnancy from three other cohorts from the Pregnancy And Childhood Epigenetics consortium (PACE). Secondarily, the impact of maternal randomization to low dose aspirin prior to pregnancy on methylation was assessed. Results Maternal CRP levels were not associated with newborn DNA methylation regardless of gestational age of measurement (i.e., CRP at approximately 8, 20, and 36 weeks among 358 newborns in EAGeR). There also was no association in the meta-analyses (all p > 0.5) with a larger sample size (n = 1603) from all participating PACE cohorts with available CRP data from first trimester (<18 weeks gestation). Randomization to aspirin was not associated with DNA methylation. On the other hand, newborn CRP levels were significantly associated with DNA methylation in the EAGeR trial, with 33 CpGs identified (FDR corrected p <0.05) when both CRP and methylation were measured at the same time point in cord blood. The top 7 CpGs most strongly associated with CRP resided in inflammation and vascular-related genes. Conclusions Maternal CRP levels measured during each trimester were not associated with cord blood DNA methylation. Rather, DNA methylation was associated with CRP levels measured in cord blood, particularly in gene regions predominately associated with angiogenic and inflammatory pathways.
  • Gaye, Amadou; Marcon, Yannick; Isaeva, Julia; LaFlamme, Philippe; Turner, Andrew; Jones, Elinor M.; Minion, Joel; Boyd, Andrew W.; Newby, Christopher J.; Nuotio, Marja-Liisa; Wilson, Rebecca; Butters, Oliver; Murtagh, Barnaby; Demir, Ipek; Doiron, Dany; Giepmans, Lisette; Wallace, Susan E.; Budin-Ljosne, Isabelle; Schmidt, Carsten Oliver; Boffetta, Paolo; Boniol, Mathieu; Bota, Maria; Carter, Kim W.; deKlerk, Nick; Dibben, Chris; Francis, Richard W.; Hiekkalinna, Tero; Hveem, Kristian; Kvaloy, Kirsti; Millar, Sean; Perry, Ivan J.; Peters, Annette; Phillips, Catherine M.; Popham, Frank; Raab, Gillian; Reischl, Eva; Sheehan, Nuala; Waldenberger, Melanie; Perola, Markus; van den Heuvel, Edwin; Macleod, John; Knoppers, Bartha M.; Stolk, Ronald P.; Fortier, Isabel; Harris, Jennifer R.; Woffenbuttel, Bruce H. R.; Murtagh, Madeleine J.; Ferretti, Vincent; Burton, Paul R. (2014)
  • Hu, Yaoyue; Ruiz, Milagros; Bobak, Martin; Martikainen, Pekka (2020)
    Background: While living alone predicts depression in diverse ageing populations, the impact of multi-generational living is unclear. This study compared mid-late life depressive symptoms by living arrangements between societies with distinct kinship ties. Methods: Repeated data on depressive symptoms and living arrangements over 4 years from 16,229 Chinese (age >= 45) and 10,403 English adults (age >= 50) were analyzed using multilevel mixed-effects logistic regression. Elevated depressive symptoms were identified using the Center for Epidemiological Depression Scale criteria in each study. Results: Higher odds ratios (ORs) of elevated depressive symptoms were found in both Chinese and English adults aged Limitations: Bias may exist because depressed participants are more likely to experience divorce or separation prior to baseline. Conclusions: The relationship between living arrangements and depressive symptoms appears robust and consistent across social contexts, although the mechanisms differ. The protective role of partners in both China and England supports targeting those who do not live with partners to reduce depression.
