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• W4308058270 abstract "HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 42, No. 12Is Genetic Testing in Hypertriglyceridemia Useful? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIs Genetic Testing in Hypertriglyceridemia Useful? Robert A. Hegele Robert A. HegeleRobert A. Hegele Correspondence to: Robert A. Hegele, MD, Robarts Research Institute 1151 Richmond Street North London, Ontario N6A 5B7, Canada. Email E-mail Address: [email protected] https://orcid.org/0000-0003-2861-5325 Robarts Research Institute and Department of Medicine, Schulich School of Medicine and Dentistry‚ Western University, London, Ontario, Canada. Search for more papers by this author Originally published3 Nov 2022https://doi.org/10.1161/ATVBAHA.122.318621Arteriosclerosis, Thrombosis, and Vascular Biology. 2022;42:1468–1470This article is a commentary on the followingGenetic Testing for Hypertriglyceridemia in Academic Lipid Clinics: Implications for Precision Medicine—Brief ReportOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 3, 2022: Ahead of Print The first patient I ever saw in Jan Breslow’s lipid clinic at Rockefeller University in 1986 was a New York City police officer with severe hypertriglyceridemia. A prior hospital admission for acute pancreatitis had shaken him and he wanted to avoid a recurrence. He also wondered whether his lipemic blood sample (see Figure) was possibly explained by genetic factors. I advised him to lose weight, exercise, and to cut down on saturated fat, sugar, and alcohol. I also prescribed gemfibrozil. Although my age and experience fell short of his expectations, he followed my advice and subsequently maintained moderately elevated (but never normal) triglyceride levels. But I could not definitively answer his question about the heritability of hypertriglyceridemia.See accompanying article on page 1461Download figureDownload PowerPointFigure. Clinical flash card for severe hypertriglyceridemia (SHTG) focusing on genetic determinants. Details are shown regarding definition, prevalence, clinical subtypes, secondary causes, main deleterious clinical outcomes, and genetic determinants. FCS indicates familial chylomicronemia syndrome; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MCS, multifactorial chylomicronemia; N‚ normal; TG‚ triglyceride; and VLDL, very low-density lipoprotein.Today, genomic research has illuminated our understanding of the complex genetic determinants of high serum triglycerides.1 Decreasing cost and increased access to next-generation technologies allows us to genetically define dyslipidemia in a detailed, objective manner.2 Perhaps somewhat ironically, treatment advice for outpatients with hypertriglyceridemia remains largely unchanged since the 1980’s,3 although some promising biological agents are nearing clinical use.4 However, the clinical utility of DNA testing in hypertriglyceridemia still remains uncertain.Severe hypertriglyceridemia is variably defined as a fasting triglyceride concentration >10 mmol/L (>885 mg/dL) in système international–based jurisdictions and >1000 mg/dL (>11.1 mmol/L) in jurisdictions using conventional units.3 This degree of triglyceride elevation is seen in ≈1 in 400 North American adults5 and is strongly correlated with the pathological presence of chylomicrons in the fasting state. If other lipoproteins, such as VLDL (very low-density lipoprotein) are concomitantly increased, the risk of atherosclerotic cardiovascular disease is also increased.6 But the imminent risk to health from chylomicronemia is acute pancreatitis. The risk begins to increase with triglycerides >10 mmol/L (>885 mg/dL) and rises sharply with triglycerides >20 mmol/L (>1770 mg/dL)7; in the latter subgroup, the risk of pancreatitis is ≈4% per year.5 Hypertriglyceridemia-related pancreatitis can be fatal and can also lead to chronic pancreatitis, pancreatic insufficiency, necrosis, pseudocyst, or abscess formation.8 Although the mechanism underlying acute pancreatitis in severe hypertriglyceridemia is undetermined, chylomicron particles are considered to play a central pathogenic role.6Chylomicronemia syndrome refers to the presence of one or more characteristic clinical features in severely