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Background and AimsAPOC3, ANGPTL3, and ANGPTL4 are circulating proteins that are actively pursued as pharmacological targets to treat dyslipidemia and reduce the risk of atherosclerotic cardiovascular disease. Here, we used human genetic data to compare the predicted therapeutic and adverse effects of APOC3, ANGPTL3, and ANGPTL4 inactivation.MethodsWe conducted drug-target Mendelian randomization analyses using variants in proximity to the genes associated with circulating protein levels to compare APOC3, ANGPTL3, and ANGPTL4 as drug targets. We obtained exposure and outcome data from large-scale genome-wide association studies and used generalized least squares to correct for linkage disequilibrium-related correlation. We evaluated five primary cardiometabolic endpoints and screened for potential side effects across 694 disease-related endpoints, 43 clinical laboratory tests, and 11 internal organ MRI measurements.ResultsGenetically lowering circulating ANGPTL4 levels reduced the odds of coronary artery disease (CAD) (odds ratio, 0.57 per s.d. protein [95%CI,0.47–0.70]) and type 2 diabetes (T2D) (odds ratio, 0.73 per s.d. protein [95%CI,0.57–0.94]). Genetically lowering circulating APOC3 levels also reduced the odds of CAD (odds ratio, 0.90 per s.d. protein [95%CI,0.82–0.99]). Genetically lowered ANGPTL3 levels via common variants were not associated with CAD. However, meta-analysis of deleterious variants revealed that ANGPTL3 inactivation protected against CAD (odds ratio, 0.79 per allele [95%CI, 0.69–0.90]). Analysis of lowered ANGPTL3, ANGPTL4, and APOC3 levels did not identify important safety concerns.ConclusionHuman genetic evidence suggests that therapies aimed at reducing circulating levels of ANGPTL3, ANGPTL4, and APOC3 reduce the risk of CAD. ANGPTL4 lowering may also reduce the risk of T2D.

Angiopoietin-like proteins, ANGPTL3, ANGPTL4, and ANGPTL8, are involved in regulating plasma lipids. In vitro and animal-based studies point to LPL and endothelial lipase (EL, LIPG) as key targets of ANGPTLs. To examine the ANGPTL mechanisms for plasma lipid modulation in humans, we pursued a genetic mimicry analysis of enhancing or suppressing variants in the LPL, LIPG, lipase C hepatic type (LIPC), ANGPTL3, ANGPTL4, and ANGPTL8 genes using data on 248 metabolic parameters derived from over 110,000 nonfasted individuals in the UK Biobank and validated in over 13,000 overnight fasted individuals from 11 other European populations. ANGPTL4 suppression was highly concordant with LPL enhancement but not HL or EL, suggesting ANGPTL4 impacts plasma metabolic parameters exclusively via LPL. The LPL-independent effects of ANGPTL3 suppression on plasma metabolic parameters showed a striking inverse resemblance with EL suppression, suggesting ANGPTL3 not only targets LPL but also targets EL. Investigation of the impact of the ANGPTL3-ANGPTL8 complex on plasma metabolite traits via the ANGPTL8 R59W substitution as an instrumental variable showed a much higher concordance between R59W and EL activity than between R59W and LPL activity, suggesting the R59W substitution more strongly affects EL inhibition than LPL inhibition. Meanwhile, when using a rare and deleterious protein-truncating ANGPTL8 variant as an instrumental variable, the ANGPTL3-ANGPTL8 complex was very LPL specific. In conclusion, our analysis provides strong human genetic evidence that the ANGPTL3-ANGPTL8 complex regulates plasma metabolic parameters, which is achieved by impacting LPL and EL. By contrast, ANGPTL4 influences plasma metabolic parameters exclusively via LPL.

Patients at a high risk for sudden cardiac death (SCD) without previous history of cardiovascular disease remain a challenge to identify. Atherosclerosis and prothrombotic states involve inflammation and non-cardiac tissue damage that may play active roles in SCD development. Therefore, we hypothesized that circulating proteins implicated in inflammation and tissue damage are linked to the future risk of SCD. We conducted a prospective nested case–control study of SCD cases with verified myocardial infarction (N = 224) and matched controls without myocardial infarction (N = 224), aged 60 ± 10 years time and median time to event was 8 years. Protein concentrations (N = 122) were measured using a proximity extension immunoassay. The analyses revealed 14 proteins significantly associated with an increased risk of SCD, from which two remained significant after adjusting for smoking status, systolic blood pressure, BMI, cholesterol, and glucose levels. We identified leukotriene A4 hydrolase (LTA4H, odds ratio 1.80, corrected confidence interval (CIcorr) 1.02–3.17) and hepatocyte growth factor (HGF; odds ratio 1.81, CIcorr 1.06–3.11) as independent risk markers of SCD. Elevated LTA4H may reflect increased systemic and pulmonary neutrophilic inflammatory processes that can contribute to atherosclerotic plaque instability. Increased HGF levels are linked to obesity-related metabolic disturbances that are more prevalent in SCD cases than the controls.

