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Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.

Survival in multiple myeloma (MM) has developed favorably over the past decades for reasons that have been ascribed to new medications and treatment. However, development of survival over a long period and comparison to other hematopoietic neoplasms (HN) is less well known. Here we used Swedish cancer data from the Nordcan database, spanning a 50-year period from 1967 to 2016, and analyzed 1- and 5-year survival data. As a novel type of analysis we calculate the difference in survival between year 1 and 5 which indicates how well survival was maintained in the 4-year period following year 1 after diagnosis. The relative 1- and 5- year survival increased constantly; the 5-year survival graph for women was almost linear. The difference between 1- and 5-year survival revealed that the 5-year survival gain was entirely due to the improvement in 1-year survival, except for the last period. Survival improvement in all HNs exceeded that in MM. The linear 5-year survival increase for female MM patients suggests a contribution by many small improvements in the first year care rather than single major events. The future challenges are to push the gains past year 1 and to extend them to old patients.

Production of reactive oxygen species (ROS) in eosinophils. Cell aggregates were excluded based on forward scatter height and area properties, then granulocytes were gated based on their forward and side scatter. Eosinophils (in red) were defined as Siglec-8+ granulocytes. It was possible to select eosinophils also by their forward and side scatter characteristics. Intracellular production of ROS was measured as the geometric median fluorescence intensity in eosinophils (red) as a comparison typical graphs of ROS production in neutrophils are shown to the left (green). The two top histograms show unstimulated (PBS) cells and the bottom two histograms show cells activated with phorbol-12-myristate-13-acetate (PMA). (PDF 141 kb)

Background While genome-wide association studies (GWAS) of multiple myeloma (MM) have identified variants at 23 regions influencing risk, the genes underlying these associations are largely unknown. To identify candidate causal genes at these regions and search for novel risk regions, we performed a multi-tissue transcriptome-wide association study (TWAS). Results GWAS data on 7319 MM cases and 234,385 controls was integrated with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues (sample sizes, N = 80–491), including lymphocyte cell lines and whole blood, to predict gene expression. We identified 108 genes at 13 independent regions associated with MM risk, all of which were in 1 Mb of known MM GWAS risk variants. Of these, 94 genes, located in eight regions, had not previously been considered as a candidate gene for that locus. Conclusions Our findings highlight the value of leveraging expression data from multiple tissues to identify candidate genes responsible for GWAS associations which provide insight into MM tumorigenesis. Among the genes identified, a number have plausible roles in MM biology, notably APOBEC3C, APOBEC3H, APOBEC3D, APOBEC3F, APOBEC3G, or have been previously implicated in other malignancies. The genes identified in this TWAS can be explored for follow-up and validation to further understand their role in MM biology. Electronic supplementary material The online version of this article (10.1186/s40246-019-0231-5) contains supplementary material, which is available to authorized users.

The percentage of eosinophils of polymorphonuclear leukocytes (PMN) and basophils of the leukocytes populations is shown when the patients are divided into active and inactive (A and B) or into GPA or MPA (C and D). Patients with active disease had lower levels of both eosinophils and basophils but no difference were seen comparing GPA and MPA. Kruskal-Wallis test and Dunn’s multiple comparisons test was used to calculate the level of significance between the three groups. Values are reported as median ± IQR. (PDF 86 kb)

Cytospin preparations of purified neutrophils and eosinophils stained with May-Grünwald Giemsa. In the first set of experiment neutrophils and eosinophils were isolated using Histopaque 1119 (Sigma) followed by Percoll (GE Healthcare) and thereafter the eosinophils were separated from the granulocytes using MACS Eosinophil Isolation Kit (Miltenyi Biotech). The cells that were removed from during the eosinophil purification step were regarded as neutrophils (A) and the ones that remained as eosinophils (B). In the second part of the experiment eosinophils were purified using the MACSXpress® Eosinophil Isolation kit (Miltenyi Biotech) (C). (PDF 199 kb)

Light microscopy picture of two eosinophils that has formed EETs after incubation with PMA for 3 h at 37 °C and 5%CO2. The white arrow indicates the web formed by the DNA and the black arrows indicate the intact granules that remains around the plasma membrane remnants. (PDF 263 kb)

The level of surface expression on eosinophils of A CD16, B CD64, C CD35, D CD193, E CD62L, F CD88, G Siglec-8, H CD11b and I CD11c was measured in healthy blood donors (HBD) and compared to anti-neutrophil cytoplasmic antibodies associated vasculitides (AAV) patients, divided into GPA and MPA patients, using flow cytometry and reported as geometric mean fluorescence intensity (MFI). Kruskal-Wallis test and Dunn’s multiple comparisons test was used to calculate the level of significance between the three groups. Values are reported as median ± IQR. No difference was seen between the GPA and MPA groups. (PDF 95 kb)

