Genetically modulated educational attainment and coronary disease risk.

AIMS: Genetic disposition and lifestyle factors are understood as independent components underlying the risk of multiple diseases. In this study, we aim to investigate the interplay between genetics, educational attainment-an important denominator of lifestyle-and coronary artery disease (CAD) risk. METHODS AND RESULTS: Based on the effect sizes of 74 genetic variants associated with educational attainment, we calculated a 'genetic education score' in 13 080 cases and 14 471 controls and observed an inverse correlation between the score and risk of CAD [P = 1.52 × 10-8; odds ratio (OR) 0.79, 95% confidence interval (CI) 0.73-0.85 for the higher compared with the lowest score quintile]. We replicated in 146 514 individuals from UK Biobank (P = 1.85 × 10-6) and also found strong associations between the 'genetic education score' with 'modifiable' risk factors including smoking (P = 5.36 × 10-23), body mass index (BMI) (P = 1.66 × 10-30), and hypertension (P = 3.86 × 10-8). Interestingly, these associations were only modestly attenuated by adjustment for years spent in school. In contrast, a model adjusting for BMI and smoking abolished the association signal between the 'genetic education score' and CAD risk suggesting an intermediary role of these two risk factors. Mendelian randomization analyses performed with summary statistics from large genome-wide meta-analyses and sensitivity analysis using 1271 variants affecting educational attainment (OR 0.68 for the higher compared with the lowest score quintile; 95% CI 0.63-0.74; P = 3.99 × 10-21) further strengthened these findings. CONCLUSION: Genetic variants known to affect educational attainment may have implications for a health-conscious lifestyle later in life and subsequently affect the risk of CAD.This work was supported by grants from the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02), the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (e:AtheroSysMed, grant 01ZX1313A-2014), and the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no HEALTH-F2-2013-601456 (CVgenes-at-target). Further grants were received from the DFG as part of the Sonderforschungsbereich CRC 1123 (B2). T.K. was supported by a DZHK Rotation Grant

Genomic risk prediction of coronary artery disease in nearly 500,000 adults: implications for early screening and primary prevention

Background Coronary artery disease (CAD) has substantial heritability and a polygenic architecture; however, genomic risk scores have not yet leveraged the totality of genetic information available nor been externally tested at population-scale to show potential utility in primary prevention. Methods Using a meta-analytic approach to combine large-scale genome-wide and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS), consisting of 1.7 million genetic variants. We externally tested metaGRS, individually and in combination with available conventional risk factors, in 22,242 CAD cases and 460,387 non-cases from UK Biobank. Findings In UK Biobank, a standard deviation increase in metaGRS had a hazard ratio (HR) of 1.71 (95% CI 1.68–1.73) for CAD, greater than any other externally tested genetic risk score. Individuals in the top 20% of the metaGRS distribution had a HR of 4.17 (95% CI 3.97–4.38) compared with those in the bottom 20%. The metaGRS had higher C-index (C=0.623, 95% CI 0.615–0.631) for incident CAD than any of four conventional factors (smoking, diabetes, hypertension, and body mass index), and addition of the metaGRS to a model of conventional risk factors increased C-index by 3.7%. In individuals on lipid-lowering or anti-hypertensive medications at recruitment, metaGRS hazard for incident CAD was significantly but only partially attenuated with HR of 2.83 (95% CI 2.61– 3.07) between the top and bottom 20% of the metaGRS distribution. Interpretation Recent genetic association studies have yielded enough information to meaningfully stratify individuals using the metaGRS for CAD risk in both early and later life, thus enabling targeted primary intervention in combination with conventional risk factors. The metaGRS effect was partially attenuated by lipid and blood pressure-lowering medication, however other prevention strategies will be required to fully benefit from earlier genomic risk stratification. Funding National Health and Medical Research Council of Australia, British Heart Foundation, Australian Heart Foundation.This study was supported by funding from National Health and Medical Research Council (NHMRC) grant APP1062227. Supported in part by the Victorian Government’s OIS Program. M.I. was supported by an NHMRC and Australian Heart Foundation Career Development Fellowship (no. 1061435). G.A. was supported by an NHMRC Early Career Fellowship (no. 1090462). N.J.S., C.P.N. and B.K. are supported by the British Heart Foundation and N.J.S. is a NIHR Senior Investigator. R.S.P. is supported by the British Heart Foundation (FS/14/76/30933). The MRC/BHF Cardiovascular Epidemiology Unit is supported by the UK Medical Research Council [MR/L003120/1], British Heart Foundation [RG/13/13/30194], and UK National Institute for Health Research Cambridge Biomedical Research Centre. J.D. is a British Heart Foundation Professor and NIHR Senior Investigator

Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults: Implications for Primary Prevention

BACKGROUND: Coronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes. OBJECTIVES: This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention. METHODS: Using a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank. RESULTS: The hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age. CONCLUSION: The genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction

Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults: Implications for Primary Prevention.