  • Merid, Simon Kebede; Novoloaca, Alexei; Sharp, Gemma C.; Kupers, Leanne K.; Kho, Alvin T.; Roy, Ritu; Gao, Lu; Annesi-Maesano, Isabella; Jain, Pooja; Plusquin, Michelle; Kogevinas, Manolis; Allard, Catherine; Vehmeijer, Florianne O.; Kazmi, Nabila; Salas, Lucas A.; Rezwan, Faisal I.; Zhang, Hongmei; Sebert, Sylvain; Czamara, Darina; Rifas-Shiman, Sheryl L.; Melton, Phillip E.; Lawlor, Debbie A.; Pershagen, Goran; Breton, Carrie V.; Huen, Karen; Baiz, Nour; Gagliardi, Luigi; Nawrot, Tim S.; Corpeleijn, Eva; Perron, Patrice; Duijts, Liesbeth; Nohr, Ellen Aagaard; Bustamante, Mariona; Ewart, Susan L.; Karmaus, Wilfried; Zhao, Shanshan; Page, Christian M.; Herceg, Zdenko; Jarvelin, Marjo-Riitta; Lahti, Jari; Baccarelli, Andrea A.; Anderson, Denise; Kachroo, Priyadarshini; Relton, Caroline L.; Bergstrom, Anna; Eskenazi, Brenda; Soomro, Munawar Hussain; Vineis, Paolo; Snieder, Harold; Bouchard, Luigi; Jaddoe, Vincent W.; Sorensen, Thorkild I. A.; Vrijheid, Martine; Arshad, S. Hasan; Holloway, John W.; Haberg, Siri E.; Magnus, Per; Dwyer, Terence; Binder, Elisabeth B.; DeMeo, Dawn L.; Vonk, Judith M.; Newnham, John; Tantisira, Kelan G.; Kull, Inger; Wiemels, Joseph L.; Heude, Barbara; Sunyer, Jordi; Nystad, Wenche; Munthe-Kaas, Monica C.; Raikkonen, Katri; Oken, Emily; Huang, Rae-Chi; Weiss, Scott T.; Anto, Josep Maria; Bousquet, Jean; Kumar, Ashish; Soderhall, Cilla; Almqvist, Catarina; Cardenas, Andres; Gruzieva, Olena; Xu, Cheng-Jian; Reese, Sarah E.; Kere, Juha; Brodin, Petter; Solomon, Olivia; Wielscher, Matthias; Holland, Nina; Ghantous, Akram; Hivert, Marie-France; Felix, Janine F.; Koppelman, Gerard H.; London, Stephanie J.; Melen, Erik (2020)
    Background Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P <1.06 x 10(- 7), of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
  • BIOS Consortium; Reese, Sarah E.; Xu, Cheng-Jian; den Dekker, Herman T.; Lahti, Jari; Kajantie, Eero; Kere, Juha; Räikkönen, Katri (2019)
    Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate <0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate <0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.
  • Steinthorsdottir, Valgerdur; McGinnis, Ralph; Williams, Nicholas O.; Stefansdottir, Lilja; Thorleifsson, Gudmar; Shooter, Scott; Fadista, Joao; Sigurdsson, Jon K.; Auro, Kirsi M.; Berezina, Galina; Borges, Maria-Carolina; Bumpstead, Suzannah; Bybjerg-Grauholm, Jonas; Colgiu, Irina; Dolby, Vivien A.; Dudbridge, Frank; Engel, Stephanie M.; Franklin, Christopher S.; Frigge, Michael L.; Frisbaek, Yr; Geirsson, Reynir T.; Geller, Frank; Gretasdottir, Solveig; Gudbjartsson, Daniel F.; Harmon, Quaker; Hougaard, David Michael; Hegay, Tatyana; Helgadottir, Anna; Hjartardottir, Sigrun; Jääskeläinen, Tiina; Johannsdottir, Hrefna; Jonsdottir, Ingileif; Juliusdottir, Thorhildur; Kalsheker, Noor; Kasimov, Abdumadjit; Kemp, John P.; Kivinen, Katja; Klungsøyr, Kari; Lee, Wai K.; Melbye, Mads; Miedzybrodska, Zosia; Moffett, Ashley; Najmutdinova, Dilbar; Nishanova, Firuza; Olafsdottir, Thorunn; Perola, Markus; FINNPEC Consortium; Laivuori, Hannele; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Kivinen, Katja; Pouta, Anneli (2020)
    Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia. Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.
