Digenic Inheritance and Gene-Environment Interaction in a Patient With Hypertriglyceridemia and Acute Pancreatitis

Abstract

The etiology of hypertriglyceridemia (HTG) and acute pancreatitis (AP) is complex. Herein, we dissected the underlying etiology in a patient with HTG and AP. The patient had a 20-year history of heavy alcohol consumption and an 8-year history of mild HTG. He was hospitalized for alcohol-triggered AP, with a plasma triglyceride (TG) level up to 21.4 mmol/L. A temporary rise in post-heparin LPL concentration (1.5–2.5 times of controls) was noted during the early days of AP whilst LPL activity was consistently low (50∼70% of controls). His TG level rapidly decreased to normal in response to treatment, and remained normal to borderline high during a ∼3-year follow-up period during which he had abstained completely from alcohol. Sequencing of the five primary HTG genes (i.e., LPL, APOC2, APOA5, GPIHBP1 and LMF1) identified two heterozygous variants. One was the common APOA5 c.553G > T (p.Gly185Cys) variant, which has been previously associated with altered TG levels as well as HTG-induced acute pancreatitis (HTG-AP). The other was a rare variant in the LPL gene, c.756T > G (p.Ile252Met), which was predicted to be likely pathogenic and found experimentally to cause a 40% loss of LPL activity without affecting either protein synthesis or secretion. We provide evidence that both a gene-gene interaction (between the common APOA5 variant and the rare LPL variant) and a gene-environment interaction (between alcohol and digenic inheritance) might have contributed to the development of mild HTG and alcohol-triggered AP in the patient, thereby improving our understanding of the complex etiology of HTG and HTG-AP.

Comparison of the structure-function properties of wild-type human apoA-V and a C-terminal truncation associated with elevated plasma triglycerides

“…We describe the opposite phenotypic and functional consequences for the premature truncation of apoA-V at residue 252. Several studies confirm apoA-V's role in determining plasma TG levels [16][17][18] and risk of hyperTG-induced acute pancreatitis [19][20][21] and coronary artery disease [22][23][24] . Moreover, recent work describes apoA-V's inhibitory role in ANGPTL3/8-mediated inhibition of LPL TG hydrolysis 25,26 .…”

“…We screened the Penn Medicine Biobank (PMBB) for rare naturally-occurring APOA5 genetic variants associated with elevated TG levels. As a positive control, we identified 73 carriers of apoA-V G162C (rs2075291), a known rare LoF variant (total allele frequency 0.00342 in gnomAD v3.1.2 dataset (GRCh38) 66 ) associated with elevated plasma TG 16,17 , CAD 22,24 , and hypertriglyceridemia-induced acute pancreatitis [19][20][21] (Table S3). Carriers of this variant in the PMBB had significantly elevated plasma TG levels (Figure 3A).…”

“…ApoA-V is remarkably effective in decreasing plasma TG levels despite its low absolute concentration in human plasma (~150 ng/ml) 15 . LoF mutations in APOA5 have been associated with elevated TGs [16][17][18] , increased risk of hyperTG-induced acute pancreatitis [19][20][21] , and increased risk of CAD [22][23][24] . Recently, work by Chen et al and Balasubramaniam et al demonstrated that apoA-V associates with a neo-epitope on the angiopoietin-like-protein 3/8 (ANGPTL3/8) complex, competing with LPL for that binding site and blocking ANGPTL3/8-mediated LPL inhibition 25,26 .…”

Serum triglyceride levels are associated with recurrence in patients with acute hypertriglyceridemic pancreatitis

“…It may be related to fatty acid toxicity, microcirculation disturbance, oxidative stress, Ca 2+ overload and gene polymorphisms ( 32 – 39 ). Qi et al ( 40 ) confirmed that the interaction between genes and the environment is extremely significant in the occurrence and development of HTGP. It is vitally important to actively control serum TG levels to reduce the occurrence of HTG and even the occurrence and recurrence of HTGP.…”

Case Report: Successful Management of a 29-Day-Old Infant With Severe Hyperlipidemia From a Novel Homozygous Variant of GPIHBP1 Gene

“…According to previous studies, hyperlipidemia was defined as two categories: severe (triglyceride concentration >10 mmol/L) and mild-to-moderate (triglyceride concentration 2-10 mmol/L). The former is more likely to have a monogenic cause triggered by gene variants which consequently cause LPL dysfunction (28)(29)(30). It has been understood that multiple factors can interact with LPL, positively or negatively, thus exerting an influence on TG lipolysis.…”