👤 Liv Tybjærg Nordestgaard

Despite significant advances in lipid-lowering therapeutics, residual lipid risk persists in patients with or at risk of atherosclerotic cardiovascular disease (ASCVD), even after optimizing low-density lipoprotein (LDL) cholesterol. Emerging evidence highlights the role of non-LDL cholesterol fractions, such as remnant cholesterol, lipoprotein(a) [Lp(a)], apolipoprotein B (apoB), and non-high-density lipoprotein (HDL) cholesterol, as key contributors to residual ASCVD risk. Remnant cholesterol, Lp(a), and LDL cholesterol represent three independent lipoprotein species causing ASCVD, while apolipoprotein B (apoB) and non-HDL cholesterol integrate the other three variables. Thus, clinically interpreting elevated apoB and non-HDL cholesterol is potentially complicated since remnants, Lp(a), and LDL cause ASCVD by different mechanisms and by varying proportions in different patients. Indeed, recent research into the pathophysiology of lipid-driven atherogenesis and development of ASCVD has revealed novel mechanisms that in turn suggest new therapeutic strategies targeting non-LDL lipid components. Elevated remnant cholesterol jointly with elevated LDL cholesterol contributes to arterial wall cholesterol deposition, plaque development, and ASCVD endpoints. Furthermore, the additional triglyceride content in remnant particles may theoretically promote intimal inflammation and possibly plaque rupture and erosion, independently contributing to atherogenesis and ASCVD. The lipid component and pro-inflammatory properties of Lp(a) could similarly contribute directly to atherosclerotic plaque development and ASCVD. In addition, the homology with plasminogen of the defining apolipoprotein(a) moiety of Lp(a) has long been speculated to confer anti-fibrinolytic and pro-thrombotic properties that could produce more severe ASCVD outcomes independent of atherogenesis. This review explores the evolving understanding of residual lipid risk in ASCVD, practical guidance for clinicians today, recent advances in therapeutic interventions, and their implications for clinical practice, aiming to optimize lipid management beyond LDL cholesterol reduction today and in the future. Show less

Emerging evidence suggests that apolipoprotein E (apoE) may be involved in the immune system and diseases driven by chronic inflammation. The impact of the full range of structural genetic variation in APOE for risk of rheumatoid arthritis, psoriasis, and psoriatic arthritis in the general population is not known. Further, whether apoE is associated with the common blood inflammatory biomarker profile warrants characterization. We systematically sequenced APOE in 10,369 individuals from the Copenhagen City Heart Study (CCHS) and genotyped nine variants (frequency ≥ 2/10,369) in 95,228 individuals from the Copenhagen General Population Study (CGPS). The UK Biobank was used for validation of the observed associations between the ε2/ε3/ε4 APOE polymorphism and disease end points. Concentrations or cell counts decreased stepwise from ε33 to ε43 to ε44 for C-reactive protein (P = 4 × 10 We found that APOE ε4 is associated with a biomarker profile consistent with a decreased general immune response. The ε32 genotype is associated with an intermediate biomarker profile and with a decreased risk of rheumatoid arthritis in the Copenhagen cohorts and of psoriasis in the meta-analysis. This suggests that the low-risk combination of apoE3 and apoE2 may play a role in the normal noninjurious inflammatory response. Show less