Supplemental figures and study acknowledgments. (PDF 154 kb)

Table S1. Genes significantly associated with risk of multiple myeloma. Table S2. New and previously implicated1-5 genes at each genome wide significant multiple myeloma locus. Table S3. Quality control filters applied to samples from the seven published GWAS. Table S4. Quality control filters applied to SNPs from each GWAS. Table S5. MM GWAS risk SNPs. Figure S1. Quantile-Quantile Plots of â log10(P-value) associations. Figure S2. TWAS power plot in EBV-transformed lymphocytes. (DOCX 1515 kb)

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R g = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM. CA extern

This thesis explores the creation of a scaling, containerized, advertisement server that will be used by Gold Town Games AB to better integrate ads into their application(s). The server is built as a Docker image that will be used to create server instances on AWS Elastic Container Service for automatic scaling and server resource configuration. The server was created with the intention that GTG will have full control over what advertisements are shown in their application(s) and to seamlessly integrate sponsored logos onto jerseys or sports fields. This will not only serve as a source of income with advertisers paying for ad space, but it will also make the game elements more realistic as we have come to expect teams and stadiums to be sponsored and plastered with company logos. Another important part when displaying advertisement is to track statistics for the ads, since without a way to show advertisers that their ads are shown and that they are generating engagement it is very hard to sell the ad space. Detta examensarbete utforskar skapandet av en skalbar, containerbaserad, reklamserver som kommer användas av Gold Town Games AB för att integrera reklam i deras applikation(er). Servern är byggd som en Docker-bild som används för att skapa instanser på AWS Elastic Container Service för automatisk skalning och serverresurshantering. Servern är utvecklad med tanken att GTG ska ha full kontroll över vilken reklam som visas i deras applikation(er) och för att kunna lägga till sponsrade loggor på matchtröjor och i arenor. Detta är inte bara en extra form av inkomst, då annonsörer betalar för reklamplatser, utan hjälper även till att få delar av spelen att kännas mer realistiska då vi är vana att lag och arenor är sponsrade och fulla av företagsloggor. En annan viktig del när man visar reklam är att kunna spara statistik för den, eftersom det skulle vara väldigt svårt att sälja reklamplatser utan att kunna visa att folk faktiskt ser reklamen.

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM. © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)

Gating strategies. (DOCX 188 kb)

The Public vs. private movement has over the past decades identified numerous significant differences between public and private organizations. The observed differences covers almost every field in administrative economics ranging from organizational structure, management accounting, goal-setting and in the past few years even leadership. Strangely, in the majority of these studies little or no regards are given to organizational characteristics or fundamental differences between compared organizations and if these organizations really are comparable when studying the effect of sector. The aim of this study is to compare leadership in relatively similar organizations from both the public and private sector and so clarify if earlier identified differences in leadership styles still surface when leaders working with approximately the same thing in a similar work context are studied. A sample of 348 Swedish principals was drawn from both municipal and private elementary schools. The respondents answered a web-based survey based on the CPE-model resulting in leadership styles mapped according to three orientations: change, production and employee. Data was analyzed with several quantitative methods and the result failed to reproduce earlier observed differences with statistical significance or with satisfying strength when leaders working with approximately same thing in similar context were compared.

Föreningsidrottandet i Sverige är en utpräglad folkrörelse bland barn och ungdomar. En majoritet av både flickor och pojkar i Sverige idrottar av något slag i en förening fram till tonåren, dock väljer en del ungdomar att sluta föreningsidrotta när de kommer upp i åldrarna mellan 13-20 år. Det största av hoppet sker i de tidiga tonåren, främst bland flickor.Syftet med uppsatsen var att studera och analysera nio flickors berättelser om varför de valt att sluta med föreningsidrotten. Litteraturen visar att några faktorer som bidragit till att flickor valt att sluta med föreningsidrottandet var att de tappade intresset, hade brist på tid, fick andra intressen, att kamraterna slutade, träningstiderna inte passade eller flyttade till annan ort. Litteraturen belyser de risker som kan uppstå vid ett fysiskt inaktivt liv men även risker vid en onormalt hög grad av fysisk aktivitet. Resultatet visar att det finns flera faktorer som inverkar i att flickorna bortprioriterar föreningsidrotten och flera anledningar till varför denna bortprioritering görs. Förändringarna och kraven från föreningarna i relation med skolans ökade krav och betygsjakt är stora bidragande faktorer, som i sin tur leder till tidsbrist och att flickorna slutligen tappar intresset för idrotten. Membership in sports associations is common among children and teenagers in Sweden. The majority of boys and girls in Sweden are members in one or another sport association until they reach the adolescence, but in the teen ages a large amount chooses to quit sports. The biggest refrain from sports activities in an association among of teenagers happens in the early stage of the teen age. The biggest group that abandon sports in the teen age are girls. The purpose of this essay is to study and analyse the stories of nine girls of why they choose to abandon sports activities in a sports association. The literature shows that the major causes of leaving sports associations among teenage girls are that they looses their interests of the sport, lack of time, that they get other interests, that friends quit, unpleasant training timetable or moving to another location. The literature also shows the risks of an inactive lifestyle but also the risk of an abnormal consume of physical activity. The results of the essay shows that there are a lot of factors involved in the girls choice to abandon sport associations and why they get other priorities then sports. The changes of the group dynamics and the pressure from the sports association combined with the pressure from the school and the hunt for better grades in school are combined influenced factors that lead to the girls lack of time and the los of interest for sport activities.

