Lipoprotein Lipase: Structure, Function, and Genetic Variation

Genes, Journal Year: 2025, Volume and Issue: 16(1), P. 55 - 55

Published: Jan. 5, 2025

Biallelic rare pathogenic loss-of-function (LOF) variants in lipoprotein lipase (LPL) cause familial chylomicronemia syndrome (FCS). Heterozygosity for these same is associated with a highly variable plasma triglyceride (TG) phenotype ranging from normal to severe hypertriglyceridemia (HTG), longitudinal variation severity seen often given carrier. Here, we provide an updated overview of genetic LPL the context HTG, focus on disease-causing and/or disease-associated variants. We curated list 300 discovered LPL, as well exon-by-exon breakdown gene and protein, highlighting impact various functional residues domains protein. also unknown or uncertain significance, many which may be upgraded pathogenic/likely classification should additional case segregation data reported. Finally, review association between benign/likely benign are common polymorphisms, TG phenotype.

Language: Английский

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A Comprehensive Review of the Genetics of Dyslipidemias and Risk of Atherosclerotic Cardiovascular Disease

Nutrients, Journal Year: 2025, Volume and Issue: 17(4), P. 659 - 659

Published: Feb. 12, 2025

Dyslipidemias are often diagnosed based on an individual's lipid panel that may or not include Lp(a) apoB. But these values alone omit key information can underestimate risk and misdiagnose disease, which leads to imprecise medical therapies reduce efficacy with unnecessary adverse events. For example, knowing whether dyslipidemia is monogenic granularly inform create opportunities for precision therapeutics. This review explores the canonical non-canonical causes of dyslipidemias how they impact atherosclerotic cardiovascular disease (ASCVD) risk. emphasizes multitude genetic cause primary hypercholesterolemia, hypertriglyceridemia, low elevated high-density lipoprotein (HDL)-cholesterol levels. Within each sections, this will explore evidence linking conditions ASCVD Where applicable, summarize approved a particular condition.

Language: Английский

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Understanding Hypertriglyceridemia: Integrating Genetic Insights

Genes, Journal Year: 2024, Volume and Issue: 15(2), P. 190 - 190

Published: Jan. 30, 2024

Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with increased risk of acute pancreatitis and cardiovascular diseases such as coronary artery disease. Its phenotype expression widely heterogeneous heavily influenced conditions obesity, alcohol consumption, or syndromes. Looking into the genetic underpinnings hypertriglyceridemia, this review focuses on variants in LPL, APOA5, APOC2, GPIHBP1 LMF1 triglyceride-regulating genes reportedly abnormal transcription translation proteins participating triglyceride-rich lipoprotein metabolism. resulting from abnormalities can be categorized monogenic polygenic. Monogenic also known familial chylomicronemia syndrome, caused homozygous compound heterozygous pathogenic five canonical genes. Polygenic multifactorial syndrome extreme cases variable penetrance affecting genes, a set common non-pathogenic (polymorphisms, using former nomenclature) well-established association triglyceride levels. We further address recent progress triglyceride-lowering treatments. Understanding basis hypertriglyceridemia opens new translational opportunities scope screening development novel therapies.

Language: Английский

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Interaction Between Primary Hyperlipidemias and Type 2 Diabetes: Therapeutic Implications

Diabetes Therapy, Journal Year: 2024, Volume and Issue: 15(9), P. 1979 - 2000

Published: July 30, 2024

There is a gap of knowledge about the clinical and pathophysiological implications resulting from interaction between primary hyperlipidemias type 2 diabetes (T2D). Most existing evidence comes sub-analyses cohorts; scant information derives randomized trials. The expected T2D in patients with an escalation their already high cardiovascular risk. need to accurately identify this dual burden adequately prescribe lipid-lowering therapies, current advancements newer therapeutic options. This review provides update on interactions hyperlipidemias, such as familial combined hyperlipidemia, hypercholesterolemia, multifactorial chylomicronemia, lipoprotein (a), diabetes.

Language: Английский

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Variability of longitudinal triglyceride phenotype in patients heterozygous for pathogenic APOA5 variants

Journal of clinical lipidology, Journal Year: 2023, Volume and Issue: 17(5), P. 659 - 665

Published: Aug. 7, 2023

Language: Английский

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What is the phenotype of heterozygous lipoprotein lipase deficiency?

Current Opinion in Lipidology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

Genetic testing of patients with severe hypertriglyceridemia often identifies a single heterozygous pathogenic variant in the LPL gene. The complex and variable phenotype associated this genotype is topic review. Previous research showed that heterozygosity for lipoprotein lipase deficiency reduced but post heparin lipolytic activity alongside inconsistent plasma lipid phenotypes ranging from normal to mild-to-moderate hypertriglyceridemia. Recent confirms extends these observations, showing individual can express highly over time, depending on presence secondary factors. About 10% (range 8-20%) or multifactorial chylomicronemia syndrome are rare variant, clinically relevant minority has recalcitrant sustained Heterozygosity predisposes hypertriglyceridemia, which sometimes factors, typically quite responsive routine interventions such as diet, lifestyle existing lipid-lowering therapies. However, many heterozygotes variants have completely lipids.

Language: Английский

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Familial chylomicronemia syndrome: an expert opinion statement from the National Lipid Association

Journal of clinical lipidology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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Small Nerve Fibre Damage and Cardiac Autonomic Dysfunction in Patients with Hypertriglyceridaemia

Atherosclerosis, Journal Year: 2025, Volume and Issue: unknown, P. 119186 - 119186

Published: April 1, 2025

Language: Английский

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Genetic variation in apolipoprotein A-V in hypertriglyceridemia

Current Opinion in Lipidology, Journal Year: 2023, Volume and Issue: 35(2), P. 66 - 77

Published: Dec. 20, 2023

While biallelic rare APOA5 pathogenic loss-of-function (LOF) variants cause familial chylomicronemia syndrome, heterozygosity for such is associated with highly variable triglyceride phenotypes ranging from normal to severe hypertriglyceridemia, often in the same individual at different time points. Here we provide an updated overview of hypertriglyceridemia.

Language: Английский

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Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype–phenotype relationship for variants reported to date

Lipids in Health and Disease, Journal Year: 2023, Volume and Issue: 22(1)

Published: Aug. 11, 2023

Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Homozygous or compound heterozygous LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), whereas simple are associated with hypertriglyceridemia (HTG) and HTG-related disorders. frameshift coding sequence usually complete functional loss of affected allele, thereby allowing exploration impact different levels function in human disease.All exons flanking intronic regions were Sanger sequenced patients acute pancreatitis (HTG-AP) HTG-AP pregnancy. Previously reported collated from Human Gene Mutation Database through PubMed keyword searching. Original reports manually evaluated following information: zygosity status variant, plasma activity variant carrier, disease referred genetic analysis, patient's age at history. SpliceAI was employed to predict potential on splicing.Two novel rare identified, 53 known collated. Of 51 informative zygosity, 30 heterozygotes, 12 homozygotes, 9 heterozygotes. Careful evaluation 55 respect their clinical data generated several interesting findings. First, we conclude that 6-7% residual could significantly delay onset FCS reduce prevalence FCS-associated syndromes. Second, a large majority completely disrupt gene "frameshift" nature, small fraction these may act wholly partly as "in-frame" variants, leading generation protein products some function. Third, identified two candidate retain based genotype-phenotype correlation SpliceAI-predicted data.This study yielded new insights into relationship it pertains variants.

Language: Английский

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