Browsing by Subject "HEART-DISEASE"

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  • Acosta, Tania; Barengo, Noel C.; Arrieta, Astrid; Ricaurte, Carlos; Tuomilehto, Jaakko O. (2018)
    Type 2 diabetes (T2D) imposes a heavy public health burden in both developed and developing countries. It is necessary to understand the effect of T2D in different settings and population groups. This report aimed to present baseline characteristics of study participants in the demonstration area for the Type 2 Diabetes Prevention in Barranquilla and Juan Mina (DEMOJUAN) project after randomization and to compare their fasting and 2-hour glucose levels according to lifestyle and T2D risk factor levels. The DEMOJUAN project is a randomized controlled field trial. Study participants were recruited from study sites using population-wide screening using the Finnish Diabetes Risk Score (FINDRISC) questionnaire. All volunteers with FINDRISC of >= 13 points were invited to undergo an oral glucose tolerance test (OGTT). Participant inclusion criteria for the upcoming field trial were either FINDRISC of >= 13 points and 2-hour post-challenge glucose level of 7.0 to 11.0mmol/L or FINDRISC of >= 13 points and fasting plasma glucose level of 6.1 to 6.9mmol/L. Lifestyle habits and risk factors for T2D were assessed by trained interviewers using a validated questionnaire. Among the 14,193 participants who completed the FINDRISC questionnaire, 35% (n=4915) had a FINDRISC score of >= 13 points and 47% (n=2306) agreed to undergo the OGTT. Approximately, 33% (n=772) of participants underwent the OGTT and met the entry criteria; these participants were randomized into 3 groups. There were no statistically significant differences found in anthropometric or lifestyle risk factors, distribution of the glucose metabolism categories, or other diabetes risk factors between the 3 groups (P>.05). Women with a past history of hyperglycaemia had significantly higher fasting glucose levels than those without previous hyperglycaemia (103 vs 99mg/dL; P Lifestyle habits and risk factors were evenly distributed among the 3 study groups. No differences were found in fasting or 2-hour glucose levels among different lifestyle or risk factor categories with the exception of body mass index, past history of hyperglycaemia, and age of 64 years in women.
  • Moller, Grith; Sluik, Diewertje; Ritz, Christian; Mikkilä, Vera; Raitakari, Olli T.; Hutri-Kähönen, Nina; Dragsted, Lars O.; Larsen, Thomas M.; Poppitt, Sally D.; Silvestre, Marta P.; Feskens, Edith J. M.; Brand-Miller, Jennie; Raben, Anne (2017)
    Higher-protein diets have been advocated for body-weight regulation for the past few decades. However, the potential health risks of these diets are still uncertain. We aimed to develop a protein score based on the quantity and source of protein, and to examine the association of the score with glycated haemoglobin (HbA1c) and estimated glomerular filtration rate (eGFR). Analyses were based on three population studies included in the PREVIEW project (PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World): NQplus, Lifelines, and the Young Finns Study. Cross-sectional data from food-frequency questionnaires (n = 76,777 subjects) were used to develop a protein score consisting of two components: 1) percentage of energy from total protein, and 2) plant to animal protein ratio. An inverse association between protein score and HbA1c (slope -0.02 +/- 0.01 mmol/mol, p <0.001) was seen in Lifelines. We found a positive association between the protein score and eGFR in Lifelines (slope 0.17 +/- 0.02 mL/min/1.73 m(2), p <0.0001). Protein scoring might be a useful tool to assess both the effect of quantity and source of protein on health parameters. Further studies are needed to validate this newly developed protein score.
  • Manach, Claudine; Milenkovic, Dragan; Van de Wiele, Tom; Rodriguez-Mateos, Ana; de Roos, Baukje; Teresa Garcia-Conesa, Maria; Landberg, Rikard; Gibney, Eileen R.; Heinonen, Marina; Tomas-Barberan, Francisco; Morand, Christine (2017)
    Bioactive compounds in plant-based foods have health properties that contribute to the prevention of age-related chronic diseases, particularly cardiometabolic disorders. Conclusive proof and understanding of these benefits in humans is essential in order to provide effective dietary recommendations but, so far, the evidence obtained from human intervention trials is limited and contradictory. This is partly due to differences between individuals in the absorption, distribution, metabolism and excretion of bioactive compounds, as well as to heterogeneity in their biological response regarding cardiometabolic health outcomes. Identifying the main factors underlying inter-individual differences, as well as developing new and innovative methodologies to account for such variability constitute an overarching goal to ultimately optimize the beneficial health effects of plant food bioactives for each and every one of us. In this respect, this position paper from the COST Action FA1403-POSITIVe examines the main factors likely to affect the individual responses to consumption of plant food bioactives and presents perspectives for assessment and consideration of inter-individual variability.
