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      Genetic Variants Associated with Gestational Hypertriglyceridemia and Pancreatitis

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          Abstract

          Severe hypertriglyceridemia is a well-known cause of pancreatitis. Usually, there is a moderate increase in plasma triglyceride level during pregnancy. Additionally, certain pre-existing genetic traits may render a pregnant woman susceptible to development of severe hypertriglyceridemia and pancreatitis, especially in the third trimester. To elucidate the underlying mechanism of gestational hypertriglyceridemic pancreatitis, we undertook DNA mutation analysis of the lipoprotein lipase ( LPL), apolipoprotein C2 ( APOC2), apolipoprotein A5 ( APOA5), lipase maturation factor 1 ( LMF1), and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 ( GPIHBP1) genes in five unrelated pregnant Chinese women with severe hypertriglyceridemia and pancreatitis. DNA sequencing showed that three out of five patients had the same homozygous variation, p.G185C, in APOA5 gene. One patient had a compound heterozygous mutation, p.A98T and p.L279V, in LPL gene. Another patient had a compound heterozygous mutation, p.A98T & p.C14F in LPL and GPIHBP1 gene, respectively. No mutations were seen in APOC2 or LMF1 genes. All patients were diagnosed with partial LPL deficiency in non-pregnant state. As revealed in our study, genetic variants appear to play an important role in the development of severe gestational hypertriglyceridemia, and, p.G185C mutation in APOA5 gene appears to be the most common variant implicated in the Chinese population. Antenatal screening for mutations in susceptible women, combined with subsequent interventions may be invaluable in the prevention of potentially life threatening gestational hypertriglyceridemia-induced pancreatitis.

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          Most cited references38

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          An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.

          Comparison of genomic DNA sequences from human and mouse revealed a new apolipoprotein (APO) gene (APOAV) located proximal to the well-characterized APOAI/CIII/AIV gene cluster on human 11q23. Mice expressing a human APOAV transgene showed a decrease in plasma triglyceride concentrations to one-third of those in control mice; conversely, knockout mice lacking Apoav had four times as much plasma triglycerides as controls. In humans, single nucleotide polymorphisms (SNPs) across the APOAV locus were found to be significantly associated with plasma triglyceride levels in two independent studies. These findings indicate that APOAV is an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease.
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            Hypertriglyceridemic pancreatitis: presentation and management.

            Hypertriglyceridemia (HTG) is reported to cause 1-4% of acute pancreatitis (AP) episodes. HTG is also implicated in more than half of gestational pancreatitis cases. Disorders of lipoprotein metabolism are conventionally divided into primary (genetic) and secondary causes, including diabetes, hypothyroidism, and obesity. Serum triglyceride (TG) levels above 1,000 mg/dl are usually considered necessary to ascribe causation for AP. The mechanism for hypertriglyceridemic pancreatitis (HTGP) is postulated to involve hydrolysis of TG by pancreatic lipase and release of free fatty acids that induce free radical damage. Multiple small studies on HTGP management have evaluated the use of insulin, heparin, or both. Many series have also reported use of apheresis to reduce TG levels. Subsequent control of HTG with dietary restrictions, antihyperlipidemic agents, and even regular apheresis has been shown anecdotally in case series to prevent future episodes of AP. However, large multicenter studies are needed to optimize future management guidelines for patients with HTGP.
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              Lipoprotein lipase: genetics, lipid uptake, and regulation.

              Lipoprotein lipase (LPL) regulates the plasma levels of triglyceride and HDL. Three aspects are reviewed. 1) Clinical implications of human LPL gene variations: common mutations and their effects on plasma lipids and coronary heart disease are discussed. 2) LPL actions in the nervous system, liver, and heart: the discussion focuses on LPL and tissue lipid uptake. 3) LPL gene regulation: the LPL promoter and its regulatory elements are described.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                16 June 2015
                2015
                : 10
                : 6
                : e0129488
                Affiliations
                [1 ]The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
                [2 ]Ren-Ji Study, Wenzhou Medical University, Wenzhou, China
                Technische Universität München, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RJ MTZ ZMH. Performed the experiments: SLX TZC. Analyzed the data: XLH. Contributed reagents/materials/analysis tools: SLX. Wrote the paper: CC SLX.

                Article
                PONE-D-14-32438
                10.1371/journal.pone.0129488
                4469420
                26079787
                042e12fb-7bd8-4a8d-ae0d-a1dede901847
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 20 July 2014
                : 8 May 2015
                Page count
                Figures: 4, Tables: 1, Pages: 11
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper.

                Uncategorized
                Uncategorized

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