Molecular analysis of three known and one novel LPL variants in patients with type I hyperlipoproteinemia

Caddeo, Andrea; Mancina, Rosellina Margherita; Pirazzi, Carlo; Russo, Cristina; Sasidharan, Kavitha; Sandstedt, Joakim; Maurotti, Samantha; Montalcini, Tiziana; Pujia, Arturo; Leren, Trond P.; Romeo, Stefano; Pingitore, Piero

doi:10.1016/j.numecd.2017.11.003

Cited by 14 publications

(25 citation statements)

References 30 publications

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“…The ANGPTL4 variant was detected in nine cases (No. 3,5,7,(11)(12)(13)16,17,23). In the ANGPTL8 gene, p.R59W was detected in nine cases.…”

Section: Discussionmentioning

confidence: 98%

“…Accepted for publication: January 8, 2020 Published online: February 29, 2020 most of which excluded cases with obesity, diabetes, and alcohol consumption and focused on single gene abnormalities 5,26,27) . However, the majority of patients with severe hypertriglyceridemia encountered in the clinic have at least one of these risk factors.…”

Section: Advance Publication Journal Of Atherosclerosis and Thrombosismentioning

confidence: 99%

“…Defects in LPL, APOA5, APOC2, GPI-HBP1, and LMF1 are closely associated with chylomicronemia 3,4) . In addition, tribbles homolog1 (TRIB1), carbohydrate response element-binding protein [ChREBP (MLXIPL)], and glucokinase regulator (GCKR) are all expressed in the liver and contribute to hepatic lipogenesis 5) . TRIB1 upregulates lipogenic gene expression via the indirect regulation of C/EBP , while ChREBP directly binds to lipogenic gene promoters.…”

Section: Introductionmentioning

confidence: 99%

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Variants of Lipid-Related Genes in Adult Japanese Patients with Severe Hypertriglyceridemia

Matsunaga

Nagashima

Yamagishi

et al. 2020

JAT

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Hypertriglyceridemia is a type of dyslipidemia that contributes to atherosclerosis and coronary heart disease. Variants in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), apolipoprotein AV (APOA5), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1 (LMF1), and glucokinase regulator (GCKR) are responsible for hypertriglyceridemia. We investigated the molecular basis of severe hypertriglyceridemia in adult patients referred to the Clinical Laboratory at Fukuoka University Hospital. Methods: Twenty-three adult patients with severe hypertriglyceridemia (1,000 mg/dL, 11.29 mmol/L) were selected. The coding regions of candidate genes were sequenced by next-generation sequencing. Forty-nine genes reportedly associated with hypertriglyceridemia were analyzed. Results: In the 23 patients, we detected 70 variants: 28 rare and 42 common ones. Among the 28 rare variants with 1% allele frequency, p.I4533L in APOB, p.M490I in MLXIPL, p.L152M in NCAN, and p.S264T in TIMD4 were novel. We did not observe single gene homozygous or compound heterozygous disease-causing rare variants in any of the 23 hypertriglyceridemia cases. However, in silico algorithms and previous reports indicated that five rare variants, APOA5 (p.T184S), GCKR (c.354 1G A), LMF1 (p.G410R), and LRP1 (p.G813R; p.R2173Q), and seven common variants, APOA5 (pG185C), APOE (p.C130R; p.E262K/p.E263K), GCKR (p.V103M), GPIHBP1 (p.C14F), LRP1 (p.Y4054F), and MLXIPL (p.Q241H), can cause hypertriglyceridemia. However, all five disease-causing rare variants detected in this study were heterozygous. Conclusions: The prevalence of disease-causing rare variants in candidate genes in severe hypertriglyceridemia patients was low. The major causes of severe hypertriglyceridemia were not single gene abnormalities, but involved multiple gene variations and environmental factors. ciency, thyroid disease, and chemotherapy. Plasma TG is largely contained in TG-rich lipoproteins, such as very low-density lipoprotein (VLDL) and chylomicron particles. Lipoprotein lipase (LPL) is a critical enzyme in determining plasma triglyceride levels and LPL variants can result in severe hypertriglyceridemia. Moreover, apoprotein (apo)A-V, apoC-II, glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1) are also co-factors involved in the activation, transportation, or matura-Copyright©2020 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