hypertriglyceridemic patients with chylomicronemia.6 These include failure to thrive in infancy, nausea and vomiting, abdominal pain, eruptive xanthomas on the trunk and limbs, lipemia retinalis, and hepatosplenomegaly.6 Less common clinical features include anemia, intestinal bleeding, diarrhea, seizures, and encephalopathy.6Two main clinical presentations of chylomicronemia syndrome are familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia (MCS).6 FCS was formerly known as Fredrickson type 1 hyperlipoproteinemia, of which LPL (lipoprotein lipase) deficiency is the most prevalent subtype. FCS accounts for at most 1% to 5% of cases of severe hypertriglyceridemia with an estimated prevalence of 1 in 100 000 to 1 000 000.9 The absence of lipolytic processing leads to accumulation of chylomicrons together with downstream deficiencies of other lipoprotein species.6,9,10 In contrast, MCS, formerly called type 5 hyperlipoproteinemia is ≈50× to 100× more common than FCS.1,6,9 Other lipoproteins, particularly VLDL and remnants, are elevated in MCS.10 FCS develops in childhood, adolescence, or early adulthood, typically in the absence of secondary factors.6 In contrast, MCS presents later in life, often in the context of secondary factors, including lifestyle and certain medical conditions or medications (see Figure).6 The lifetime relative risk of pancreatitis is higher in FCS than MCS patients (ie, 70%–80% versus 20%–30%), but the population-attributable risk of pancreatitis is larger in MCS patients due to their much higher prevalence.10FCS is a Mendelian recessive condition caused by biallelic rare pathogenic loss-of-function variants in one of 5 genes, namely LPL (in 60%–80% of cases), APOC2, APOA5, GPIHBP1, and LMF1.1,11 In contrast, MCM is a non-Mendelian disorder with two main types of genetic determinants: (1) heterozygosity for a pathogenic variant in one of the above genes in 15% to 20% of affected subjects12,13; or (2) polygenic predisposition in 30% to 50% of subjects.12,13 Polygenic risk accrues from accumulation of dozens or hundreds of common single nucleotide polymorphisms from across the genome, each exerting a small triglyceride-raising effect; their cumulative influence is integrated into a polygenic risk score.14,15 Although genetic variation plays a deterministic causal role in FCS, the relationship between genotype and phenotype in MCS is by contrast probabilistic. In other words, the genetic determinant raises the odds that the patient will develop severe hypertriglyceridemia but it does not guarantee that this will occur.For instance, although 15% to 20% of subjects with MCS have a heterozygous rare pathogenic variant, so do 3% to 4% of people with normal lipids.1,12,13 Similarly, a high polygenic risk score defined as >10th percentile of the distribution is seen in 10% of normolipidemic people, but this is significantly enriched to 30% to 50% of MCS individuals.12,13 Thus, the presence or absence of either genetic factor guarantees neither development of nor protection from severe hypertriglyceridemia, respectively. Furthermore, in multi-generational families, high triglycerides do not cosegregate with either heterozygous rare variants or high polygenic scores. Given the complex genetic architecture in most patients with severe hypertriglyceridemia, is there any value in DNA testing?In this issue of ATVB, Deshotels et al16 report an observational analysis of 363 individuals from three tertiary referral lipid clinics of whom 176, 129, and 58 had triglyceride levels <200 mg/dL (<2.3 mmol/L), 200 to 999 mg/dL (2–3–11.1 mmol/L) and >1000 mg/dL (>11.1 mmol/L), respectively. Subjects were genotyped using a commercial method that included both targeted gene sequencing to detect rare variants in LPL, APOC2, APOA5, GPIHBP1, and LMF1 and a proprietary polygenic score for high triglyceride levels. The authors found that three individuals had biallelic pathogenic variants, consistent with FCS, whereas 34 had heterozygous pathogenic variants characteristic of MCS. In addition, 59 individuals had a high polygenic score for triglycerides (somewhat unclearly defined) and 20 individuals had both a heterozygous pathogenic variant and a high polygenic score.Of 37 individuals who experienced acute pancreatitis, 35 