Identification of a novel LPL nonsense variant and further insights into the complex etiology and expression of hypertriglyceridemia-induced acute pancreatitis

Abstract

Background: Hypertriglyceridemia (HTG) is a leading cause of acute pancreatitis. HTG can be caused by either primary (genetic) or secondary etiological factors, and there is increasing appreciation of the interplay between the two kinds of factors in causing severe HTG. Objectives: The main aim of this study was to identify the genetic basis of hypertriglyceridemia-induced acute pancreatitis (HTG-AP) in a Chinese family with three affected members (the proband, his mother and older sister). Methods: The entire coding and flanking sequences of LPL, APOC2, APOA5, GPIHBP1 and LMF1 genes were analyzed by Sanger sequencing. The newly identified LPL nonsense variant was subjected to functional analysis by means of transfection into HEK-293 T cells followed by Western blot and activity assays. Previously reported pathogenic LPL nonsense variants were collated and compared with respect to genotype and phenotype relationship. Results: We identified a novel nonsense variant, p.Gln118* (c.351C > T), in the LPL gene, which co-segregated with HTG-AP in the Chinese family. We provided in vitro evidence that this variant resulted in a complete functional loss of the affected LPL allele. We highlighted a role of alcohol abuse in modifying the clinical expression of the disease in the proband. Additionally, our survey of 12 previously reported pathogenic LPL nonsense variants (in 20 carriers) revealed that neither serum triglyceride levels nor occurrence of HTG-AP was distinguishable among the three carrier groups, namely, simple homozygotes, compound heterozygotes and simple heterozygotes. Conclusions: Our findings, taken together, generated new insights into the complex etiology and expression of HTG-AP.

Prediction of infected pancreatic necrosis in acute necrotizing pancreatitis by the modified pancreatitis activity scoring system

“…In addition, hypertriglyceridemia‐associated AP accounts for approximately 50% of the study subjects, significantly different from cohorts reported in other areas of the world 29,30 . The increase in hypertriglyceridemia‐induced AP in the Chinese population might be attributed to dramatic changes in dietary habits 31 and genetic factors 32 . Although the performance of mPASS‐4 in predicting IPN did not change after involving the etiologies as a confounder, the distinct etiological distribution may weaken the generalizability of our observed results.…”

“… 29 , 30 The increase in hypertriglyceridemia‐induced AP in the Chinese population might be attributed to dramatic changes in dietary habits 31 and genetic factors. 32 Although the performance of mPASS‐4 in predicting IPN did not change after involving the etiologies as a confounder, the distinct etiological distribution may weaken the generalizability of our observed results.…”

Immune enhancement in patients with predicted severe acute necrotising pancreatitis: a multicentre double-blind randomised controlled trial

“…Last, nearly 50% of the study patients had hypertriglyceridemia as etiology, significantly higher than results from an international registry [ 47 ]. The increase of hypertriglyceridemia-induced AP in Chinese cohorts might be attributed to changes in dietary habits [ 48 ] and genetic factors [ 49 ]. Although the effect of Tα1 did not vary across patients caused by hypertriglyceridemia or other etiologies, the distinct etiological distribution leaves the generalisability of the observed results in doubt.…”

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

“…LPL mass was determined using a human LPL Elisa kit (TSZ Biological Trade Co., Ltd., San Francisco, CA, United States) in accordance with the manufacturer’s instructions. To measure LPL activity, plasma total lipase activity and hepatic lipase activity were first determined by a LPL-mediated lipolysis reaction; this was performed by means of a free fatty acid (FFA) release assay kit [Wako kit# NEFA-HR(2), Japan], using TG-rich plasma from GPIHBP1 -deficient ( GPIHBP1 –/– ) mice as the lipolytic substrate ( Li et al, 2020 ; Shi et al, 2020 ). It should be noted that, for the hepatic lipase activity assay, the sample was pretreated with 1 M NaCl and incubated for 60 min at 4°C in order to inactivate LPL.…”

“…The wild-type LPL cDNA expression vector has been previously described ( Li et al, 2020 ; Shi et al, 2020 ) and was used here to generate the mutant [c.756T > G (p.Ile252Met)] expression vector by site-directed mutagenesis. The mutated site was verified by Sanger sequencing.…”