Elevated lipoprotein(a) predicts high risk of cardiovascular disease among a modest proportion of healthy individuals, an issue that complicates screening guidelines. To examine spline models, clinical thresholds, and percentiles of baseline lipoprotein(a) levels as 30-year determinants of cardiovascular risk. This cohort study was conducted among female health professionals participating in the Women's Health Study, who were followed up prospectively from 1993 to 2023. Women without cardiovascular disease, cancer, and other major chronic illnesses had blood samples taken at baseline. All individuals with lipoprotein(a) measurements and/or of European ancestry with genotype information for the LPA rs3798220 variation were included. Data analyses were performed from January through April 2025. Continuously valued baseline lipoprotein(a), lipoprotein(a) clinical thresholds and percentiles, and LPA rs3798220 genotypes known to predict lipoprotein(a) levels among individuals of European ancestry. The primary outcomes were incident major cardiovascular events, coronary heart disease, ischemic stroke, and cardiovascular death. Age- and multivariable-adjusted cause-specific Cox models were used to calculated hazard ratios for the cardiovascular outcomes. The hypothesis was formulated after collection of the data. A total of 27 748 women with baseline lipoprotein(a) measurements and 23 279 women of European ancestry with rs3798220 genotype information were included (median [IQR] age, 53 [49-60] years), among whom 3707 and 3165 major cardiovascular events, respectively, accrued during a median (IQR) follow-up period of 27.8 (22.8-29.4) years. Among women with lipoprotein(a) measurements, lipoprotein(a) levels above 30 mg/dL or the 75th percentile (31 mg/dL) were associated with increased 30-year risk of major cardiovascular events and coronary heart disease. Levels above 120 mg/dL or the 99th percentile (131 mg/dL) were associated with increased risk of ischemic stroke and cardiovascular death. Multivariable adjusted hazard ratios for levels above 120 mg/dL vs below 10 mg/dL or above the 99th percentile vs below the 50th percentile (11 mg/dL) were 1.54 (95% CI, 1.24-1.92) and 1.74 (95% CI, 1.35-2.25) for major cardiovascular events, 1.80 (95% CI, 1.36-2.37) and 2.06 (95% CI, 1.49-2.84) for coronary heart disease, 1.41 (95% CI, 0.93-2.15) and 1.85 (95% CI, 1.17-2.93) for ischemic stroke, and 1.63 (95% CI, 1.16-2.28) and 1.86 (95% CI, 1.26-2.72) for cardiovascular death, respectively. Among women with genotype information, rs3798220 minor allele carriers had a higher risk of major cardiovascular events. Per the results of this cohort study, very high lipoprotein(a) levels correlated with increased 30-year risk of cardiovascular disease among healthy women. Screening for elevated lipoprotein(a) in the general population may be warranted. Show less

Anti-obesity therapies co-targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor achieve greater weight loss compared with glucagon-like peptide-1 receptor agonists. However, the implications for cardiovascular risk reduction and the mechanisms involved remain unclear. This study aimed to (i) investigate whether genetically proxied body weight reduction via the GIP receptor pathway lowers cardiovascular disease risk and (ii) compare the effect to polygenic weight reduction, excluding GIP-related genes, to assess if the observed benefits are attributable to weight loss per se or involve additional GIP-related effects. Genetic scores were constructed using four variants in GIP-related genes associated with lower body mass index (BMI) and 31 variants linked to lower BMI in general. Observational and one-sample Mendelian randomization (MR) analyses were performed in 408 056 individuals from the UK Biobank and two-sample MR analyses using summary statistics from 419 821 individuals in FinnGen. In one-sample MR analyses, 1 kg/m² lower BMI via the GIP/GIPR score was associated with 29% lower risk of major adverse cardiovascular events (MACE) (P = .0002) and 43% lower risk of heart failure (P = 5 × 10⁻⁵). Corresponding lower risks with the polygenic BMI score were 3% (P = .002) and 13% (P < 1 × 10-300). Two-sample MR analyses showed similar results. Of the reduced risk via the GIP/GIPR score, BMI and glycated haemoglobin (HbA1c) mediated 13% and 22% of the lower risk of MACE and 16% and 17% of the lower risk of heart failure (all P ≤ 7 × 10-5). Genetic proxies for body weight reduction via GIP receptor targeting reduces the risk of MACE and heart failure, mediated partly through lower BMI and partly through lower HbA1c. Show less

We tested whether genetically proxied non-high-density lipoprotein cholesterol (non-HDL-C)-lowering drug targets reduce risk of all-cause dementia. We included 1,091,775 individuals from three prospective general population cohorts with individual-level data and two consortia with summary-level data. We selected genetic variants within HMGCR, NPC1L1, PCSK9, ANGPTL4, LPL, and CETP associated with non-HDL-C. These variants were used as exposures in Cox regression and one- and two-sample Mendelian randomization. Results were meta-analyzed. Meta-analysis of one-sample Mendelian randomization odds ratios per 1 mmol/L (39 mg/dL) lower non-HDL-C was 0.24 (0.18-0.31) for HMGCR, 0.18 (0.12-0.25) for NPC1L1, 0.97 (0.70-1.35) for PCSK9, 1.66 (0.52-5.36) for ANGPTL4, 1.41 (0.63-3.16) for LPL, and 0.30 (0.26-0.34) for CETP. Cox regression and two-sample Mendelian randomization results were mostly directionally consistent. Genetic lowering of non-HDL cholesterol via HMGCR, NPC1L1, and CETP reduces the risk of dementia. This reflects the effect of lifelong differences in non-HDL cholesterol on risk of dementia. Variants in HMGCR, NPC1L1, and CETP reduce the risk of dementia via non-high-density lipoprotein cholesterol (non-HDL-C). An effect of PCSK9, ANGPTL4, and LPL variants on dementia risk cannot be excluded. This reflects the effect of lifelong lower non-HDL-C on risk of dementia. Show less