Title:”Speed cameras - an prevention of crime and a standard forming instrument of control?” Authors: Markus Hansson Tutors: Bo Isenberg & Carl Hult Examinator: Ulf Drugge The School of Human Sciences University of Kalmar The studys purpose is to get a absorbed understanding for peoples attitude, and effect of speed cameras. The disposition for the study is to integrate earlier studies in the matter, combined with elevating interesting sociological conceptions. As an attempt to understand speed cameras as an instrument of force on the individual have Michel Foucaults concept Panopticon been used to see its effect, and it’s look upon how crime prevention will be formulated, which can give an explanation of why speed cameras are being used as an instrument of control on the traffic area. The study builds on questionnaire surveys that were made at two different surroundings around Kalmar. The places were chosen on the basis of being equivalent, with speed cameras in the traffic environment between the village and the bigger town of Kalmar. The basis for the study builds on 200 questionnaires that are distributed on the basis of sexes and age structure in the survey areas. The processing of data have been made with the statistics program SPSS. The framing of the questions that has been used to answer the purpose are 1)How is the attitude towards speed cameras?, 2)How does speed cameras effect road-users driving behaviour?, 3)The respondents view of causes for speed infringements. Some of the results that the study showed were that 41 percent had a positive attitude towards speed cameras. The study also pointed on a clear connection to the driving behaviour of the respondent have been calmer after the speed cameras have been introduced in the traffic environment, where particularly men experienced themselves to drive calmer. The cameras limited effect on the drive behaviour were obvious when 36 percent answered that they changed their driving behaviour by driving faster between the cameras and brake when they pass them. 1/5 of the respondents experience that the cameras disturb their concentration and make their driving poorer. The result can question the authorities purpose as “lifesavers”, and even turn the cameras into a increased traffic risk. The reason why road users exceed speed limits is among other things that the road users experience that the roads are suited for higher speed limits. This leads to a low acceptance towards the prevailing speed limits. The most common stated reason to why speed limits exceeds is that the road users don’t realize the risks that comes with driving to fast. This interprets that the speed cameras effect in order to change this view is not sufficient. In order to increase risk awareness other moves should be used like more information. In line with Brå:s report 2007:29 is criticism that is being emphasized in the study among other things a blind faith in cameras effectiveness in preventing crimes. The study shall be seen as an independent study that weighs authorities’ reports and results against this study's result. Keywords: Speed cameras, speeding offence, road users, questionnaire survey, panopticon, prevention, SARTRE, SPSS, Borgholm, Rälla, Ljungbyholm, Kalmar, Öland Studien syftar till att få en fördjupad förståelse för individers inställning till, och påverkan av hastighetskameror. Upplägget för studien är att integrera tidigare studier i ämnet, i kombination med att lyfta fram intressanta sociologiska begrepp. Som ett försök att förstå hastighetskamerors som maktmedel på individen har Michel Foucalts begrepp Panopticon använt för att se dess verkan, samt Ingrid Sahlins syn på hur brottsprevention ska utformas, vilket kan ge en bild av varför hastighetskameror används som styrmedel på trafikområdet. Studiens bygger på en enkätundersökning som genomfördes vid två olika närområden till Kalmar. Platserna valdes utifrån förutsättningarna att vara likvärdiga, med hastighetskameror i trafikmiljön mellan orten och den större staden Kalmar. Underlaget för studien bygger på 200 enkäter som är fördelat utifrån kön- och åldersfördelningen i undersökningsområdena. Behandling av data har skett genom statistikprogrammet SPSS. De frågeställningar som använts för att besvara syftet är 1)Hur är inställningen till hastighetskameror? 2)Hur påverkar hastighetskameror trafikanters körbeteende? 3)Respondenternas syn på orsaker till hastighetsöverträdelser. Några av de resultat som studien visade var att 41 procent hade en positiv inställning till hastighetskameror. Studien visade också på ett tydligt samband till att respondenterna körbeteende blivit lugnare efter det att hastighetskameror införts i trafikmiljön, där främst män upplevde sig köra lugnare. Kamerornas begränsade inverkan på körbeteendet visade sig då 36 procent uppgav att de anpassat sitt körbeteende genom att köra fortare mellan hastighetskamerorna och bromsar in när de passerar dem. 1/5-del av respondenterna upplever att kamerorna stör koncentrationen och gör dem till sämre bilförare. Resultatet kan ifrågasätta myndigheternas syfte med kamerorna som ”livräddare”, till att även utgöra en ökad trafikrisk. Orsaken till varför trafikanter överskrider hastighetsöverträdelser beror bland annat på att trafikanterna upplever att vägarna är anpassade att köra fortare på än vad hastigheten tillåter. Detta leder till en låg acceptans för rådande hastighetsbegränsningarna. Att trafikanter inte inser riskerna med att köra för fort, är den vanligast angivna orsaken till varför hastighetsbegränsningar överskrids. Detta tyder på att hastighetskamerors inverkan för att ändra denna uppfattning inte är tillräcklig. För att öka riskmedvetenhet borde det förmodligen istället satsas på åtgärder som ökad information. I linje med Brå:s Rapport 2007:29 är kritik som lyfts fram i studien bland annat övertron på kamerors effektivitet för att förebygga brott. Arbetet ska ses som en oberoende studie som väger myndigheters rapporter och resultat, mot denna studies resultat.

