Identification and functional characterization of a novel heterozygous missense variant in the <i>LPL</i> associated with recurrent hypertriglyceridemia‐induced acute pancreatitis in pregnancy

Shi, Xiaolei; Yang, Qi; Pu, Na; Li, Xiaoyao; Chen, Wei‐Wei; Zhou, Jing; Li, Gang; Tong, Zhihui; Férec, Claude; Cooper, David Neil; Chen, Jianmin; Li, Weiqin

doi:10.1002/mgg3.1048

Cited by 11 publications

(11 citation statements)

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“…Third, most of the HTG-associated rare LPL missense variants reported to date result in a complete or >90% functional loss of the affected allele, with this functional loss often being linked to upstream effects on protein synthesis, transport and secretion rather than to an isolated effect on enzyme activity ( Rouis et al, 1996 ; Murano et al, 2005 ; Yu et al, 2006 ; Liu et al, 2016 ; Shi et al, 2020 ). To date, we are aware of only one rare LPL missense variant in the literature (i.e., a homozygous p.Ala203Thr variant found in a LPL-deficient patient) that specifically disrupted enzyme activity ( Beg et al, 1990 ).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

Section: Methodsmentioning

confidence: 99%

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

Yang

et al. 2021

Front. Genet.

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Yang

et al. 2021

Front. Genet.

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“…Factors increasing the risk of sHTG in pregnancy include diabetes with poor metabolic control, metabolic syndrome and obesity, alcoholism and drugs (for example, corticosteroids, beta-blockers and antipsychotics). 36 Most cases of severe gestational HTG are associated with familial chylomicronaemia syndrome (FCS) or familial HTG 37 and rare mutations in the LPL, APO E, APO C2, and APO A5 genes, which cause chylomicronaemia in pregnancy. [37][38][39] Table 2 shows these familial disorders and the possible genes involved.…”

Section: Hypertriglyceridaemia and Hypercholesterolaemia In Pregnancymentioning

confidence: 99%

Hyperlipidaemia and severe hypertriglyceridaemia in pregnancy

Bashir

Navti

Ahmed

et al. 2023

The Obstetric & Gynaecologis

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Lipid and triglyceride levels increase in pregnancy and do not pose problems for most women. However, pregnancy-specific factors and genetic aberrations, especially mutations, may result in supraphysiological hypercholesterolaemia (HC) and severe hypertriglyceridaemia (sHTG). HC and sHTG are associated with complications in pregnancy, including acute pancreatitis, hyperviscosity syndrome and pre-eclampsia. Abnormally high levels of lipids and triglycerides also affect fetal growth and the onset of gestational diabetes. The clinical presentation and diagnosis of HC and sHTG are varied. Management options include lifestyle and dietary restriction/ modification, omega-3, bile-acid sequestrants, fenofibrate, statins and plasmapheresis. Learning objectivesTo understand the physiological changes that occur in lipids in pregnancy and how these are modulated. To appreciate the importance of severe HC and HTG in pregnancy, including their effects on maternal morbidity and mortality. To understand the various approaches to management and the importance of multidisciplinary management. Ethical issuesShould every woman be screened for HTG and HC during pregnancy? How safe are statins and other treatments for lipid disorders in pregnancy? Should women with very severe HTG be discouraged from getting pregnant?

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“…Importantly estrogen therapy is often not discontinued by clinicians in women with a history of HTG-induced pancreatitis (84). Endogenous hyperestrogenemia may cause severe gestational HTG and pancreatitis in women with HTG in the second or third trimesters of pregnancy, where it can be difficult to control, particularly in subjects with monogenic CS or with other aggravating factors such as diabetes (85,86).…”

Section: Estrogen Estrogen Receptor Agonists and Pregnancymentioning

confidence: 99%

A Comprehensive Update on the Chylomicronemia Syndrome

Goldberg

Chait

2020

Front. Endocrinol.

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The chylomicronemia syndrome is characterized by severe hypertriglyceridemia and fasting chylomicronemia and predisposes affected individuals to acute pancreatitis. When due to very rare monogenic mutations in the genes encoding the enzyme, lipoprotein lipase, or its regulators, APOC2, APOA5, GPIHBP1, and LMF1, it is referred to as the familial chylomicronemia syndrome. Much more frequently, the chylomicronemia syndrome results from a cluster of minor genetic variants causing polygenic hypertriglyceridemia, which is exacerbated by conditions or medications which increase triglyceride levels beyond the saturation point of triglyceride removal systems. This situation is termed the multifactorial chylomicronemia syndrome. These aggravating factors include common conditions such as uncontrolled diabetes, overweight and obesity, alcohol excess, chronic kidney disease and pregnancy and several medications, including diuretics, non-selective beta blockers, estrogenic compounds, corticosteroids, protease inhibitors, immunosuppressives, antipsychotics, antidepressants, retinoids, L-asparaginase, and propofol. A third uncommon cause of the chylomicronemia syndrome is familial forms of partial lipodystrophy. Development of pancreatitis is the most feared complication of the chylomicronemia syndrome, but the risk of cardiovascular disease as well as non-alcoholic steatohepatitis is also increased. Treatment consists of dietary fat restriction and weight reduction combined with the use of triglyceride lowering medications such as fibrates, omega 3 fatty acids and niacin. Effective management of aggravating factors such as improving diabetes control, discontinuing alcohol and replacing or reducing the dose of medications that raise triglyceride levels is essential. Importantly, many if not most cases of the chylomicronemia syndrome can be prevented by effective identification of polygenic hypertriglyceridemia in people with conditions that increase its likelihood or before starting medications that may increase triglyceride levels. Several new pharmacotherapeutic agents are being tested that are likely to considerably improve treatment of hypertriglyceridemia in people at risk.

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Identification and functional characterization of a novel heterozygous missense variant in the LPL associated with recurrent hypertriglyceridemia‐induced acute pancreatitis in pregnancy

Cited by 11 publications

References 41 publications

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

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

Hyperlipidaemia and severe hypertriglyceridaemia in pregnancy

A Comprehensive Update on the Chylomicronemia Syndrome

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