Remnant cholesterol is receiving increasing attention as a target to reduce residual atherosclerotic cardiovascular disease (ASCVD) risk in individuals already treated with statins. New therapeutic options as antisense oligonucleotides, small interfering RNA, and monoclonal antibodies allow specific targeting of genes and proteins to counter pathological pathways promoted by these genes. Identifying genetic determinants of remnant cholesterol and relating these to risk of ASCVD is thus an appealing path to identifying and evaluating new and existing drug targets. Human genetic epidemiology has identified several genetic variants in genes involved in lipoprotein metabolism with effect on plasma concentrations of remnant cholesterol. Lipoprotein lipase (LPL) is central to the metabolism of remnant lipoproteins and plasma concentrations of remnant cholesterol, and several genes, including APOC3 , ANGPTL3 and ANGPTL4 , whose gene products regulate activity of LPL, are important determinants of remnant cholesterol. Current opinion is that remnant cholesterol is a likely causal factor in the development of ASCVD. Human genetic studies have identified several genes, many involved in LPL function, affecting remnant cholesterol concentrations, some of which are already used as therapeutic targets, and others which are subject to investigation of their remnant cholesterol and triglyceride-lowering effect in clinical trials. Show less

Lipid-lowering therapy is typically initiated at high low-density lipoprotein(LDL) cholesterol marked by elevated apolipoprotein B(apoB). We tested the hypothesis that elevated apoB alternatively due to high remnant cholesterol confers equally high risk of atherosclerotic cardiovascular disease(ASCVD) but less initiation of lipid-lowering therapy, compared to elevated apoB due to high LDL cholesterol. From the Copenhagen General Population Study, 94 299 lipid-lowering therapy naïve adults without a history of ASCVD were included in 2003-2015. Discordance groups were formed by median levels of remnant cholesterol, LDL cholesterol and apoB. In the national Danish health registries, individuals were followed for a prescription of lipid-lowering therapy and for incident ASCVD until December 2021. During a median follow-up of 12 years, 9269 developed ASCVD. Compared to individuals with concordant low values of remnant cholesterol, apoB, and LDL cholesterol, those with high remnant cholesterol and high apoB but low LDL cholesterol had a hazard ratio(HR) of 1.45 (95% confidence interval: 1.34-1.56) for ASCVD and an odds ratio(OR) of 3.0 (2.5-3.6) for starting lipid-lowering therapy within one year. Correspondingly, those with low remnant cholesterol but high apoB and high LDL cholesterol had a HR of 1.20 (1.11-1.30) for ASCVD and an OR of 5.1 (4.3-5.9) for starting lipid-lowering therapy. In a primary prevention setting, elevated apoB due to high remnant cholesterol confers high risk of ASCVD but less initiation of lipid-lowering therapy compared to elevated apoB due to high LDL cholesterol, representing a guideline-based limitation and an unmet medical need. Show less

Individuals with familial hypercholesterolemia (FH) are at high risk of premature cardiovascular disease. A healthy lifestyle and lipid-lowering medication are essential to reduce this risk. We examined if adherence to a heart healthy diet provides additional risk reduction independent of lipid-lowering medication. The Dutch Lipid Clinic Network (DLCN) criteria was used to diagnose FH (n=559 individuals with probable or definite FH) in the Copenhagen General Population Study(n=106,899) and the Copenhagen City Heart Study(n=7,451). Individuals were categorised by their level of heart healthy dietary adherence to Danish dietary guidelines, corresponding to international guidelines. Concentrations of low-density lipoprotein (LDL) cholesterol, apolipoprotein B (apoB), non-high-density lipoprotein (HDL) cholesterol, remnant cholesterol, triglycerides, and lipoprotein(a) (Lp(a)), and risk of ischaemic heart disease (IHD) were assessed by clinical FH category and level of dietary adherence. Women had a higher heart healthy dietary adherence compared to men. Mean concentrations of LDL cholesterol, apoB, non-HDL cholesterol, remnant cholesterol, and triglycerides increased stepwise by lower dietary adherence category, regardless of clinical FH category. Lp(a) concentration did not change by adherence to dietary guidelines. Results were similar in individuals taking lipid-lowering medication. Risk of ischemic heart disease (IHD) was lower in individuals with a higher dietary adherence (ranging from 8 to 57 % lower risk) compared to individuals with a very low dietary adherence regardless of clinical FH category. Adherence to a heart healthy diet is associated with lower concentrations of atherogenic lipids and lipoproteins, and lower risk of IHD in individuals with clinical FH, independent of treatment with lipid-lowering medication. Dietary adherence should be emphasised as an important tool in addition to treatment with lipid-lowering medication in individuals with FH. Show less

