👤 Anette Varbo

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

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

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

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