  • Laitinen, Tomi T.; Ruohonen, Saku; Juonala, Markus; Magnussen, Costan G.; Mikkila, Vera; Mikola, Hanna; Hutri-Kahonen, Nina; Laitinen, Tomi; Tossavainen, Paivi; Jokinen, Eero; Niinikoski, Harri; Jula, Antti; Viikari, Jorma S. A.; Ronnemaa, Tapani; Raitakari, Olli T.; Pahkala, Katja (2017)
    Background: Ideal cardiovascular health (CVH), defined by the American Heart Association, is associated with incident cardiovascular disease in adults. However, association of the ideal CVH in childhood with current and future cardiac structure and function has not been studied. Methods and results: The sample comprised 827 children participating in the longitudinal Special Turku Coronary Risk Factor Intervention Project (STRIP) and The Cardiovascular Risk in Young Finns Study (YFS). In STRIP, complete data on the seven ideal CVH metrics and left ventricular (LV) mass measured with echocardiography were available at the age of 15 (n= 321), 17 (n= 309) and 19 (n= 283) years. In YFS, the cohort comprised children aged 12-18 years (n = 506) with complete ideal CVH metrics data from childhood and 25 years later in adulthood, and echocardiography performed in adulthood. In STRIP, ideal CVH score was inversely associated with LV mass during childhood (P = 0.036). In YFS, childhood ideal CVH score was inversely associated with LV mass, LV end-diastolic volume, E/e' ratio, and left atrium end-systolic volume in adulthood (all P <0.01). In addition, improvement of the ideal CVH score between childhood and adulthood was inversely associated with LV mass, LV end-diastolic volume, E/e' ratio, and left atrium end-systolic volume (all P Conclusions: Childhood ideal CVH score has a long-lasting effect on cardiac structure and function, and the association is evident already in childhood. Our findings support targeting the ideal CVHmetrics as part of primordial prevention of cardiovascular diseases. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Virtanen, Marianna; Ervasti, Jenni; Head, Jenny; Oksanen, Tuula; Salo, Paula; Pentti, Jaana; Kouvonen, Anne; Väänänen, Ari; Suominen, Sakari; Koskenvuo, Markku; Vahtera, Jussi; Elovainio, Marko; Zins, Marie; Goldberg, Marcel; Kivimäki, Mika (2018)
    Background Lifestyle factors influence the risk of morbidity and mortality, but the extent to which they are associated with employees' absence from work due to illness is unclear. We examined the relative contributions of smoking, alcohol consumption, high body-mass index, and low physical activity to diagnosis-specific sickness absence. Methods We did a multicohort study with individual-level data of participants of four cohorts from the UK, France, and Finland. Participants' responses to a lifestyle survey were linked to records of sickness absence episodes, typically lasting longer than 9 days; for each diagnostic category, the outcome was the total number of sickness absence days per year. We estimated the associations between lifestyle factors and sickness absence by calculating rate ratios for the number of sickness absence days per year and combining cohort-specific estimates with meta-analysis. The criteria for assessing the evidence included the strength of association, consistency across cohorts, robustness to adjustments and multiple testing, and impact assessment by use of population attributable fractions (PAF), with both internal lifestyle factor prevalence estimates and those obtained from European populations (PAF external). Findings For 74 296 participants, during 446 478 person-years at risk, the most common diagnoses for sickness absence were musculoskeletal diseases (70.9 days per 10 person-years), depressive disorders (26.5 days per 10 person-years), and external causes (such as injuries and poisonings; 12.8 days per 10 person-years). Being overweight (rate ratio [adjusted for age, sex, socioeconomic status, and chronic disease at baseline] 1.30, 95% CI 1.21-1.40; PAF external 8.9%) and low physical activity (1.23, 1.14-1.34; 7.8%) were associated with absences due to musculoskeletal diseases; heavy episodic drinking (1.90, 1.41-2.56; 15.2%), smoking (1.70, 1.42-2.03; 11.8%), low physical activity (1.67, 1.42-1.96; 19.8%), and obesity (1.38, 1.11-1.71; 5.6%) were associated with absences due to depressive disorders; heavy episodic drinking (1.64, 1.33-2.03; 11.3%), obesity (1.48, 1.27-1.72; 6.6%), smoking (1.35, 1.20-1.53; 6.3%), and being overweight (1.20, 1.08-1.33; 6.2%) were associated with absences due to external causes; obesity (1.82, 1.40-2.36; 11.0%) and smoking (1.60, 1.30-1.98; 10.3%) were associated with absences due to circulatory diseases; low physical activity (1.37, 1.25-1.49; 12.0%) and smoking (1.27, 1.16-1.40; 4.9%) were associated with absences due to respiratory diseases; and obesity (1.67, 1.34-2.07; 9.7%) was associated with absences due to digestive diseases. Interpretation Lifestyle factors are associated with sickness absence due to several diseases, but observational data cannot determine the nature of these associations. Future studies should investigate the cost-effectiveness of lifestyle interventions aimed at reducing sickness absence and the use of information on lifestyle for identifying groups at risk. Copyright (c) The Author (s). Published by Elsevier Ltd. This is an open access article under the CC BY 4.0 license.