For decades, studies have tried to identify the cholesterol marker that best reflects risk of atherosclerotic cardiovascular disease(ASCVD). Comparing low-density-lipoprotein(LDL) cholesterol, non-high-density-lipoprotein(non-HDL) cholesterol, and apolipoprotein B(apoB) as ASCVD risk markers has been challenged by high correlation between them. Thus, discordance analyses, directly addressing disagreements between the cholesterol markers, have emerged. Approaches adopted to define discordance originate in one of three methods: discordance by cut-points, discordance by percentiles, or discordance by residuals. Commonly, concordant lipid levels serve as reference examining the association between discordant lipid levels with risk of ASCVD. Importantly, concordant reference groups present heterogeneity of clinical relevance across different discordance methods as concordant low lipid levels associate with lowest ASCVD risk while concordant high lipid levels associate with highest risk. Thus, results from different discordance approaches cannot be directly compared. Moreover, discordance between cholesterol markers is more frequently seen in individuals treated with lipid-lowering medication than in individuals not treated with lipid-lowering medication. Accordingly, studies performing discordance analyses have reported inconsistent and even conflicting results. Discordance by cut-points appears the most intuitive and clinically applicable method; results from these analyses suggest that elevated LDL cholesterol, non-HDL cholesterol, or apoB levels in individuals not treated with lipid-lowering medication confer increased ASCVD risk while in individuals treated with lipid-lowering medication, elevated non-HDL cholesterol and apoB levels best indicate residual risk. Results from discordance analyses comparing LDL cholesterol, non-HDL cholesterol, and apoB in risk of ASCVD as well as complexities of discordance analyses and considerations regarding interpretations are discussed in this review. Show less

Randomized clinical trials of remnant cholesterol lowering drugs show 50 % and 80 % reduction in remnant cholesterol with apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) inhibitors. However, how many of atherosclerotic cardiovascular disease(ASCVD) cases that could be prevented lowering remnant cholesterol by these therapies is unknown. The aim of the study was to estimate the potential of APOC3 and ANGPTL3 inhibitors to reduce the ASCVD burden through lowering of remnant cholesterol. Of 98,311 individuals from the Copenhagen General Population Study without ASCVD at study entry 8,506 were statin users and 89,805 were statin non-users. Cause-specific Cox regression was used to model rates of ASCVD and non-cardiovascular death conditional on remnant cholesterol and risk factors. Based on these models the potential 10-year absolute risk reduction of ASCVD in individuals with remnant cholesterol >1 mmol/L (>39 mg/dL) for 15 %, 30 %, 50 %, and 80 % lower remnant cholesterol was predicted. The predicted average 10-year absolute risk of ASCVD was 20 % for statin users and 11 % for statin non-users with remnant cholesterol >1 mmol/L (>39 mg/dL). The predicted 10-year absolute risk reduction of ASCVD in individuals with remnant cholesterol >1 mmol/L (>39 mg/dL) for 50 % and 80 % lower remnant cholesterol were 2.7 % (95 % confidence interval: 2.2-3.2 %), and 4.1 % (3.4-4.8 %) for statin users and 1.4 % (1.3-1.5 %), and 2.1 % (2.0-2.3 %) for statin non-users. We have shown that significant ASCVD risk reductions are expected for remnant cholesterol lowering drugs in at-risk populations, if intervention trials with novel remnant cholesterol lowering drugs show expected reductions in remnants in large cardiovascular outcomes trials. Show less