  • Inouye, Michael; Silander, Kaisa; Hämäläinen, Eija; Salomaa, Veikko; Harald, Kennet; Jousilahti, Pekka; Mannisto, Satu; Eriksson, Johan G.; Saarela, Janna; Ripatti, Samuli; Perola, Markus; van Ommen, Gert-Jan B.; Taskinen, Marja-Riitta; Palotie, Aarno; Dermitzakis, Emmanouil T.; Peltonen, Leena (2010)
  • Tucker, Philip; Harma, Mikko; Ojajärvi, Anneli; Kivimäki, Mika; Leineweber, Constanze; Oksanen, Tuula; Salo, Paula; Vahtera, Jussi (2019)
    Objective This study examined the associations between shift work and use of antihypertensive, lipid-lowering, and antidiabetic medications. Methods Survey data from two cohorts of Finnish men (N=11998) and women (N=49 944) working in multiple occupations where shift work was used were linked to national Drug Prescription Register data, with up to 11 years of follow-up. In each cohort, age-stratified Cox proportional hazard regression models were computed to examine any incident use of prescription medication for each of the three medical conditions, separately comparing each of two groups of rotating shift workers (those whose schedules included night shifts. and those whose schedules did not include night shifts) with day workers who worked in a similar range of occupations. Results In the larger cohort, among participants aged 40-49 at baseline, shift work without night shifts was associated with increased use of type-2 diabetes medication after adjustments for sex, occupational status, marital status, alcohol consumption, smoking, and physical activity [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.01-1.62], while shift work with night shifts was associated with increased use of dyslipidemia medication after adjustments (HR 1.33, 95% CI 1.12-1.57). There were no such associations among younger and older shift workers. Also in the larger cohort, among those aged Conclusions There was mixed evidence regarding the use of medications for cardiovascular risk factors by shift workers. Selection effects may have affected the associations.
  • Mikkola, Tuija M.; Kautiainen, Hannu; von Bonsdorff, Mikaela B.; Salonen, Minna K.; Wasenius, Niko; Kajantie, Eero; Eriksson, Johan G. (2020)
    Purpose Most studies examining the associations between body composition and health-related quality of life (HRQoL) in older age have been cross-sectional and analyzed only fat or lean mass. Hence, it is poorly known whether fat and lean mass are independently associated with subsequent changes in HRQoL. We investigated whether baseline lean and fat mass are associated with changes in HRQoL over a 10-year period in older adults. Methods We studied 1044 men and women from the Helsinki Birth Cohort Study (age 57-70 years at baseline). Bioelectrical impedance analysis was used to derive baseline fat mass index (FMI, fat mass/height(2)) and lean mass index (lean mass/height(2)), dichotomized at sex-specific medians. HRQoL was assessed using RAND 36-item Health Survey at baseline and follow-up 10 years later. Results When controlled for lean mass and adjusted for potential confounders, high baseline FMI was associated with a greater decline in general health (standardized regression coefficient [beta] = - 0.13, p = 0.001), physical functioning (beta = - 0.11, p = 0.002), role physical (beta = - 0.13, p = 0.003), vitality (beta = - 0.08, p = 0.027), role emotional (beta = - 0.12, p = 0.007), and physical component score (beta = - 0.14, p <0.001). High baseline FMI was also associated with low HRQoL in all physical domains at baseline (beta: from - 0.38 to - 0.10). Lean mass was not strongly associated with HRQoL at baseline or change in HRQoL. Conclusion In older community-dwelling adults, higher fat mass is, independent of lean mass, associated with lower physical HRQoL and greater decline in HRQoL. Prevention of adiposity may contribute to preservation of a good quality of life in older age.
