Identification and metabolic profiling of patients with lysosomal acid lipase deficiency

Pullinger, Clive R.; Stock, Eveline Oestreicher; Movsesyan, Irina; Malloy, Mary J.; Frost, Petter; Tripuraneni, Radhika; Quinn, Anthony G.; Ishida, Brian Y.; Schaefer, Ernst J.; Asztalos, Bela F.; Kane, John P.

doi:10.1016/j.jacl.2015.07.008

Cited by 34 publications

(28 citation statements)

References 27 publications

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“…HL has primarily triglyceride lipase activity and acts on all lipoprotein classes, while EL hydrolyzes phospholipids primarily on HDL. In contrast to these lipases, we have not found significantly altered HDL subpopulation profile in patients with lysosomal acid-lipase (LAL) deficiency despite having significantly decreased HDL-C levels (29). It is worth noting that so far, neither EL- nor LAL-deficiency has been found to be significantly associated with CVD risk.…”

Section: Discussionmentioning

confidence: 71%

High-density lipoprotein subpopulation profiles in lipoprotein lipase and hepatic lipase deficiency

et al. 2016

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Background and aims Our aim was to gain insight into the role that lipoprotein lipase (LPL) and hepatic lipase (HL) plays in HDL metabolism and to better understand LPL- and HL-deficiency states. Methods We examined the apolipoprotein (apo) A-I-, A-II-, A-IV-, C-I-, C-III-, and E-containing HDL subpopulation profiles, assessed by native 2-dimensional gel-electrophoresis and immunoblotting, in 6 homozygous and 11 heterozygous LPL-deficient, 6 homozygous and 4 heterozygous HL-deficient, and 50 control subjects. Results LPL-deficient homozygotes had marked hypertriglyceridemia and significant decreases in LDL-C, HDL-C, and apoA-I. Their apoA-I-containing HDL subpopulation profile was shifted toward small HDL particles compared to controls. HL-deficient homozygotes had moderate hypertriglyceridemia, modest increases in LDL-C and HDL-C level, but normal apoA-I concentration. HL-deficient homozygotes had a unique distribution of apoA-I-containing HDL particles. The normally apoA-I:A-II, intermediate-size (α-2 and α-3) particles were significantly decreased, while the normally apoA-I only (very large α-1, small α-4, and very small preβ-1) particles were significantly elevated. In contrast to control subjects, the very large α-1 particles of HL-deficient homozygotes were enriched in apoA-II. Homozygous LPL- and HL-deficient subjects also had abnormal distributions of apo C-I, C-III, and E in HDL particles. Values for all measured parameters in LPL- and HL-deficient heterozygotes were closer to values measured in controls than in homozygotes. Conclusions Our data are consistent with the concept that LPL is important for the maturation of small discoidal HDL particles into large spherical HDL particles, while HL is important for HDL remodeling of very large HDL particles into intermediate-size HDL particles.

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Section: Discussionmentioning

confidence: 71%

High-density lipoprotein subpopulation profiles in lipoprotein lipase and hepatic lipase deficiency

et al. 2016

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“…15 From UCSF, genomic DNA was isolated as previously described. 16 Preparation of genomic DNA for sequencing has been described in detail previously. 15,17 In brief, samples were enriched for genomic areas in accordance with our ''Lipid-Seq'' panel, which captures 73 genes (all exons, and 50 bases into the intron from each splice junction) and 185 SNPs associated with dyslipidemia and other metabolic disorders.…”

Section: Dna Preparation and Targeted Sequencingmentioning

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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“…A genetic study by the Cardiovascular Research Institute of University of California used next-generation sequencing to look for the presence of known pathogenic mutations in 1357 subjects identified with various phenotypes of dyslipidaemia, including low HDL-C 13. This study was based on a subset of the Genomic Resource in Arteriosclerosis and Metabolic Disease study (n=27 000), which included children.…”

Section: Discussionmentioning

confidence: 99%

Identification of rare diseases by screening a population selected on the basis of routine pathology results—the PATHFINDER project: lysosomal acid lipase/cholesteryl ester storage disease substudy

Reynolds¹,

Mewies²,

Hamilton³

et al. 2018

J Clin Pathol

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Identification and metabolic profiling of patients with lysosomal acid lipase deficiency

Cited by 34 publications

References 27 publications

High-density lipoprotein subpopulation profiles in lipoprotein lipase and hepatic lipase deficiency

High-density lipoprotein subpopulation profiles in lipoprotein lipase and hepatic lipase deficiency

Severe hypertriglyceridemia is primarily polygenic

Identification of rare diseases by screening a population selected on the basis of routine pathology results—the PATHFINDER project: lysosomal acid lipase/cholesteryl ester storage disease substudy

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