Progressive atherosclerotic cardiovascular disease (ASCVD) associated with high Lp(a) (>60 mg/dl) has been approved as indication for regular lipoprotein apheresis (LA) in Germany since 2008. This observational multicenter study enrolled 170 consecutive patients with high Lp(a) and progressive ASCVD despite effective treatment of other ASCVD risk factors as required for approval of reimbursement to analyse the long-term effect of LA on cardiovascular event rates. Additionally cardiovascular event rates were compared to an appropriate UK-Biobank cohort (UKBBC) with established ASCVD and verified impact of elevated Lp(a) on ASCVD risk. Investigations were conducted on patients retrospectively over a 5-year period before the initiation of regular LA, prospectively 5 years after the commencement of LA, and again retrospectively until the completion of 12 years of LA. 154 patients (90.6 %) completed 5 years follow-up, 129 patients (75.9 %) were available in year 12. A decline in the mean annual rate of cardiovascular events per patient was observed from y-5 to y-1 (0.27 ± 0.25) versus y+1 until y+12 (0.06 ± 0.08) (p < 0.001). One year before commencing LA mean event rates per 100 patient years of the primary composite endpoint parameter of major adverse cardiac events (MACE) including nonfatal ischemic stroke (IS) were significantly higher in Pro(a)LiFe patients compared to the UKBBC. Most importantly they were significantly lower one year after commencing LA. Regular LA was associated with a decreased rate of cardiovascular events in patients with high Lp(a) (>60 mg/dl) and progressive ASCVD up to 12 years. Comparison with corresponding incidence rates in the UKBBC supports the clinical efficacy of LA to bring progressive ASCVD associated with high Lp(a) to a halt. However, this comparative analysis cannot replace a true control group or determine the exact effect size. Show less

Cost-effectiveness of Lipoprotein(a) [Lp(a)] testing is not established. We aimed to evaluate the cost-effectiveness of Lp(a) testing in the cardiovascular disease (CVD) primary prevention population from healthcare and societal perspectives. We constructed and validated a multi-state microsimulation Markov model for a population of 10,000 individuals aged between 40 and 69 years without CVD, selected randomly from the UK Biobank. The model evaluated Lp(a) testing in individuals not initially classified as high-risk based on age, diabetes status, or the SCORE-2 algorithm. Those with an Lp(a) level ≥105 nmol/L (50 mg/dL) were treated as high risk (initiation of a statin plus blood pressure lowering). The Lp(a) testing intervention was compared to standard of care. The primary analyses were conducted from the Australian and UK healthcare perspectives in 2023AUD/GBP. A cost adaptation method estimated cost-effectiveness in multiple European countries, Canada, and the USA. Among 10,000 individuals, 1,807 had their treatment modified from Lp(a) testing. This led to 217 and 255 quality-adjusted life years gained in Australia and the UK, respectively, with corresponding incremental cost-effectiveness ratios of 12,134 (cost-effective) and -3,491 (cost-saving). From a societal perspective, Lp(a) testing saved $85 and £263 per person in Australia and the UK, respectively. Lp(a) testing was cost-saving among all countries tested in the cost adaptation analysis. Lp(a) testing in the primary prevention population to reclassify CVD risk and treatment is cost-saving and warranted to prevent CVD. Show less

Chronic kidney disease confers a high risk of atherosclerotic cardiovascular disease (ASCVD), partly due to hyperlipidemia. Although statins reduce the risk of ASCVD in chronic kidney disease, residual risk persists. We investigated whether higher remnant cholesterol is associated with an increased risk of ASCVD in statin users and nonusers with impaired renal function. We included 107 925 individuals from CGPS (Copenhagen General Population Study) initiated in 2003 to 2015, of whom 10 427 had impaired renal function (estimated glomerular filtration rate, <60 mL/min per 1.73 m In individuals with impaired renal function during up to 15 years of follow-up, 597 were diagnosed with myocardial infarction, 618 with ischemic stroke, and 1182 with ASCVD. In these individuals, a 1-mmol/L (39 mg/dL) higher remnant cholesterol level was associated with multivariable-adjusted hazard ratios of 1.22 (95% CI, 1.05-1.42) for myocardial infarction, 1.16 (95% CI, 0.97-1.38) for ischemic stroke, and 1.21 (95% CI, 1.08-1.36) for ASCVD. Corresponding hazard ratios for ASCVD were 1.40 (95% CI, 1.07-1.83) in statin users and 1.16 (95% CI, 1.01-1.34) in nonusers. Of the 1.36-fold excess risk of ASCVD in impaired versus normal renal function, elevated remnant cholesterol and elevated LDL (low-density lipoprotein) cholesterol explained 25% (95% CI, 2.5%-47%) and 0% in statin users and 8.3% (95% CI, 2.4%-14%) and 14% (95% CI, 6.4%-22%) in nonusers, respectively. Our results suggest that higher remnant cholesterol is a good marker of increased risk of ASCVD in individuals with impaired renal function, while higher LDL cholesterol may not be. Patients with chronic kidney disease who have high levels of remnant cholesterol are identifiable through higher non-HDL (high-density lipoprotein) cholesterol or apoB levels. Show less