  • Manty, Minna; Kouvonen, Anne; Lallukka, Tea; Lahti, Jouni; Lahelma, Eero; Rahkonen, Ossi (2015)
    Objectives The aim this study was to examine the effect of changes in physical and psychosocial working conditions on physical health functioning among ageing municipal employees. Methods Follow-up survey data were collected from midlife employees of the City of Helsinki, Finland, at three time points: wave 1(2000-2002), wave 2(2007), and wave 3 (2012). Changes in physical and psychosocial working conditions were assessed between waves 1 and 2. Physical health functioning was measured by the physical component summary (PCS) of the Short-Form 36 questionnaire at each of the three waves. In total, 2784 respondents (83% women) who remained employed over the follow-up were available for the analyses. Linear mixed-effect models were used to assess the associations and adjust for key covariates (age, gender, obesity, chronic diseases, and health behaviors). Results Repeated and increased exposure to adverse physical working conditions was associated with greater decline in physical health functioning over time. In contrast, decrease in exposures reduced the decline Of the psychosocial working conditions, changes in job demands had no effects on physical health functioning. However, decreased job control was associated with greater decline and repeated high or increased job control reduced the decline in physical health functioning over time. Conclusions Adverse changes in physical working conditions and job control were associated with greater decline in physical health functioning over time, whereas favorable changes in these exposures reduced the decline. Preventing deterioration and promoting improvement of working conditions are likely to help maintain better physical health functioning among ageing employees.
  • Vogt, Susanne; Wahl, Simone; Kettunen, Johannes; Breitner, Susanne; Kastenmueller, Gabi; Gieger, Christian; Suhre, Karsten; Waldenberger, Melanie; Kratzsch, Juergen; Perola, Markus; Salomaa, Veikko; Blankenberg, Stefan; Zeller, Tanja; Soininen, Pasi; Kangas, Antti J.; Peters, Annette; Grallert, Harald; Ala-Korpela, Mika; Thorand, Barbara (2016)
    Background: Numerous observational studies have observed associations between vitamin D deficiency and cardiometabolic diseases, but these findings might be confounded by obesity. A characterization of the metabolic profile associated with serum 25-hydroxyvitamin D [25(OH)D] levels, in general and stratified by abdominal obesity, may help to untangle the relationship between vitamin D, obesity and cardiometabolic health. Methods: Serum metabolomics measurements were obtained from a nuclear magnetic resonance spectroscopy (NMR)- and a mass spectrometry (MS)-based platform. The discovery was conducted in 1726 participants of the population-based KORA-F4 study, in which the associations of the concentrations of 415 metabolites with 25(OH)D levels were assessed in linear models. The results were replicated in 6759 participants (NMR) and 609 (MS) participants, respectively, of the population-based FINRISK 1997 study. Results: Mean [standard deviation (SD)] 25(OH)D levels were 15.2 (7.5) ng/ml in KORA F4 and 13.8 (5.9) ng/ml in FINRISK 1997; 37 metabolites were associated with 25(OH) D in KORA F4 at P <0.05/415. Of these, 30 associations were replicated in FINRISK 1997 at P <0.05/37. Among these were constituents of (very) large very-low-density lipoprotein and small low-density lipoprotein subclasses and related measures like serum triglycerides as well as fatty acids and measures reflecting the degree of fatty acid saturation. The observed associations were independent of waist circumference and generally similar in abdominally obese and non-obese participants. Conclusions: Independently of abdominal obesity, higher 25(OH)D levels were associated with a metabolite profile characterized by lower concentrations of atherogenic lipids and a higher degree of fatty acid polyunsaturation. These results indicate that the relationship between vitamin D deficiency and cardiometabolic diseases is unlikely to merely reflect obesity-related pathomechanisms.
  • Kareinen, Ilona; Baumann, Marc; Su Duy Nguyen,; Maaninka, Katariina; Anisimov, Andrey; Tozuka, Minoru; Jauhiainen, Matti; Lee-Rueckert, Miriam; Kovanen, Petri T. (2018)
    ApoA-I, the main structural and functional protein of HDL particles, is cardioprotective, but also highly sensitive to proteolytic cleavage. Here, we investigated the effect of cardiac mast cell activation and ensuing chymase secretion on apoA-I degradation using isolated rat hearts in the Langendorff perfusion system. Cardiac mast cells were activated by injection of compound 48/80 into the coronary circulation or by low-flow myocardial ischemia, after which lipid-free apoA-I was injected and collected in the coronary effluent for cleavage analysis. Mast cell activation by 48/80 resulted in apoA-I cleavage at sites Tyr(192) and Phe(229), but hypoxic activation at Tyr(192) only. In vitro, the proteolytic end-product of apoA-I with either rat or human chymase was the Tyr(192)-truncated fragment. This fragment, when compared with intact apoA-I, showed reduced ability to promote migration of cultured human coronary artery endothelial cells in a wound-healing assay. We propose that C-terminal truncation of apoA-I by chymase released from cardiac mast cells during ischemia impairs the ability of apoA-I to heal damaged endothelium in the ischemic myocardium.