  • Kettunen, Johannes; Holmes, Michael V.; Allara, Elias; Anufrieva, Olga; Ohukainen, Pauli; Oliver-Williams, Clare; Wang, Qin; Tillin, Therese; Hughes, Alun D.; Kähönen, Mika; Lehtimäki, Terho; Viikari, Jorma; Raitakari, Olli T.; Salomaa, Veikko; Järvelin, Marjo-Riitta; Perola, Markus; Smith, George Davey; Chaturvedi, Nish; Danesh, John; Di Angelantonio, Emanuele; Butterworth, Adam S.; Ala-Korpela, Mika (2019)
    Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.
  • Kivimäki, Mika; Virtanen, Marianna; Kawachi, Ichiro; Nyberg, Solja T.; Alfredsson, Lars; Batty, G. David; Bjorner, Jakob B.; Borritz, Marianne; Brunner, Eric J.; Burr, Hermann; Dragano, Nico; Ferrie, Jane E.; Fransson, Eleonor I.; Hamer, Mark; Heikkila, Katriina; Knutsson, Anders; Koskenvuo, Markku; Madsen, Ida E. H.; Nielsen, Martin L.; Nordin, Maria; Oksanen, Tuula; Pejtersen, Jan H.; Pentti, Jaana; Rugulies, Reiner; Salo, Paula; Siegrist, Johannes; Steptoe, Andrew; Suominen, Sakari; Theorell, Tres; Vahtera, Jussi; Westerholm, Peter J. M.; Westerlund, Hugo; Singh-Manoux, Archana; Jokela, Markus (2015)
    Background Working long hours might have adverse health effects, but whether this is true for all socioeconomic status groups is unclear. In this meta-analysis stratified by socioeconomic status, we investigated the role of long working hours as a risk factor for type 2 diabetes. Methods We identified four published studies through a systematic literature search of PubMed and Embase up to April 30, 2014. Study inclusion criteria were English-language publication; prospective design (cohort study); investigation of the effect of working hours or overtime work; incident diabetes as an outcome; and relative risks, odds ratios, or hazard ratios (HRs) with 95% CIs, or sufficient information to calculate these estimates. Additionally, we used unpublished individual-level data from 19 cohort studies from the Individual-Participant-Data Meta-analysis in Working-Populations Consortium and international open-access data archives. Effect estimates from published and unpublished data from 222 120 men and women from the USA, Europe, Japan, and Australia were pooled with random-effects meta-analysis. Findings During 1.7 million person-years at risk, 4963 individuals developed diabetes (incidence 29 per 10 000 person-years). The minimally adjusted summary risk ratio for long (>= 55 h per week) compared with standard working hours (35-40 h) was 1.07 (95% CI 0.89-1.27, difference in incidence three cases per 10 000 person-years) with significant heterogeneity in study-specific estimates (I-2 = 53%, p = 0.0016). In an analysis stratified by socioeconomic status, the association between long working hours and diabetes was evident in the low socioeconomic status group (risk ratio 1.29, 95% CI 1.06-1.57, difference in incidence 13 per 10 000 person-years, I-2 = 0%, p = 0.4662), but was null in the high socioeconomic status group (1. 00, 95% CI 0.80-1.25, incidence diff erence zero per 10 000 person-years, I-2 = 15%, p = 0.2464). The association in the low socioeconomic status group was robust to adjustment for age, sex, obesity, and physical activity, and remained after exclusion of shift workers. Interpretation In this meta-analysis, the link between longer working hours and type 2 diabetes was apparent only in individuals in the low socioeconomic status groups. Copyright (C) Kivimaki et al. Open Access article distributed under the terms of CC BY.
  • Wurtz, Peter; Wang, Qin; Soininen, Pasi; Kangas, Antti J.; Fatemifar, Ghazaleh; Tynkkynen, Tuulia; Tiainen, Mika; Perola, Markus; Tillin, Therese; Hughes, Alun D.; Mantyselka, Pekka; Kahonen, Mika; Lehtimaki, Terho; Sattar, Naveed; Hingorani, Aroon D.; Casas, Juan-Pablo; Salomaa, Veikko; Kivimaki, Mika; Jarvelin, Marjo-Riitta; Smith, George Davey; Vanhala, Mauno; Lawlor, Debbie A.; Raitakari, Olli T.; Chaturvedi, Nish; Kettunen, Johannes; Ala-Korpela, Mika (2016)
    BACKGROUND Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. OBJECTIVES This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. METHODS Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. RESULTS Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R-2 = 0.94, slope 1.00 +/- 0.03). CONCLUSIONS Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms. (C) 2016 by the American College of Cardiology Foundation.
