Severe hypertriglyceridemia is primarily polygenic

Abstract

BACKGROUND: Hypertriglyceridemia (HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinants of HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenic and polygenic, is thus incomplete.OBJECTIVE: The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinants and molecular contributors.METHODS: We concurrently assessed rare and common variants in two independent cohorts of 251 and 312 Caucasian patients with severe HTG. DNA was subjected to targeted next-generation sequencing of 73 genes and 185 SNPs associated with dyslipidemia. LPL, APOC2, GPIHBP1, APOA5, and LMF1 genes were screened for rare variants, and a polygenic risk score was used to assess the accumulation of common variants.RESULTS: As there were no significant differences in the prevalence of genetic determinants between cohorts, data were combined for all 563 patients: 1.1% had biallelic (homozygous or compound heterozygous) rare variants, 14.4% had heterozygous rare variants, 32.0% had an extreme accumulation of common variants (ie, high polygenic risk), and 52.6% remained genetically undefined. Patients with HTG were 5.77 times (95% CI [4.26-7.82]; P , .0001) more likely to carry one of these types of genetic susceptibility compared with controls.CONCLUSIONS: We report the most in-depth, systematic evaluation of genetic determinants of severe HTG to date. The predominant feature was an extreme accumulation of common variants (high polygenic risk score), whereas a substantial proportion of patients also carried heterozygous rare

Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia

“…Consistent with a strong drug effect outweighing any genetic predisposition, we found no single SNPs of genome‐wide significance to explain maximum triglyceride measurement or longitudinal triglyceride clustering, although our power to detect novel genetic predisposition is limited by relatively small sample sizes. As hypertriglyceridemia is a highly studied polygenic phenotype, we applied a previously developed triglyceride‐PRS and confirmed that this PRS was a significant risk factor for hypertriglyceridemia at all time points, particularly at baseline, in European ancestry patients. However, our observation that the triglyceride‐PRS explained less of the variation in triglycerides after treatment suggests that the hypertriglyceridemia phenotype was driven by therapy more than genetic factors.…”

“…It has been previously proposed that hypertriglyceridemia is polygenic. 38,39 To this end, we selected a set of 16 previously discovered SNPs used to develop a triglyceride polygenic risk score (triglyceride-PRS) associated with elevated triglycerides in the general European population (Table S2) 38,39 and calculated a triglyceride-PRS for European ancestry patients (>90% Northern European genetic ancestry) in TXV and TXVI (n = 642).…”

Conservative management in hypertriglyceridemia‐associated pancreatitis

“…HTG can sometimes result from a monogenic cause, such as bi-allelic genetic mutations affecting lipoprotein lipase (LPL) or its cofactors [6][7][8][9][10][11]. However, severe HTG is most often the result of polygenic influences [12] and the presence of secondary factors, including excessive alcohol intake, uncontrolled diabetes mellitus or hypothyroidism, pregnancy [13,14], obesity, nephrotic syndrome, renal failure, multiple myeloma, systemic lupus erythematosus or certain drugs [1][2][3][4][5][6][7]15,16].…”

Spectrum of Mutations and Long-Term Clinical Outcomes in Genetic Chylomicronemia Syndromes

“…1 It is usually diagnosed when fasting plasma concentration of total triglycerides exceeds 10 mmol/L (≥885 mg/dL) on multiple occasions. 2,3 The clinical relevance of severe hypertriglyceridemia is due to its association with about 2-fold higher risk of acute pancreatitis (AP) 4 with a stepwise increase of this risk over time. 5 In addition to being a potentially life-threatening medical emergency, AP may also lead to several clinical complications such as chronic pancreatitis, pancreatic insufficiency, and type 2 diabetes mellitus.…”

“…7 FCS is inherited as an autosomal recessive disease, and its diagnosis is based on the detection of rare, biallelic (homozygous or compound heterozygous) mutations in LPL (lipoprotein lipase) and in other genes encoding proteins required for LPL activity, such as APOC2, APOA5, GPIHBP1, and LMF1. 2,6 Consequently, the LPL-mediated lipolysis of triglycerides in chylomicrons and other TRLs is severely impaired with massive accumulation of chylomicrons during fasting and postprandial state. Additional clinical symptoms associated with FCS include transient eruptive xanthomas, often appearing on the trunk and extremities, and lipemia retinalis, the milky appearance of the retinal vessels.…”