  • Lee, Jiwoo; Kiiskinen, Tuomo; Mars, Nina; Jukarainen, Sakari; Ingelsson, Erik; Neale, Benjamin; Ripatti, Samuli; Natarajan, Pradeep; Ganna, Andrea (2021)
    Background: Acute coronary syndrome (ACS) is a clinically significant presentation of coronary heart disease. Genetic information has been proposed to improve prediction beyond well-established clinical risk factors. While polygenic scores (PS) can capture an individual's genetic risk for ACS, its prediction performance may vary in the context of diverse correlated clinical conditions. Here, we aimed to test whether clinical conditions impact the association between PS and ACS. Methods: We explored the association between 405 clinical conditions diagnosed before baseline and 9080 incident cases of ACS in 387 832 individuals from the UK Biobank. Results were replicated in 6430 incident cases of ACS in 177 876 individuals from FinnGen. Results: We identified 80 conventional (eg, stable angina pectoris and type 2 diabetes) and unconventional (eg, diaphragmatic hernia and inguinal hernia) associations with ACS. The association between PS and ACS was consistent in individuals with and without most clinical conditions. However, a diagnosis of stable angina pectoris yielded a differential association between PS and ACS. PS was associated with a significantly reduced (interaction P=2.87x10(-8)) risk for ACS in individuals with stable angina pectoris (hazard ratio, 1.163 [95% CI, 1.082-1.251]) compared with individuals without stable angina pectoris (hazard ratio, 1.531 [95% CI, 1.497-1.565]). These findings were replicated in FinnGen (interaction P=1.38x10(-6)). Conclusions: In summary, while most clinical conditions did not impact utility of PS for prediction of ACS, we found that PS was substantially less predictive of ACS in individuals with prevalent stable coronary heart disease. PS may be more appropriate for prediction of ACS in asymptomatic individuals than symptomatic individuals with clinical suspicion for coronary heart disease.
  • Mantyselka, Pekka; Niskanen, Leo; Kautiainen, Hannu; Saltevo, Juha; Wurtz, Peter; Soininen, Pasi; Kangas, Antti J.; Ala-Korpela, Mika; Vanhala, Mauno (2014)
  • Vuorio, Alpo; Kovanen, Petri T. (2018)
    This review covers the current knowledge about plant stanol esters as a dietary treatment option for heterozygous familial hypercholesterolemia (he-FH) children. The current estimation of the prevalence of he-FH is about one out of 200-250 persons. In this autosomal dominant disease, the concentration of plasma low-density lipoprotein cholesterol (LDL-C) is strongly elevated since birth. Quantitative coronary angiography among he-FH patients has revealed that stenosing atherosclerotic plaques start to develop in he-FH males in their twenties and in he-FH females in their thirties, and that the magnitude of the plaque burden predicts future coronary events. The cumulative exposure of coronary arteries to the lifelong LDL-C elevation can be estimated by calculating the LDL-C burden (LDL-C level x years), and it can also be used to demonstrate the usefulness of dietary stanol ester treatment. Thus, when compared with untreated he-FH patients, the LDL-C burden of using statin from the age of 10 is 15% less, and if he-FH patients starts to use dietary stanol from six years onwards and a combination of statin and dietary stanol from 10 years onwards, the LDL-C burden is 21% less compared to non-treated he-FH patients. We consider dietary stanol treatment of he-FH children as a part of the LDL-C-lowering treatment package as safe and cost-effective, and particularly applicable for the family-centered care of the entire he-FH families.