LPL is a key player in plasma triglyceride metabolism. Consequently, LPL is regulated by several proteins during synthesis, folding, secretion, and transport to its site of action at the luminal side of capillaries, as well as during the catalytic reaction. Some proteins are well known, whereas others have been identified but are still not fully understood. We set out to study the effects of the natural variations in the plasma levels of all known LPL regulators on the activity of purified LPL added to samples of fasted plasma taken from 117 individuals. The enzymatic activity was measured at 25°C using isothermal titration calorimetry. This method allows quantification of the ability of an added fixed amount of exogenous LPL to hydrolyze triglyceride-rich lipoproteins in plasma samples by measuring the heat produced. Our results indicate that, under the conditions used, the normal variation in the endogenous levels of apolipoprotein C1, C2, and C3 or the levels of angiopoietinlike proteins 3, 4, and 8 in the fasted plasma samples had no significant effect on the recorded activity of the added LPL. Instead, the key determinant for the LPL activity was a lipid signature strongly correlated to the average size of the VLDL particles. The signature involved not only several lipoprotein and plasma lipid parameters but also apolipoprotein A5 levels. While the measurements cannot fully represent the action of LPL when attached to the capillary wall, our study provides knowledge on the interindividual variation of LPL lipolysis rates in human plasma.

Under de tre år som provfisket i Vaxholm har pågått har fångstsammansättningen varit relativt konstant.  Under 2018 fångades 75 fiskar per ansträngning (antal individer per nät och natt) fördelat på 12 arter. Totalfångsten var större än 2016 och 2017. Mört var den vanligaste arten i fångsten (50 procent), följt av abborre, strömming, braxen och gärs.  Den totala fångsten av karpfisk i Vaxholm var stor, under 2018 fångades 44 individer per ansträngning vilket var högre än tidigare år. De arter av karpfisk som fångats i Vaxholm är mört, braxen, löja, björkna, id och sutare.  Det fångades relativt många stora individer (> 30 centimeter) i Vaxholm och fångsten var något större 2018 än under de två tidigare åren. Av stora fiskar dominerar braxen och abborre, men även individer av gös, sik, mört och sutare över 30 centimeter fångades.  I provfiskefångsten utgjorde abborre 98 procent av all rovfisk. Förutom abborre förekom även rovfisken gös i fångsten. Antalet abborrar såväl som antalet rovfiskar var fler under 2018 än tidigare år.  Diversitetsindexet och den trofiska medelnivån har varit likartad under de tre år provfisket pågått, och är i nivå med närliggande provfiskeområden.  Ett- till fyra-åriga abborrar var efter den varma sommaren 2018 större vid given ålder jämfört med tidigare år.  Ett lågt siktdjup i kombination med den stora fångsten av karpfisk antyder att Vaxholm är påverkat av hög näringsbelastning.

I Vaxholm uppmättes något högre medeltemperatur samt lägre siktdjup och salthalt jämfört med närliggande provfiskestationerna i Lagnö. Det lägre siktdjupet indikerar att Vaxholm kan vara mer påverkat av övergödning än Lagnö. Sammanlagt fångades 13 arter under provfisket 2016. Mört är den vanligaste arten i fångsten (43 procent), följt av abborre, strömming, gers och braxen. Fångsten av stora individer (> 30 cm) domineras av braxen och abborre men även gös och sik förekommer i fångsten. Under provfisket 2016 fångades mer än tre gånger så många stora abborrar (25 cm och över) mot vad som fångades i det närliggande provfiskeområdet Lagnö under 2016. Även fångsterna av gös över 30 respektive 40 cm var högre än i Lagnö. Den totala fångsten av karpfisk i Vaxholm var 28,9 individer per ansträngning vilket är högt jämfört med det närliggande provfiskeområdet i Lagnö. 2016 är första året som provfiske utförs i Vaxholm och med anledning av detta är det svårt att dra några slutsatser om fisksamhällets struktur och funktion. Överlag är det dock inga stora avvikelser jämfört med närliggande områden frånsett den höga andelen mört, vilket kan bero på att området runt Vaxholm är näringsrikt. Intressant är även att det fångades förhållandevis mycket stor abborre, detta trots att området är mycket populärt för fritidsfiske.