Clinical and Biochemical Assessments of LPL FCS and non-LPL FCS Genes

APRIL 30, 2018
Krista Rossi
A recent study published by the Journal of Clinical Lipidology was highlighted at the National Lipid Association’s (NLA) Scientific Sessions in Las Vegas this past weekend.

The study evaluated the the clinical and biochemical features of different molecular etiologies of familial chylomicronemia syndrome (FCS), and among the findings, the lipoprotein lipase (LPL) gene was found to play a significant role in FCS. Specifically, LPL FCS and non-LPL FCS were discovered to be the most prominent mutations in genes with similarities and differences appearing in both mutations.

On the biochemical level, FCS is an ultra-rare phenotype that is usually caused by biallelic mutations in the LPL gene encoding lipoprotein lipase, or less often in APOC2, APOA5, LMF1, or GPIHBP1 genes encoding cofactors or interacting proteins. Consequently, recurrent and potentially fatal acute pancreatitis (AP) are the most severe clinical consequences of FCS.

In order to avoid such episodes, patients are restricted to extremely low-fat diets (≤20 g daily), abstinence from alcohol, and simple-carbohydrate intakes.1

An evaluation of the baseline phenotypes among FCS participants who followed a restrictive diet of ≤20 g of fat daily in a phase 3 randomized placebo-controlled trial of volanesorsen served as the trial’s primary aim, and 52 FCS patients were enrolled for 52 weeks. Participants were randomized 1:1 to receive either volanesorsen 300 mg via subcutaneous administration or placebo injections. A percent change in triglyceride (TG) levels at 13 weeks was the primary outcome.
 
Methods used in the study included the assessment of baseline clinical, fasting, and postfat load metabolic markers. Fasting plasma was used to performs baseline lipids, lipoproteins, apolipoproteins, and metabolic assays. Fasting venous blood samples were taken 10 minutes preintravenous and postintravenous infusion of heparin (50 U/kg), and total postheparin lipolytic activity was determined. A subset of markers was examined 4 hours after liquid-formulated high-fat test meal (4800 kJ, 130 g of fat, 17 g of protein and 21 g of carbohydrate).

In addition, targeted next-generation DNA sequencing plus custom bioinformatics was used to genotype subjects. Genomic DNA was isolated from whole blood, and target candidate genes in lipid metabolism were generated genomic libraries of indexed and pooled patient samples. Coding regions, >150 base pairs (bp) at intron-exon boundaries, and standards of the American College of Medical Genetics were included as measures in assessing the potential pathogenicity of identified mutations.

Subjects with biallelic pathogenic mutations in LPL were classified as “LPL-FCS,” while those with pathogenic mutations in the other genes were classified as “non-LPL-FCS.” Simple heterozygotes for loss-of-function mutations were excluded from the analysis.

According to the results, 41 participants, respectively, had biallelic LPL gene mutations (LPL-FCS patients): 82%, 7%, and 11% were missense, nonsense, and splicing variants. Eleven participants, respectively, had non-LPL-FCS; 2 had mutations in APOA5, 5 in GPIHBP1, and 1 each in LMF1 and APOC2 genes. Additionally, 2 other individuals were double heterozygotes, each with 1 normal LPL allele.

Additionally, extremely high triglycerides (TGs) and chylomicrons, but very low levels of other lipoproteins, were found in all participants. Non-LPL-FCS subjects, when compared with LPL-FCS subjects, were very similar for most traits but had significantly higher postheparin LPL activity; higher 4-hour postprandial insulin and C-peptide levels; and higher low-density lipoprotein cholesterol levels. Compared to those with LPL-FCS, non-LPL-FCS subjects also showed nonsignificant trends toward lower levels of total and chylomicron TGs, lower 4-hour postprandial chylomicron TG levels, and higher very-low-density lipoprotein TG levels.
 
Based off of its results, it was concluded that LPL FCS and non-LPL FCS genes are meaningfully phenotypically similar. However, LPL FCS patients have lower postheparin LPL activity and a trend toward higher TGs, while, conversely, low-density lipoprotein cholesterol is higher in non-LPL-FCS patients.
  
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