BACKGROUND: Coronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes. OBJECTIVES: This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention. METHODS: Using a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank. RESULTS: The hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age. CONCLUSIONS: The genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction

Selvitys toiminnanohjausjärjestelmistä ja niiden käyttöönotosta U-landshjälp från Folk till Folk i Finland rf:lle

Tämän opinnäytetyön aiheena oli selvittää, mitä on otettava huomioon toiminnanohjausjärjestelmää hankkiessa ja millainen olisi sopivin. Työn tilaaja oli Nurmijärvellä Klaukkalassa toimiva U-landshjälp från Folk till Folk i Finland rf, kansankielellä UFF. Yhdistys kerää lahjoitusvaatteita ympäri Suomea kehitysapukohteidensa avustamiseksi. Tavoitteena opinnäytetyössä oli luoda kattava ohje tukemaan päätöstä toiminnanohjausjärjestelmän hankkimiseksi. Opinnäytetyö rajattiin käsittelemään toiminnanohjausjärjestelmän hankinnan kannalta tärkeisiin teorioihin ja käyttöönottoon sekä vertailevaan analyysiin muutamasta markkinoilla olevista järjestelmästä. Opinnäytetyö aloitettiin perehtymällä toiminnanohjausjärjestelmien teoriaan ja käyttöönot-toon sekä UFF:n toimintaan kattavasti. Tietolähteinä käytettiin haastatteluja, alan kirjallisuutta sekä ohjelmistotalojen esitelmiä. Opinnäytetyön alussa käsitellään toiminnanohjausjärjestelmien toiminta ja teoria monipuolisesti ja perusteellisesti. Tämän jälkeen käydään kattavasti UFF:n historia, luvut ja toiminta vaihe vaiheelta. Seuraavassa osiossa pohditaan, miten toiminnanohjausjärjestelmän käyttöönotto vaikuttaisi UFF:n keräystoimintaan. Lopussa esitellään valitut vaihtoehdot toiminnanohjausjärjestelmäksi UFF:lle ja vertaillaan näitä pistetaulukon avulla. Lopputuloksen jälkeen pohditaan vielä, mitkä voisivat olla UFF:n seuraavat loogiset kehityskohteet tämän toiminnan parantamiseksi tulevaisuudessa. Toiminnanohjausjärjestelmän löytäminen UFF:n kaltaiselle yhdistykselle loi monia kriteerejä ja vaatimuksia verrattuna tavallisiin kuljetusyrityksiin. Toiminta oli kuitenkin helposti verrattavissa jätealan kuljetustoimintaan, jota käytetiin vertailuja tehdessä referenssinä. Tämä opinnäytetyö antaa kattavan tietopaketin toiminnanohjausjärjestelmän valintaan ja sen hankintaan. Työn tilaajaa ja toiminnanohjausjärjestelmän valintaa koskeva osuus on luovutettu vain työn tilaajan käyttöön.The objective of this Bachelors’ thesis was to determine what needs to be taken into ac-count when acquiring and implementing an ERP in a company and finding the most suitable system. This thesis was commissioned by U-landshjälp från Folk till Folk i Finland rf, commonly known as UFF. The organization collects donated clothes all around Finland to aid their development cooperation. The goal for this thesis was to create a comprehensive guide to support the decision to procure and ERP. The thesis covers the vital theories regarding the ERP and its implementation and a comparative analysis of a few software systems on the market. The study was started by familiarizing with the theories and implementation of an ERP and taking a close look on how UFF operates. The data was gathered by interviews, literature and presentations from software companies. Firstly, the principles and theories of ERP were covered diversely and thoroughly. Secondly, the history, key figures and the operation of UFF were detailed step by step. In the next section, it was examined how the implementation of an ERP would affect the collection of donations in UFF. After this, a few potential software companies and their software systems were showcased and compared to find the most suitable ERP for UFF using a score chart. Finally, it was discussed on what could be the next step to improve the operations of UFF in the future. Finding an ERP for UFF created certain criteria and demands compared to the more traditional transport companies. Operations are correlative with garbage transportations and this was used as a basis when making references. This thesis contains a comprehensive amount of information when choosing, procuring and implementing an ERP and suggests a few alternative solutions. The sections concerning the organization and the ERP selection have been made available only for the client

Association analyses based on false discovery rate implicate new loci for coronary artery disease

Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10 '8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n cases = 10,801) as well as a stricter definition without angina (HARD; n cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation