Clinical and biochemical features of different molecular etiologies of familial chylomicronemia

Hegele, Robert A.; Berberich, Amanda J.; Ban, Matthew R.; Wang, Jian; Digenio, Andrés; Alexander, Veronica J.; D’Erasmo, Laura; Arca, Marcello; Jones, Alan; Bruckert, Éric; Stroes, Erik S.G.; Bergeron, Jean; Civeira, Fernando; Witztum, Joseph L.; Gaudet, Daniel

doi:10.1016/j.jacl.2018.03.093

Cited by 118 publications

(114 citation statements)

References 45 publications

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“…Amongst 14 individuals who consented to genetic testing, we found similar complex genetic influences as we observed previously in other severe HTG cohorts [12]: 0/14 had bi-allelic large-effect mutations in LPL or related genes [57] whilst 2/14 had heterozygous mutations in these genes (APOA5 p.G185C and LPL p.G300R) and 7/14 had a polygenic risk score (PRS) for HTG in the top 80th percentile or higher. A high PRS for HTG is the most common genetic profile seen in adults with TG >10 mmol L À1 [49].…”

Section: Resultssupporting

confidence: 80%

Conservative management in hypertriglyceridemia‐associated pancreatitis

et al. 2019

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Background Severe hypertriglyceridemia (serum triglyceride >10 mmol L−1) is implicated in ~9% of acute pancreatitis cases. Certain guidelines list severe hypertriglyceridemia as an indication for plasmapheresis. Objective We assembled the natural trajectory of triglyceride levels in patients with acute pancreatitis due to severe hypertriglyceridemia who were managed conservatively without plasmapheresis to evaluate the effectiveness of this approach. Methods A retrospective chart review was performed on 22 hospital admissions for acute pancreatitis episodes considered to be caused by severe hypertriglyceridemia. Patients were managed supportively, with cessation of oral intake (NPO) and intravenous hydration. Insulin infusion was used in 12 patients to manage concurrent hyperglycaemia. Results Triglyceride levels for the group were evaluated using a mixed‐effects model. The average triglyceride level fell from 45.4 mmol L−1 on presentation to 13.3 mmol L−1 within 48 h, corresponding to a mean 69.8% decrease. Regression analysis showed a triglyceride half‐life of 30.6 h. Findings were similar for NPO‐only and insulin infusion subgroups. Conclusion Patients with severe hypertriglyceridemia and acute pancreatitis can be conservatively managed safely and effectively without plasmapheresis.

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Section: Resultssupporting

confidence: 80%

Conservative management in hypertriglyceridemia‐associated pancreatitis

et al. 2019

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“…In addition, 84.2% of MCS patients achieved at least once a triglyceride level <500 mg/dL, whereas this cutoff value was reached by only 33.3% of FCS patients. In agreement with previous studies, 39 we found that LPL-driven FCS was the genotype most resistant to therapies. In fact, while all non-LPL FCS patients experienced, at least once, a triglyceride value <500 mg/dL during follow-up, this result was achieved in only 20% of LPL FCS.…”

Section: Translational Sciences -Alsupporting

confidence: 93%

Spectrum of Mutations and Long-Term Clinical Outcomes in Genetic Chylomicronemia Syndromes

D’Erasmo

Costanzo

Cassandra

et al. 2019

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OBJECTIVE: Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS) are the prototypes of monogenic and polygenic conditions underlying genetically based severe hypertriglyceridemia. These conditions have been only partially investigated so that a systematic comparison of their characteristics remains incomplete. We aim to compare genetic profiles and clinical outcomes in FCS and MCS. APPROACH AND RESULTS:Thirty-two patients with severe hypertriglyceridemia (triglyceride >1000 mg/dL despite lipid-lowering treatments with or without history of acute pancreatitis) were enrolled. Rare and common variants were screened using a panel of 18 triglyceride-raising genes, including the canonical LPL, APOC2, APOA5, GP1HBP1, and LMF1. Clinical information was collected retrospectively for a median period of 44 months. Across the study population, 37.5% were classified as FCS due to the presence of biallelic, rare mutations and 59.4% as MCS due to homozygosity for nonpathogenic or heterozygosity for pathogenic variants in canonical genes, as well as for rare and low frequency variants in noncanonical genes. As compared with MCS, FCS patients showed a lower age of hypertriglyceridemia onset, higher levels of on-treatment triglycerides, and 3-fold higher incidence rate of acute pancreatitis. CONCLUSIONS:Our data indicate that the genetic architecture and natural history of FCS and MCS are different. FCS expressed the most severe clinical phenotype as determined by resistance to triglyceride-lowering medications and higher incidence of acute pancreatitis episodes. The most common genetic abnormality underlying FCS was represented by biallelic mutations in LPL while APOA5 variants, in combination with high rare polygenic burden, were the most frequent genotype of MCS. VISUAL OVERVIEW:An online visual overview is available for this article.

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“…differences depending on the underlying genetic basis, such as in the case of patients with FCS who have biallelic LPL variants vs those with biallelic variants in the four minor canonical genes. 44 Another tendency when dealing with quantitative traits is to assume that more extreme deviations reflect stronger genetic components. This has been observed in FH, where patients with higher LDL cholesterol levels were more likely to have monogenic FH.…”

Section: Discussionmentioning

confidence: 99%

Severe hypertriglyceridemia is primarily polygenic

Dron

Wang

Cao

et al. 2019

Journal of Clinical Lipidology

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BACKGROUND: Hypertriglyceridemia (HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinants of HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenic and polygenic, is thus incomplete.OBJECTIVE: The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinants and molecular contributors.METHODS: We concurrently assessed rare and common variants in two independent cohorts of 251 and 312 Caucasian patients with severe HTG. DNA was subjected to targeted next-generation sequencing of 73 genes and 185 SNPs associated with dyslipidemia. LPL, APOC2, GPIHBP1, APOA5, and LMF1 genes were screened for rare variants, and a polygenic risk score was used to assess the accumulation of common variants.RESULTS: As there were no significant differences in the prevalence of genetic determinants between cohorts, data were combined for all 563 patients: 1.1% had biallelic (homozygous or compound heterozygous) rare variants, 14.4% had heterozygous rare variants, 32.0% had an extreme accumulation of common variants (ie, high polygenic risk), and 52.6% remained genetically undefined. Patients with HTG were 5.77 times (95% CI [4.26-7.82]; P , .0001) more likely to carry one of these types of genetic susceptibility compared with controls.CONCLUSIONS: We report the most in-depth, systematic evaluation of genetic determinants of severe HTG to date. The predominant feature was an extreme accumulation of common variants (high polygenic risk score), whereas a substantial proportion of patients also carried heterozygous rare

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Clinical and biochemical features of different molecular etiologies of familial chylomicronemia

Abstract: Thus, LPL FCS and non-LPL FCS are largely phenotypically similar. However, LPL FCS patients have lower postheparin LPL activity and a trend toward higher TGs, whereas low-density lipoprotein cholesterol was higher in non-LPL-FCS patients.

Cited by 118 publications

References 45 publications

Conservative management in hypertriglyceridemia‐associated pancreatitis

Conservative management in hypertriglyceridemia‐associated pancreatitis

Spectrum of Mutations and Long-Term Clinical Outcomes in Genetic Chylomicronemia Syndromes

Severe hypertriglyceridemia is primarily polygenic

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