Individuals with diabetes face increased risk of atherosclerotic cardiovascular disease (ASCVD), in part due to hyperlipidemia. Even after LDL cholesterol-lowering, residual ASCVD risk persists, part of which may be attributed to elevated remnant cholesterol. We describe the impact of elevated remnant cholesterol on ASCVD risk in diabetes. Preclinical, observational, and Mendelian randomization studies robustly suggest that elevated remnant cholesterol causally increases risk of ASCVD, suggesting remnant cholesterol could be a treatment target. However, the results of recent clinical trials of omega-3 fatty acids and fibrates, which lower levels of remnant cholesterol in individuals with diabetes, are conflicting in terms of ASCVD prevention. This is likely partly due to neutral effects of these drugs on the total level of apolipoprotein B(apoB)-containing lipoproteins. Elevated remnant cholesterol remains a likely cause of ASCVD in diabetes. Remnant cholesterol-lowering therapies should also lower apoB levels to reduce risk of ASCVD. Show less

The balance between the potential long-term clinical benefits and harms associated with genetic cholesteryl ester transfer protein (CETP) deficiency, mimicking pharmacologic CETP inhibition, is unknown. To assess the relative benefits and harms associated with genetic CETP deficiency. This study examined 2 similar prospective cohorts of the Danish general population, with data on a total of 102 607 participants collected from October 10, 1991, through December 7, 2018. Weighted CETP allele scores. Incident cardiovascular mortality, ischemic heart disease, myocardial infarction, ischemic stroke, peripheral arterial disease, vascular dementia, Alzheimer disease, all-cause mortality, and age-related macular degeneration (AMD). The study first tested whether a CETP allele score was associated with morbidity and mortality, when scaled to genetically lower levels of non-high-density lipoprotein (HDL) cholesterol (ie, 17 mg/dL), corresponding to the reduction observed for anacetrapib vs placebo in the Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial. Second, the study assessed how much of the change in morbidity and mortality was associated with genetically lower levels of non-HDL cholesterol. Finally, the balance between the potential long-term clinical benefits and harms associated with genetic CETP deficiency was quantified. For AMD, the analyses also included higher levels of HDL cholesterol associated with genetic CETP deficiency. Of 102 607 individuals in the study, 56 559 (55%) were women (median age, 58 years [IQR, 47-67 years]). Multivariable adjusted hazard ratios showed that a genetically lower level of non-HDL cholesterol (ie, 17 mg/dL) was associated with a lower risk of cardiovascular mortality (hazard ratio [HR], 0.77 [95% CI, 0.62-0.95]), ischemic heart disease (HR, 0.80 [95% CI, 0.68-0.95]), myocardial infarction (HR, 0.72 [95% CI, 0.55-0.93]), peripheral arterial disease (HR, 0.80 [95% CI, 0.63-1.02]), and vascular dementia (HR, 0.38 [95% CI, 0.18-0.80]) and an increased risk of AMD (HR, 2.33 [95% CI, 1.63-3.30]) but was not associated with all-cause mortality (HR, 0.91 [95% CI, 0.81-1.02]), ischemic stroke (HR, 1.05 [95% CI, 0.81-1.36]), or Alzheimer disease (HR, 1.25 [95% CI, 0.89-1.76]). When scaled to a higher level of HDL cholesterol, the increased risk of AMD was even larger. A considerable fraction of the lower risk of cardiovascular end points was associated with genetically lower levels of non-HDL cholesterol, while the higher risk of AMD was associated with genetically higher levels of HDL cholesterol. Per 1 million person-years, the projected 1916 more AMD events associated with genetically higher levels of HDL cholesterol was similar to the 1962 fewer events of cardiovascular mortality and myocardial infarction combined associated with genetically lower levels of non-HDL cholesterol. This study suggests that genetic CETP deficiency, mimicking pharmacologic CETP inhibition, was associated with a lower risk of cardiovascular morbidity and mortality, but with a markedly higher risk of AMD. Show less