had triglyceride >1000 mg/dL.16 Furthermore, compared with the reference subgroup who had neither a pathogenic variant nor a high polygenic score, the authors observed: (1) no increased risk of acute pancreatitis among those with either a pathogenic variant or high polygenic risk score; but (2) a significant 5-fold increased risk of pancreatitis among those with both a pathogenic variant and a high polygenic risk score. The authors concluded that genetic analysis identified patients at particularly high pancreatitis risk who were candidates for closer medical attention. But is this claim valid or practical?Perhaps unsurprisingly, the subgroup with highest genetic burden of risk—that is those with both a heterozygous variant plus a high polygenic score—had the highest median triglyceride levels at 2016 mg/dL (22.8 mmol/L), thus confirming the relationship between very severe triglyceride elevation and acute pancreatitis risk. Would genetic testing in these people truly enhance prediction of pancreatitis risk compared with biochemical lipid profiling alone? Furthermore, the authors’ polygenic risk score seemed to underperform in their cohort. For instance, the subgroup of individuals with just a high polygenic score had a median triglyceride level of only 142 mg/dL (1.61 mmol/L) which was lower than the mean triglyceride level of the entire cohort. Other reported polygenic scores in contrast are much more strongly associated with hypertriglyceridemia.12,17 For instance, in 563 patients with severe hypertriglyceridemia and mean triglyceride of 25 mmol/L (2200 mg/dL), 14% had a heterozygous rare variant (odds ratio, >4), and 32% had a high polygenic score determined conventionally (odds ratio also >4).12 Furthermore, in a clinical trial of volanesorsen in 114 patients with mean baseline triglyceride 14.3 mmol/L (1270 mg/dL), 19% had a heterozygous rare variant (odds ratio, >5), and 49% had the same high polygenic score (odds ratio >10).13 The underwhelming relationship between hypertriglyceridemia and Deshotels’ polygenic score reminds us of the importance of rigorous standards for polygenic scores.18Would our newfound genetic understanding have helped my police officer patient? He, like most adults with severe hypertriglyceridemia likely did not have FCS but rather had MCS. For these patients, there is no evidence yet that DNA analysis adds actionable information over and above the triglyceride level itself. For instance, in 2 clinical trials of the APOC3 antisense oligonucleotide volanesorsen, there was no difference in triglyceride lowering efficacy among (1) FCS patent subgroups stratified by biallelic LPL versus non-LPL pathogenic variants19; and (2) MCS patient subgroups stratified according to presence of a pathogenic variant, high polygenic risk or neither.13 However, for children with severe hypertriglyceridemia and strong suspicion of FCS, DNA sequencing to document biallelic pathogenic variants would be essential for diagnosis‚ medical advice, prognosis, family counseling, and access to novel therapies.20 But in most cases in adults, severe hypertriglyceridemia‚ irrespective of its genetic basis‚ drives expression of acute pancreatitis. Until future controlled prospective studies prove otherwise, the triglyceride level rather than the genotype should serve as the primary guide along the treatment pathway for most patients with severe hypertriglyceridemia.Article InformationSources of FundingR.A. Hegele is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair, and the Martha G. Blackburn Chair in Cardiovascular Research. R.A. Hegele holds operating grants from the Canadian Institutes of Health Research (Foundation award), the Heart and Stroke Foundation of Ontario (G-21-0031455) and the Academic Medical Association of Southwestern Ontario (INN21-011).Disclosures R.A. Hegele reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Boston Heart, HLS Therapeutics, Novartis, Pfizer, Regeneron, Sanofi, and Ultragenyx.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1470.Correspondence to: Robert A. Hegele, MD, Robarts Research Institute 1151 Richmond Street North London, Ontario N6A 5B7, Canada. Email [email protected]caReferences1. Dron JS, Hegele RA. Genetics of hypertriglyceridemia.Front Endocrinol (Lausanne). 