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“…The ANGPTL4 variant was detected in nine cases (No. 3,5,7,(11)(12)(13)16,17,23). In the ANGPTL8 gene, p.R59W was detected in nine cases.…”

Section: Discussionmentioning

confidence: 98%

Section: Advance Publication Journal Of Atherosclerosis and Thrombosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Variants of Lipid-Related Genes in Adult Japanese Patients with Severe Hypertriglyceridemia

Matsunaga

Nagashima

Yamagishi

et al. 2020

JAT

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“…Furthermore, some studies assumed the presence of HPLI without any consistent confirmation. [11][12][13] Preparative ultracentrifugation is considered the reference method to quantify low-density lipoprotein cholesterol (LDL-C) 14 and high-density lipoprotein cholesterol (HDL-C) specially in hypertriglyceridemic patients. 15 Preparative ultracentrifugation also allows the isolation of the plasma chylomicron-like and VLDL sub-fractions.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the chylomicron‐TG to VLDL‐TG ratio for type I hyperlipoproteinemia diagnostic

Rioja

Ariza

García‐Casares

et al. 2020

Eur J Clin Investigation

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Background: The aim of this study is to confirm the diagnostic performance of the Chylomicron to very low-density lipoproteins triglycerides (CM/VLDL-TG) ratio, the triglycerides to cholesterol ratio (TG/TC) and a dichotomic rule including the tryglycerides to apolipoprotein B (TG/APOB) ratio for the presence of Type I hyperlipoproteinemia (HPLI) in patients with severe hypertriglyceridemia (sHTG) that were at high risk for familial chylomicronemia syndrome (FCS). Methods: Two cohorts (derivation and validation) of patients with sHTG were included in the study. Anthropometric, clinical, biochemical and genetic data were obtained. The CM/VLDL-TG, TG/TC and TG/APOB ratios were calculated. Finally, a diagnostic performance study was developed to establish sensitivity, specificity and cutoffs by a ROC curve analysis in the derivation cohort as well as agreement and predictive values in the validation cohort. Results: Patients with FCS in both cohorts showed an earlier presence in pancreatitis, greater number of acute pancreatitis episodes and lower BMI. FCS patients also showed higher ratios of CM/VLDL-TG, TG/TC and TG/APOB ratios, whereas their HDL-C, LDL-C and APOB levels were lower than in non-FCS patients. Sensitivity and agreement were low for both the TG/TC and TG/APOB ratios, although predictive values were good. The CM/VLDL-TG ratio showed greatest sensitivity, specificity, agreement and predictive values for cutoff of 3.8 and 4.5.

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“…This time, child was given omega-3 fatty acid, fenofibrate and niacin along with low-fat diet. Genetic testing by exome sequencing confirmed homozygous c.644G > A (p.Gly215Glu) LPL pathogenic variant [2]. At 4 months follow-up, serum TG was maintained below 400 mg/dl, without recurrence of pancreatitis.…”

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confidence: 90%

White Serum – A Clue to Diagnosis of Acute Recurrent Pancreatitis

et al. 2020

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Molecular analysis of three known and one novel LPL variants in patients with type I hyperlipoproteinemia

Abstract: We characterized at the molecular level three known and one novel LPL variants causing type I hyperlipoproteinemia showing that all these variants are pathogenic.

Cited by 14 publications

References 30 publications

Variants of Lipid-Related Genes in Adult Japanese Patients with Severe Hypertriglyceridemia

Variants of Lipid-Related Genes in Adult Japanese Patients with Severe Hypertriglyceridemia

Evaluation of the chylomicron‐TG to VLDL‐TG ratio for type I hyperlipoproteinemia diagnostic

White Serum – A Clue to Diagnosis of Acute Recurrent Pancreatitis

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