Almost one third of adults in the West have increased plasma levels of triglycerides. Even mild to moderate hypertriglyceridemia (2-10 mmol/L or 177-886 mg/dL) is associated with an increased risk of acute pancreatitis. However, it is not clear whether hypertriglyceridemia is a cause or result of acute pancreatitis. Lipoprotein lipase degrades plasma triglycerides. Variants in LPL, APOA5, APOC3, ANGPTL3, and ANGPTL4, which regulate the lipoprotein lipase pathway, result in increased or reduced plasma triglyceride levels. We investigated associations between these variants and acute pancreatitis in a study of the general population. In a prospective cohort study, men and women randomly selected from the area of Copenhagen were invited to complete a questionnaire, undergo a physical examination, and provide blood samples for biochemical and genetic analyses, from 2003 through 2015. We obtained triglyceride measurements from 117,427 participants. We examined for 15 genetic variants that are associated with lipoprotein lipase function in DNA samples from 102,888 participants and analyzed data from 117,427 participants in observational analyses. Diagnoses of acute pancreatitis (970 diagnoses among participants in the genetic analysis and 527 among participants in the observational study) were obtained from Danish registries. We performed a 1-sample Mendelian randomization analysis in which specific variants were used as markers of the plasma level of triglycerides to determine the association between the plasma level of triglyceride and acute pancreatitis. We calculated unweighted, internally weighted, and externally weighted allele scores for each participant by adding numbers of triglyceride-increasing alleles. The highest genetic allele score correlated with a higher plasma level of triglycerides of 0.54 mmol/L (48 mg/dL). Among participants with the highest vs the lowest genetic allele score, the odds ratio for acute pancreatitis was 1.55 (95% CI, 1.08-2.23). Using instrumental variable analysis, integrating the effect of genotype on both triglycerides levels and risk of acute pancreatitis, we associated higher unweighted allele scores with an increased risk of acute pancreatitis (odds ratio [OR], 1.76; 95% CI, 1.16-2.65), as well as internally weighted higher allele scores (OR, 1.41; 95% CI, 1.01-1.97) and externally weighted higher allele scores (OR, 1.44; 95% CI, 1.01-2.04). Every 1 mmol/L (89 mg/dL) increase in triglycerides was observationally associated with an increase in OR of 1.09 (95% CI, 1.05-1.14) after multivariable adjustment. Based on an analysis of individuals with genetic variants associated with an increased level of triglycerides, via their effects on the lipoprotein lipase pathway, we associated an increased plasma levels of triglycerides with an increased risk of acute pancreatitis. Strategies to reduce plasma levels of triglycerides, by increasing lipoprotein lipase function, might be developed for prevention of acute pancreatitis. Show less

The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis. We examined the effect of a gain-of-function variant in A fixed-effect meta-analysis of all 7 cohorts found that the Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis. Show less

High lipoprotein(a) levels are observationally and causally, from human genetics, associated with increased risk of cardiovascular disease including myocardial infarction and aortic valve stenosis. The European Atherosclerosis Society recommends screening for elevated lipoprotein(a) levels in high-risk patients. Different therapies have been suggested and some are used to treat elevated lipoprotein(a) levels such as niacin, PCSK9 inhibitors, and CETP inhibitors; however, to date, no randomized controlled trial has demonstrated that lowering of lipoprotein(a) leads to lower risk of cardiovascular disease. Synthetic oligonucleotides can be used to inactivate genes involved in disease processes. To lower lipoprotein(a), two antisense oligonucleotides have been developed, one targeting apolipoprotein B and one targeting apolipoprotein(a). Mipomersen is an antisense oligonucleotide targeting apolipoprotein B and thereby reducing levels of all apolipoprotein B containing lipoproteins in the circulation. Mipomersen has been shown to lower lipoprotein(a) by 20-50% in phase 3 studies. AKCEA-APO(a)-L Show less

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. Show less

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 × 10 Show less

New treatment opportunities are emerging in the field of lipid-lowering therapy through gene-silencing approaches. Both antisense oligonucleotide inhibition and small interfering RNA technology aim to degrade gene mRNA transcripts to reduce protein production and plasma lipoprotein levels. Elevated levels of LDL, remnant lipoproteins, and lipoprotein(a) all cause cardiovascular disease, whereas elevated levels of triglyceride-rich lipoproteins in some patients can cause acute pancreatitis. The levels of each of these lipoproteins can be reduced using gene-silencing therapies by targeting proteins that have an important role in lipoprotein production or removal (for example, the protein products of ANGPTL3, APOB, APOC3, LPA, and PCSK9). Using this technology, plasma levels of these lipoproteins can be reduced by 50-90% with 2-12 injections per year; such dramatic reductions are likely to reduce the incidence of cardiovascular disease or acute pancreatitis in at-risk patients. The reported adverse effects of these new therapies include injection-site reactions, flu-like symptoms, and low blood platelet counts. However, newer-generation drugs are more efficiently delivered to liver cells, requiring lower drug doses, which leads to fewer adverse effects. Although these findings are promising, robust evidence of cardiovascular disease reduction and long-term safety is needed before these gene-silencing technologies can have widespread implementation. Before the availability of such evidence, these drugs might have roles in patients with unmet medical needs through orphan indications. Show less

