Genetics of hypertriglyceridemia and atherosclerosis

Abstract

Purpose of reviewThe relationship between elevated triglyceride levels (i.e. hypertriglyceridemia) and risk of atherosclerotic cardiovascular disease (ASCVD) has been investigated for decades. Recent genetic studies have sought to resolve the decades-old question of a causal relationship. Recent findingsGenetic studies seem to demonstrate associations between elevated triglyceride levels and ASCVD risk. Mendelian randomization studies suggest this association may be causal. However, simultaneous pleiotropic effects of metabolically linked lipid variables -such as non-HDL cholesterol, apolipoprotein B and HDL cholesterol -often go unaccounted for in these studies. Complex underlying pleiotropic interactions of triglycerides with these lipid fractions together with unmeasured intercalated nonlipid-related mechanisms, such as inflammation and coagulation, impair the ability of genetic studies to implicate a direct role for triglycerides on ASCVD risk. One potential mechanism seems largely driven by the cholesterol carried within triglyceride-rich lipoproteins and their remnants, rather than their triglyceride content.

Relationship Between Low Skeletal Muscle Mass and Arteriosclerosis in Western China: A Cross-Sectional Study

“…Among the traditional risk factors for arteriosclerosis, the association between hypertension, diabetes, cholesterol, and arteriosclerosis is significant in all subjects and in different sex or age subgroups, and triglycerides are associated with arteriosclerosis in young and middle-aged people, which is consistent with the hypothesis that increased triglyceride levels favor the development of atherosclerosis (43), however, the association became insignificant in older subjects. The relationship between triglycerides and arteriosclerosis has always been controversial.…”

“…Hypertriglyceridemia is the most difficult lipid disease to evaluate and treat, and is related to several acquired diseases, such as IR. In addition, in a review by Gill et al, the patients with an increased risk of atherosclerotic CVD have a broader spectrum of plasma lipoprotein abnormalities, especially increased triglyceride-rich remnant particles, in which cholesterol (but not triglycerides) content promotes atherosclerosis (43). Therefore, since most of the people included in our study were young and middle-aged people, and this is a retrospective study and no additional data were collected from the older people, such as comorbidities, statins, or other usage, and no more confounding factors can be corrected.…”

A Tale of Two New Targets for Hypertriglyceridaemia: Which Choice of Therapy?

“…A commonly agreed global definition of HTG is a plasma triglyceride concentration persistently ≥ 1.7 mmol/L (≥ 150 mg/dL) [8]. Over 95% of people susceptible to HTG carry multiple genes that interact with non-genetic factors and perturb the metabolism of TRLs [1,[9][10][11][12].…”

Remnants, LDL, and the Quantification of Lipoprotein-Associated Risk in Atherosclerotic Cardiovascular Disease

“…The first was the demonstration in the proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor trials that achieving very low levels of LDL cholesterol (LDL-C) led to a further decrease in the risk of atherosclerotic cardiovascular disease (ASCVD) [1]. Second, genetic studies have revealed that plasma triglyceride (TG) is a probable causal risk factor for ASCVD [2,3], bringing to a close (for many commentators at least) decades of controversy concerning the role of TG-rich lipoproteins (TRL)-chylomicrons and VLDL-in atherosclerosis [2, 3, 4•, 5••, 6]. These seminal investigations were followed by consistent reports that plasma TG was a significant contributor to the residual risk of an ASCVD event in patients who had well-treated LDL-C levels [7][8][9][10].…”

“…Consequently, there is now a twin focus on improving the accuracy and precision of various methods for assessing LDL-C at levels below 1.8 mmol/l (70 mg/dl), and on the development of biomarkers that capture satisfactorily the ASCVD risk associated with elevated plasma TG. In regard to the latter, attention is currently centred on the cholesterol content of TRL and their remnants [2,3,4 Revisions to international guidelines for the prevention of cardiovascular disease have incorporated these key observations, and modified their recommendations and treatment strategies accordingly [11•, 12]. There is now a move to more aggressive LDL-C lowering goals; in the case of the latest European guidelines [11•], the goal in the highestrisk category is < 1.4 mmol/l (55 mg/dl), and for those with repeated events within a 2-year period, it is < 1.0 mmol/l (40 mg/dl).…”