Robert A Hegele1, Amanda J Berberich2, Matthew R Ban3, Jian Wang3, Andres Digenio4, Veronica J Alexander5, Laura D'Erasmo6, Marcello Arca6, Alan Jones7, Eric Bruckert8, Erik S Stroes9, Jean Bergeron10, Fernando Civeira11, Joseph L Witztum12, Daniel Gaudet13. 1. Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address: hegele@robarts.ca. 2. Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. 3. Robarts Research Institute, Western University, London, Ontario, Canada. 4. Akcea Therapeutics, Cambridge, MA, USA. 5. Ionis Pharmaceuticals, Carlsbad, CA, USA. 6. Department of Internal Medicine and Allied Sciences, Sapienza University of Rome, Rome, Italy. 7. Department of Clinical Biochemistry and Immunology, Heart of England NHS Foundation Trust, Birmingham, West Midlands, UK. 8. Endocrinologie Métabolisme et Prévention Cardiovasculaire, Institut E3M et IHU Cardiométabolique (ICAN), Hôpital Pitié Salpêtrière, Paris, France. 9. Department Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. 10. Départements de Médecine et de Biologie Médicale, Centre Hospitalier Universitaire de Québec-Université Laval, Québec, Canada. 11. Hospital Miguel Servet, IIS Aragon, CIBERCV, Universidad de Zaragoza, Spain. 12. University of California San Diego, La Jolla, CA, USA. 13. Lipidology Unit, Community Genomic Medicine Centre and ECOGENE-21, Department of Medicine, Université de Montréal, Saguenay, Québec, Canada.
Abstract
BACKGROUND:Familial chylomicronemia syndrome (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. OBJECTIVES: We evaluated baseline phenotypes among FCS participants in a phase 3 randomized placebo-controlled trial of volanesorsen (NCT02211209). METHODS:Baseline clinical, fasting, and postfat load metabolic markers were assessed. Targeted next-generation DNA sequencing plus custom bioinformatics was used to genotype subjects. RESULTS: Among 52 FCS individuals, 41 had biallelic LPL gene mutations (LPL-FCS patients): 82%, 7%, and 11% were missense, nonsense, and splicing variants, respectively. Eleven individuals had non-LPL-FCS; 2 had mutations in APOA5, 5 in GPIHBP1, and 1 each in LMF1 and APOC2 genes, respectively. Two other individuals were double heterozygotes, each with 1 normal LPL allele. All subjects had extremely high triglycerides (TGs) and chylomicrons, but very low levels of other lipoproteins. Compared with LPL-FCS individuals, non-LPL-FCS individuals 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. In non-LPL-FCS individuals compared to those with LPL-FCS, there were also 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. CONCLUSION: 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.
RCT Entities:
BACKGROUND:Familial chylomicronemia syndrome (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. OBJECTIVES: We evaluated baseline phenotypes among FCS participants in a phase 3 randomized placebo-controlled trial of volanesorsen (NCT02211209). METHODS: Baseline clinical, fasting, and postfat load metabolic markers were assessed. Targeted next-generation DNA sequencing plus custom bioinformatics was used to genotype subjects. RESULTS: Among 52 FCS individuals, 41 had biallelic LPL gene mutations (LPL-FCS patients): 82%, 7%, and 11% were missense, nonsense, and splicing variants, respectively. Eleven individuals had non-LPL-FCS; 2 had mutations in APOA5, 5 in GPIHBP1, and 1 each in LMF1 and APOC2 genes, respectively. Two other individuals were double heterozygotes, each with 1 normal LPL allele. All subjects had extremely high triglycerides (TGs) and chylomicrons, but very low levels of other lipoproteins. Compared with LPL-FCS individuals, non-LPL-FCS individuals were very similar for most traits, but had significantly higher postheparinLPL activity, higher 4-hour postprandial insulin and C-peptide levels; and higher low-density lipoprotein cholesterol levels. In non-LPL-FCS individuals compared to those with LPL-FCS, there were also 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. CONCLUSION: Thus, LPL FCS and non-LPL FCS are largely phenotypically similar. However, LPL FCS patients have lower postheparinLPL activity and a trend toward higher TGs, whereas low-density lipoprotein cholesterol was higher in non-LPL-FCS patients.
Authors: Jacqueline S Dron; Jian Wang; Adam D McIntyre; Henian Cao; John F Robinson; P Barton Duell; Priya Manjoo; James Feng; Irina Movsesyan; Mary J Malloy; Clive R Pullinger; John P Kane; Robert A Hegele Journal: J Lipid Res Date: 2019-09-13 Impact factor: 5.922
Authors: Louis St L O'Dea; James MacDougall; Veronica J Alexander; Andres Digenio; Brant Hubbard; Marcello Arca; Patrick M Moriarty; John J P Kastelein; Eric Bruckert; Handrean Soran; Joseph L Witztum; Robert A Hegele; Daniel Gaudet Journal: J Endocr Soc Date: 2019-10-11
Authors: Veronica J Alexander; Shuting Xia; Eunju Hurh; Steven G Hughes; Louis O'Dea; Richard S Geary; Joseph L Witztum; Sotirios Tsimikas Journal: Eur Heart J Date: 2019-09-01 Impact factor: 29.983