  • Shuhei, Nakanishi; Söderlund, Sanni; Jauhiainen, Matti; Taskinen, Marja-Riitta (2010)
  • Nordentoft, Mads; Rod, Naja H.; Bonde, Jens Peter; Bjorner, Jakob B.; Madsen, Ida E. H.; Pedersen, Line R. M.; Cleal, Bryan; Hanson, Linda L. Magnusson; Nexo, Mette A.; Pentti, Jaana; Stenholm, Sari; Sterud, Tom; Vahtera, Jussi; Rugulies, Reiner (2020)
    Objective: To examine the prospective relation between effort-reward imbalance at work and risk of type 2 diabetes. Methods: We included 50,552 individuals from a national survey of the working population in Denmark, aged 30-64 years and diabetes-free at baseline. Effort-reward imbalance was defined, in accordance with the literature, as a mismatch between high efforts at work (e.g. high work pace, time pressure), and low rewards received in return (e.g. low recognition, job insecurity) and assessed as a continuous and a categorical variable. Incident type 2 diabetes was identified in national health registers. Using Cox regression we calculated hazard ratios (HR) and 95% confidence intervals (95% CI) for estimating the association between effort-reward imbalance at baseline and risk of onset of type 2 diabetes during follow-up, adjusted for sex, age, socioeconomic status, cohabitation, children at home, migration background, survey year and sample method. Results: During 136,239 person-years of follow-up (mean = 2.7 years) we identified 347 type 2 diabetes cases (25.5 cases per 10,000 person-years). For each one standard deviation increase of the effort-reward imbalance score at baseline, the fully adjusted risk of type 2 diabetes during follow-up increased by 9% (HR: 1.09, 95% CI: 0.98-1.21). When we used effort-reward imbalance as a dichotomous variable, exposure to effort-reward imbalance was associated with an increased risk of type 2 diabetes with a HR of 1.27 (95% CI: 1.02-1.58). Conclusion The results of this nationwide study of the Danish workforce suggest that effort-reward imbalance at work may be a risk factor for type 2 diabetes.
  • Sanna, Serena; Li, Bingshan; Mulas, Antonella; Sidore, Carlo; Kang, Hyun M.; Jackson, Anne U.; Piras, Maria Grazia; Usala, Gianluca; Maninchedda, Giuseppe; Sassu, Alessandro; Serra, Fabrizio; Palmas, Maria Antonietta; Wood, William H.; Njolstad, Inger; Laakso, Markku; Hveem, Kristian; Tuomilehto, Jaakko; Lakka, Timo A.; Rauramaa, Rainer; Boehnke, Michael; Cucca, Francesco; Uda, Manuela; Schlessinger, David; Nagaraja, Ramaiah; Abecasis, Goncalo R. (2011)
  • Bertone-Johnson, Elizabeth R.; Virtanen, Jyrki K.; Nurmi, Tarja; Niskanen, Leo; Mursu, Jaakko; Voutilainen, Sari; Ronkainen, Kimmo; Kauhanen, Jussi; Tuomainen, Tomi-Pekka (2018)
    Recent studies of perimenopausal women suggest that follicle-stimulating hormone (FSH) levels may be associated with atherosclerosis, independent of estradiol. Whether FSH is related to atherosclerosis in older postmenopausal women, who have completed the menopausal transition, remains unknown. We assessed the relationship of serum FSH and estradiol levels with carotid artery intima-media thickness (IMT) among 587 postmenopausal participants in the Kuopio Ischemic Heart Disease Risk Factor Study (Kuopio, Finland). Participants were aged 53-73 years and not using hormone therapy at baseline (1998-2001). Mean IMT was measured via high-resolution ultrasonography. We observed a significant inverse association between FSH levels and IMT. Mean IMTs among women in quartiles 1-4 of FSH were 0.94 mm, 0.91 mm, 0.87 mm, and 0.85 mm, respectively (P-trend <0.001). After adjustment for age, estradiol, testosterone, body mass index (weight (kg)/height (m)(2)), lipids, and other factors, FSH levels remained significantly associated with IMT (regression coefficients for quartiles 2-4 vs. quartile 1 were -0.038, -0.045, and -0.062, respectively; P-trend = 0.01). Findings were strongest in women aged 64-73 years (P-trend = 0.006) and did not vary by body mass index. In contrast, estradiol levels were not related to IMT. In summary, high postmenopausal FSH levels were associated with a lower atherosclerotic burden, independent of estradiol, adiposity, and other factors. Our findings warrant replication and the further exploration of potential underlying mechanisms.
