👤 Shehroze Tabassum

Genome-wide association studies of lipid species have identified several loci shared with various diseases, however, the relationship between lipid species and disease risk remains poorly understood. Here we investigated whether the plasma levels of lipid species are causally linked to disease risk. We built genetic predictors of 179 lipid species, measured in 7174 Finnish individuals, by utilising either 11 high-impact genomic loci or genome-wide polygenic scores (PGS). We assessed the impact of the lipid species on seven diseases by performing disease association across FinnGen (n = 500,348), UK Biobank (n = 420,531), and Generation Scotland (n = 20,032). We performed univariable Mendelian randomisation (MR) and multivariable MR (MVMR) analyses to examine whether lipid species impact disease risk independently of standard lipids. PGS explained >4% of the variance for 34 lipid species but variants outside the high-impact loci had only a marginal contribution. Variants within the high-impact loci showed association with all seven diseases. MVMR supported a causal role of ApoB in ischaemic heart disease after accounting for lipid species. Phosphatidylethanolamine-increasing LIPC variants seemed to lower age-related macular degeneration risk independently of HDL-cholesterol. MVMR suggested a protective effect of four lipid species containing arachidonic acid on cholelithiasis risk independently of Total Cholesterol. Our study demonstrates how genetic predictors of lipid species can be utilised to gain insights into disease risk. We report potential links between lipid species and age-related macular degeneration and cholelithiasis risk, which can be explored for their utility in disease risk prediction and therapy. The funders had no role in the study design, data analyses, interpretation, or writing of this article. Show less

Hypertriglyceridemia is an independent risk factor for cardiovascular diseases. In previous trials, apolipoprotein C-III (APOC3) inhibition through the antisense oligonucleotides volanesorsen, olezarsen, and plozasiran reduced triglyceride levels. However, the three medications' safety and efficacy have yet to be compared. A network meta-analysis was performed to compare multiple doses of the three medications to each other through the placebo. Randomized controlled trials (RCTs) were retrieved by searching PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane until November 22nd, 2024. The mean difference (MD) and 95% confidence interval (CI) were used for continuous outcomes. The risk ratio (RR) and 95% CI were used for dichotomous outcomes. Ten RCTs with a total of 1,129 patients were included. volanesorsen 300 mg once weekly showed the most significant percent reduction in triglyceride levels (MD = -91.0%, 95% CI: (-109.2%; -72.8%); P < 0.01). Only plozasiran once monthly, regardless of the dose, showed a non-significant percent reduction in triglycerides. This finding should be taken cautiously as the data were derived from a phase 1 trial with a small sample size. All the regimens significantly reduced APOC3 levels compared to placebo, with plozasiran 100 mg monthly and volanesorsen 300 mg once weekly showing the most significant reduction (MD range: -92.8% to -88.5%; P < 0.01). None of the treatments showed a statistically significant difference in overall adverse events rate compared to the placebo. APOC3 antisense oligonucleotide inhibitors effectively reduced triglyceride and APOC3 levels in hypertriglyceridemia with an acceptable safety profile. However, the results should be interpreted cautiously due to the small sample size. Further research is needed to confirm the beneficial effects of APOC3 inhibitors and show strong evidence of the impact of each regimen. Show less

Apolipoprotein C3 (ApoC3) is a major constituent of VLDL and is a modulator of triglyceride metabolism. Recent genetic studies have implicated several ApoC3 gene polymorphisms in the development of insulin resistance and type 2 diabetes mellitus (T2DM). Considering the high prevalence of T2DM in Saudi Arabia, we sought to examine the possible association of ApoC3 gene variants with diabetes risk in Saudi population. The 3238C>G and -482C>T polymorphisms of ApoC3 gene were studied in 268 T2DM patients and 255 healthy controls by TaqMan probe based real time polymerase chain reaction assays. Diabetic patients displayed significantly increased systolic blood pressure, fasting plasma glucose, insulin resistance, and dyslipidemia compared to control. Patients also had markedly elevated plasma VLDL levels. Genotype distribution of 3238C>G polymorphism was significantly different between patients and control. Consistently, this variant was found to be significantly associated with T2DM risk. Contrastingly, no significant relationship was found between -482C>T polymorphism and T2DM risk. Association of disease risk with 3238C>G polymorphism remained significant even after accounting for the established risk factors. Genotype-based stratification revealed a significant correlation of GG genotype of 3238C>G with elevated plasma triglycerides, insulin resistance, and VLDL, whereas the TT genotype of -482C>T correlated with elevated triglyceride and VLDL levels. Thus, 3238C>G polymorphism of ApoC3 gene appears to augment the propensity to develop T2DM, while -482C>T to negatively affect lipid metabolism in Saudi subjects. Show less