Genetic trans-effects link triglyceride-rich lipoproteins to blood pressure

Abstract

Background: Genome-wide association studies (GWASs) have identified thousands of genomic regions in which common variants affect blood pressure, but have yielded limited mechanistic insight. This study used a novel method of genetic analysis based on identifying core genes on which the _trans_-effects of common variants coalesce to influence blood pressure. Methods: We undertook GWASs of mean arterial pressure (MAP) and body mass index (BMI) in 373,882 individuals aged less than 60 years in the Our Future Health study. We used summary statistics from GWASs of proteins on the SomaScan and Olink platforms to compute genome-wide aggregated trans-effects (GATE) scores for each protein, and tested for association of MAP with these scores. Results: The strongest GATE score association with MAP was for lipoprotein lipase (LpL, encoded by LPL_. Genetic up-regulation of circulating levels of LpL was associated with lower MAP but higher BMI. Associations of MAP and BMI with GATE scores for circulating levels of proteins encoded by three other genes involved in lipid handling -- CD300LG, ADIPOQ, TIMP4 -- were similar to those with LpL. GATE scores for all four of these proteins were inversely associated with measurements by NMR spectroscopy of plasma triglyceride in chylomicrons and extremely large VLDL particles. Conclusions: These results point to a key role in hypertension for proteins that regulate post-prandial clearance of triglyceride-rich lipoproteins, independently of adiposity. This is consistent with experimental studies showing that accumulation of lipids in endothelial cells impairs endothelial function.