  • Baars, Adája E.; Rubio-Valverde, Jose R.; Hu, Yannan; Bopp, Matthias; Brønnum-Hansen, Henrik; Kalediene, Ramune; Leinsalu, Mall; Martikainen, Pekka; Regidor, Enrique; White, Chris; Wojtyniak, Bogdan; Mackenbach, Johan P.; Nusselder, Wilma J. (2019)
    ObjectivesTo assess to what extent educational differences in total life expectancy (TLE) and disability-free life expectancy (DFLE) could be reduced by improving fruit and vegetable consumption in ten European countries.MethodsData from national census or registries with mortality follow-up, EU-SILC, and ESS were used in two scenarios to calculate the impact: the upward levelling scenario (exposure in low educated equals exposure in high educated) and the elimination scenario (no exposure in both groups). Results are estimated for men and women between ages 35 and 79years.ResultsVarying by country, upward levelling reduced inequalities in DFLE by 0.1-1.1years (1-10%) in males, and by 0.0-1.3years (0-18%) in females. Eliminating exposure reduced inequalities in DFLE between 0.6 and 1.7years for males (6-15%), and between 0.1years and 1.8years for females (3-20%).ConclusionsUpward levelling of fruit and vegetable consumption would have a small, positive effect on both TLE and DFLE, and could potentially reduce inequalities in TLE and DFLE.
  • Gusarova, Viktoria; O'Dushlaine, Colm; Teslovich, Tanya M.; Benotti, Peter N.; Mirshahi, Tooraj; Gottesman, Omri; Van Hout, Cristopher V.; Murray, Michael F.; Mahajan, Anubha; Nielsen, Jonas B.; Fritsche, Lars; Wulff, Anders Berg; Gudbjartsson, Daniel F.; Sjogren, Marketa; Emdin, Connor A.; Scott, Robert A.; Lee, Wen-Jane; Small, Aeron; Kwee, Lydia C.; Dwivedi, Om Prakash; Prasad, Rashmi B.; Bruse, Shannon; Lopez, Alexander E.; Penn, John; Marcketta, Anthony; Leader, Joseph B.; Still, Christopher D.; Kirchner, H. Lester; Mirshahi, Uyenlinh L.; Wardeh, Amr H.; Hartle, Cassandra M.; Habegger, Lukas; Fetterolf, Samantha N.; Tusie-Luna, Teresa; Morris, Andrew P.; Holm, Hilma; Steinthorsdottir, Valgerdur; Sulem, Patrick; Thorsteinsdottir, Unnur; Rotter, Jerome I.; Chuang, Lee-Ming; Damrauer, Scott; Birtwell, David; Brummett, Chad M.; Khera, Amit V.; Natarajan, Pradeep; Orho-Melander, Marju; Flannick, Jason; Lotta, Luca A.; Hansson, Ola; Groop, Leif (2018)
    Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 x 10(-10)), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.
  • Byars, Sean G.; Huang, Qin Qin; Gray, Lesley-Ann; Bakshi, Andrew; Ripatti, Samuli; Abraham, Gad; Stearns, Stephen C.; Inouye, Michael (2017)
    Traditional genome-wide scans for positive selection have mainly uncovered selective sweeps associated with monogenic traits. While selection on quantitative traits is much more common, very few signals have been detected because of their polygenic nature. We searched for positive selection signals underlying coronary artery disease (CAD) in worldwide populations, using novel approaches to quantify relationships between polygenic selection signals and CAD genetic risk. We identified new candidate adaptive loci that appear to have been directly modified by disease pressures given their significant associations with CAD genetic risk. These candidates were all uniquely and consistently associated with many different male and female reproductive traits suggesting selection may have also targeted these because of their direct effects on fitness. We found that CAD loci are significantly enriched for lifetime reproductive success relative to the rest of the human genome, with evidence that the relationship between CAD and lifetime reproductive success is antagonistic. This supports the presence of antagonistic-pleiotropic tradeoffs on CAD loci and provides a novel explanation for the maintenance and high prevalence of CAD in modern humans. Lastly, we found that positive selection more often targeted CAD gene regulatory variants using HapMap3 lymphoblastoid cell lines, which further highlights the unique biological significance of candidate adaptive loci underlying CAD. Our study provides a novel approach for detecting selection on polygenic traits and evidence that modern human genomes have evolved in response to CAD-induced selection pressures and other early-life traits sharing pleiotropic links with CAD.
  • SUMMIT Steering Comm; CARDIOGRAMplusC4D Steering Comm; van Zuydam, Natalie R.; Ladenvall, Claes; Vlachopoulou, Efthymia; Perola, Markus; Sinisalo, Juha; Salomaa, Veikko; Groop, Leif; Ripatti, Samuli (2020)
    BACKGROUND: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). METHODS: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). RESULTS: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. CONCLUSIONS: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.