2020; 11:455. doi: 10.3389/fendo.2020.00455CrossrefMedlineGoogle Scholar2. Schaefer EJ, Geller AS, Endress G. The biochemical and genetic diagnosis of lipid disorders.Curr Opin Lipidol. 2019; 30:56–62. doi: 10.1097/MOL.0000000000000590CrossrefMedlineGoogle Scholar3. Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides.Eur Heart J. 2020; 41:99–109c. doi: 10.1093/eurheartj/ehz785CrossrefMedlineGoogle Scholar4. Berberich AJ, Hegele RA. A modern approach to dyslipidemia.Endocr Rev. 2022; 43:611–653. doi: 10.1210/endrev/bnab037CrossrefMedlineGoogle Scholar5. Berberich AJ, Ouedraogo AM, Shariff SZ, Hegele RA, Clemens KK. Incidence, predictors and patterns of care of patients with very severe hypertriglyceridemia in Ontario, Canada: a population-based cohort study.Lipids Health Dis. 2021; 20:98. doi: 10.1186/s12944-021-01517-6CrossrefMedlineGoogle Scholar6. Chait A, Eckel RH. The chylomicronemia syndrome Is most often multifactorial: a narrative review of causes and treatment.Ann Intern Med. 2019; 170:626–634. doi: 10.7326/M19-0203CrossrefMedlineGoogle Scholar7. Sandhu S, Al-Sarraf A, Taraboanta C, Frohlich J, Francis GA. 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Clinical and biochemical features of different molecular etiologies of familial chylomicronemia.J Clin Lipidol. 2018; 12:920–927.e4. doi: 10.1016/j.jacl.2018.03.093CrossrefMedlineGoogle Scholar12. Dron JS, Wang J, Cao H, McIntyre AD, Iacocca MA, Menard JR, Movsesyan I, Malloy MJ, Pullinger CR, Kane JPet al. Severe hypertriglyceridemia is primarily polygenic.J Clin Lipidol2019; 13:80–88. doi: 10.1016/j.jacl.2018.10.006CrossrefMedlineGoogle Scholar13. Gouni-Berthold I, Alexander VJ, Yang Q, Hurh E, Steinhagen-Thiessen E, Moriarty PM, Hughes SG, Gaudet D, Hegele RA, O'Dea LSLet al; COMPASS study group. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS):a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.Lancet Diabetes Endocrinol. 2021; 9:264–275. doi: 10.1016/S2213-8587(21)00046-2CrossrefMedlineGoogle Scholar14. Dron JS, Hegele RA. The evolution of genetic-based risk scores for lipids and cardiovascular disease.Curr Opin Lipidol. 2019; 30:71–81. doi: 10.1097/MOL.0000000000000576CrossrefMedlineGoogle Scholar15. Trinder M, Brunham LR. Polygenic scores for dyslipidemia: the emerging genomic model of plasma lipoprotein trait inheritance.Curr Opin Lipidol. 2021; 32:103–111. doi: 10.1097/MOL.0000000000000737CrossrefMedlineGoogle Scholar16. Deshotels MR, Hadley TD, Roth M, Agha AM, Pulpati VP, Nugent AK, Virani SS, Nambi V, Moriarty PM, Davidson MHet al. Genetic testing for hypertriglyceridemia in academic lipid clinics: implications for precision medicine—brief report. Arterioscler Thromb Vasc Biol. 2022; 42:1461–1467. doi: 10.1161/ATVBAHA.122.318445LinkGoogle Scholar17. Dron JS, Wang J, McIntyre AD, Iacocca MA, Robinson JF, Ban MR, Cao H, Hegele RA. Six years’ experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias.BMC Med Genomics. 2020; 13:23. doi: 10.1186/s12920-020-0669-2CrossrefMedlineGoogle Scholar18. Wand H, Knowles JW, Clarke SL. The need for polygenic score reporting standards in evidence-based practice: lipid genetics use case.Curr Opin Lipidol. 2021; 32:89–95. doi: 10.1097/MOL.0000000000000733CrossrefMedlineGoogle Scholar19. Witztum JL, Gaudet D, Freedman SD, Alexander VJ, Digenio A, Williams KR, Yang Q, Hughes SG, Geary RS, Arca Met al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome.N Engl J Med. 2019; 381:531–542. doi: 10.1056/NEJMoa1715944CrossrefMedlineGoogle Scholar20. Shamsudeen I, Hegele RA. Safety and efficacy of therapies for chylomicronemia.Expert Rev Clin Pharmacol2022; 15:395–405. doi: 10.1080/17512433.2022.2094768CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesGenetic Testing for Hypertriglyceridemia in Academic Lipid Clinics: Implications for Precision Medicine—Brief ReportMatthew R. Deshotels, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2022;42:1461-1467 December 2022Vol 42, Issue 12 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.122.318621PMID: 36325898 Originally publishedNovember 3, 2022 Keywordscardiovascular diseaseEditorialslipoproteinpancreatitistriglyceridehypertriglyceridemiaPDF download Advertisement" @default.
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