  • Beenackers, Marielle A.; Doiron, Dany; Fortier, Isabel; Noordzij, J. Mark; Reinhard, Erica; Courtin, Emilie; Bobak, Martin; Chaix, Basile; Costa, Giuseppe; Dapp, Ulrike; Roux, Ana V. Diez; Huisman, Martijn; Grundy, Emily M.; Krokstad, Steinar; Martikainen, Pekka; Raina, Parminder; Avendano, Mauricio; van Lenthe, Frank J. (2018)
    Background: Urbanization and ageing have important implications for public mental health and well-being. Cities pose major challenges for older citizens, but also offer opportunities to develop, test, and implement policies, services, infrastructure, and interventions that promote mental well-being. The MINDMAP project aims to identify the opportunities and challenges posed by urban environmental characteristics for the promotion and management of mental well-being and cognitive function of older individuals. Methods: MINDMAP aims to achieve its research objectives by bringing together longitudinal studies from 11 countries covering over 35 cities linked to databases of area-level environmental exposures and social and urban policy indicators. The infrastructure supporting integration of this data will allow multiple MINDMAP investigators to safely and remotely co-analyse individual-level and area-level data. Individual-level data is derived from baseline and follow-up measurements of ten participating cohort studies and provides information on mental well-being outcomes, sociodemographic variables, health behaviour characteristics, social factors, measures of frailty, physical function indicators, and chronic conditions, as well as blood derived clinical biochemistry-based biomarkers and genetic biomarkers. Area-level information on physical environment characteristics (e.g. green spaces, transportation), socioeconomic and sociodemographic characteristics (e.g. neighbourhood income, residential segregation, residential density), and social environment characteristics (e.g. social cohesion, criminality) and national and urban social policies is derived from publically available sources such as geoportals and administrative databases. The linkage, harmonization, and analysis of data from different sources are being carried out using piloted tools to optimize the validity of the research results and transparency of the methodology. Discussion: MINDMAP is a novel research collaboration that is combining population-based cohort data with publicly available datasets not typically used for ageing and mental well-being research. Integration of various data sources and observational units into a single platform will help to explain the differences in ageing-related mental and cognitive disorders both within as well as between cities in Europe, the US, Canada, and Russia and to assess the causal pathways and interactions between the urban environment and the individual determinants of mental well-being and cognitive ageing in older adults.
  • Stenholm, Sari; Head, Jenny; Kivimaki, Mika; Kawachi, Ichiro; Aalto, Ville; Zins, Marie; Goldberg, Marcel; Zaninotto, Paola; Hanson, Linda Magnuson; Westerlund, Hugo; Vahtera, Jussi (2016)
    Background: Smoking, physical inactivity and obesity are modifiable risk factors for morbidity and mortality. The aim of this study was to examine the extent to which the co-occurrence of these behaviour-related risk factors predict healthy life expectancy and chronic disease-free life expectancy in four European cohort studies. Methods: Data were drawn from repeated waves of four cohort studies in England, Finland, France and Sweden. Smoking status, physical inactivity and obesity (body mass index >= 30 kg/m(2)) were examined separately and in combination. Health expectancy was estimated by using two health indicators: suboptimal self-rated health and having a chronic disease (cardiovascular disease, cancer, respiratory disease and diabetes). Multistate life table models were used to estimate sex-specific healthy life expectancy and chronic disease-free life expectancy from ages 50 to 75 years. Results: Compared with men and women with at least two behaviour-related risk factors, those with no behaviour-related risk factors could expect to live on average8 years longer in good health and 6 years longer free of chronic diseases between ages 50 and 75.Having any single risk factor was also associated with reduction in healthy years. No consistent differences between cohorts were observed. Conclusions: Data from four European countries show that persons with individual and co-occurring behaviour-related risk factors have shorter healthy life expectancy and shorter chronic disease-free life expectancy. Population level reductions in smoking, physical inactivity and obesity could increase life-years lived in good health.