I den här uppsatsen har vi undersökt och behandlat låneförbudet som återfinns i ABL 12:7 och i kap 21 i nya ABL. Vi har undersökt om lagen uppfyller sina syften samt vilka syften som lagstiftaren har haft. Intressant är att en ny ABL träder i kraft den 1 januari 2006. Vi har utgått från lagstiftningen och sedan följt upp med rättspraxis och doktrin. Under arbetets gång upptäckte vi luckor i lagstiftningen vilket medför att syftena bakom lagstiftningen inte kom till sin fulla rätt. Luckorna öppnar möjligheter att kringgå låneförbudet med tämligen enkla metoder. Vi har bland annat undersökt kringgående av lagstiftningen med hjälp utav efterföljande finansiering samt ett kringgående med hjälp av andra rättsobjekt. Med efterföljande finansiering menas att ett bolag köps med bolagets egna pengar, med hjälp av undantaget för koncernlån. Ett kringgående med hjälp utav andra rättsobjekt kan se ut på lite olika sätt. I vårt arbete har vi använt av oss utav en fysisk person samt ett handelsbolag. Ett kringgående av lagstiftningen möjliggörs genom att andra rättsobjekt än aktiebolag ej lyder under aktiebolagslagen i stora drag. Dessa handlingar rör sig inom ett grått område inom juridiken och gör låneförbudet till ett tämligen trubbigt redskap. Eftersom låneförbudet tillhör specialstraffrätten möjliggörs kringgående av lagstiftningen då restriktiv lagtolkning måste användas. Faller en handling inte in ordagrant i vad som står i lagtexten är kringgåendet av låneförbudet både i nya och gamla ABL ett faktum.

I den här uppsatsen har vi undersökt och behandlat låneförbudet som återfinns i ABL 12:7 och i kap 21 i nya ABL. Vi har undersökt om lagen uppfyller sina syften samt vilka syften som lagstiftaren har haft. Intressant är att en ny ABL träder i kraft den 1 januari 2006. Vi har utgått från lagstiftningen och sedan följt upp med rättspraxis och doktrin. Under arbetets gång upptäckte vi luckor i lagstiftningen vilket medför att syftena bakom lagstiftningen inte kom till sin fulla rätt. Luckorna öppnar möjligheter att kringgå låneförbudet med tämligen enkla metoder. Vi har bland annat undersökt kringgående av lagstiftningen med hjälp utav efterföljande finansiering samt ett kringgående med hjälp av andra rättsobjekt. Med efterföljande finansiering menas att ett bolag köps med bolagets egna pengar, med hjälp av undantaget för koncernlån. Ett kringgående med hjälp utav andra rättsobjekt kan se ut på lite olika sätt. I vårt arbete har vi använt av oss utav en fysisk person samt ett handelsbolag. Ett kringgående av lagstiftningen möjliggörs genom att andra rättsobjekt än aktiebolag ej lyder under aktiebolagslagen i stora drag. Dessa handlingar rör sig inom ett grått område inom juridiken och gör låneförbudet till ett tämligen trubbigt redskap. Eftersom låneförbudet tillhör specialstraffrätten möjliggörs kringgående av lagstiftningen då restriktiv lagtolkning måste användas. Faller en handling inte in ordagrant i vad som står i lagtexten är kringgåendet av låneförbudet både i nya och gamla ABL ett faktum.

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

BACKGROUND We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.