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD. Show less

Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10 We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk. Show less

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10 Show less

High plasma levels of nonfasting triglycerides are associated with an increased risk of ischemic cardiovascular disease. Whether lifelong low levels of nonfasting triglycerides owing to mutations in the gene encoding apolipoprotein C3 (APOC3) are associated with a reduced risk of ischemic cardiovascular disease in the general population is unknown. Using data from 75,725 participants in two general-population studies, we first tested whether low levels of nonfasting triglycerides were associated with reduced risks of ischemic vascular disease and ischemic heart disease. Second, we tested whether loss-of-function mutations in APOC3, which were associated with reduced levels of nonfasting triglycerides, were also associated with reduced risks of ischemic vascular disease and ischemic heart disease. During follow-up, ischemic vascular disease developed in 10,797 participants, and ischemic heart disease developed in 7557 of these 10,797 participants. Participants with nonfasting triglyceride levels of less than 1.00 mmol per liter (90 mg per deciliter) had a significantly lower incidence of cardiovascular disease than those with levels of 4.00 mmol per liter (350 mg per deciliter) or more (hazard ratio for ischemic vascular disease, 0.43; 95% confidence interval [CI], 0.35 to 0.54; hazard ratio for ischemic heart disease, 0.40; 95% CI, 0.31 to 0.52). Heterozygosity for loss-of-function mutations in APOC3, as compared with no APOC3 mutations, was associated with a mean reduction in nonfasting triglyceride levels of 44% (P<0.001). The cumulative incidences of ischemic vascular disease and ischemic heart disease were reduced in heterozygotes as compared with noncarriers of APOC3 mutations (P=0.009 and P=0.05, respectively), with corresponding risk reductions of 41% (hazard ratio, 0.59; 95% CI, 0.41 to 0.86; P=0.007) and 36% (hazard ratio, 0.64; 95% CI, 0.41 to 0.99; P=0.04). Loss-of-function mutations in APOC3 were associated with low levels of triglycerides and a reduced risk of ischemic cardiovascular disease. (Funded by the European Union and others.). Show less

Elevated non-fasting triglycerides mark elevated levels of remnant cholesterol. Using a Mendelian randomization approach, we tested whether genetically increased remnant cholesterol in hypertriglyceridaemia due to genetic variation in the apolipoprotein A5 gene (APOA5) associates with an increased risk of myocardial infarction (MI). We resequenced the core promoter and coding regions of APOA5 in individuals with the lowest 1% (n = 95) and highest 2% (n = 190) triglyceride levels in the Copenhagen City Heart Study (CCHS, n = 10 391). Genetic variants which differed in frequency between the two extreme triglyceride groups (c.-1131T > C, S19W, and c.*31C > T; P-value: 0.06 to <0.001), thus suggesting an effect on triglyceride levels, were genotyped in the Copenhagen General Population Study (CGPS), the CCHS, and the Copenhagen Ischemic Heart Disease Study (CIHDS), comprising a total of 5705 MI cases and 54 408 controls. Genotype combinations of these common variants associated with increases in non-fasting triglycerides and calculated remnant cholesterol of, respectively, up to 68% (1.10 mmol/L) and 56% (0.40 mmol/L) (P < 0.001), and with a corresponding odds ratio for MI of 1.87 (95% confidence interval: 1.25-2.81). Using APOA5 genotypes in instrumental variable analysis, the observational hazard ratio for a doubling in non-fasting triglycerides was 1.57 (1.32-2.68) compared with a causal genetic odds ratio of 1.94 (1.40-1.85) (P for comparison = 0.28). For calculated remnant cholesterol, the corresponding values were 1.67(1.38-2.02) observational and 2.23(1.48-3.35) causal (P for comparison = 0.21). These data are consistent with a causal association between elevated levels of remnant cholesterol in hypertriglyceridaemia and an increased risk of MI. Limitations include that remnants were not measured directly, and that APOA5 genetic variants may influence other lipoprotein parameters. Show less