Influence of Polygenic Background on the Clinical Presentation of Familial Hypercholesterolemia.

BACKGROUND: Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH. METHODS: We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease. RESULTS: Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant. CONCLUSIONS: Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.

Advances in familial hypercholesterolemia.

Familial hypercholesterolemia (FH), a semi-dominant genetic disease affecting more than 25 million people worldwide, is associated with severe hypercholesterolemia and premature atherosclerotic cardiovascular disease. Over the last decade, advances in data analysis, screening, diagnosis and cardiovascular risk stratification has significantly improved our ability to deliver precision medicine for these patients. Furthermore, recent updates on guideline recommendations and new therapeutic approaches have also proven to be highly beneficial. It is anticipated that both ongoing and upcoming clinical trials will offer further insights for the care and treatment of FH patients.

Prevalence of Dysbetalipoproteinemia in the UK Biobank According to Different Diagnostic Criteria.

CONTEXT: Dysbetalipoproteinemia (DBL) is a multifactorial disorder that disrupts the normal metabolism of remnant lipoproteins, causing increased risk of cardiovascular disease. However, establishing a proper diagnosis is difficult and the true prevalence of the disease in the general population remains unknown. OBJECTIVE: The objectives were to study the prevalence of the disease and to validate the performance of different clinical diagnostic criteria in a large population-based cohort. METHODS: This study included 453 437 participants from the UK Biobank. DBL was established in participants having an ε2ε2 genotype with mixed dyslipidemia or lipid-lowering therapy use (n=964). The different diagnostic criteria for DBL were applied in individuals without lipid-lowering medication (n=370 039, n=534 DBL), to compare their performance. RESULTS: Overall, 0.6% of participants had an ε2ε2 genotype, of which 36% were classified as DBL, for a disease prevalence of 0.2% (1:469). The prevalence of DBL was similar between the different genetic ancestries (≤0.2%). Several diagnostic criteria showed good sensitivity for the diagnosis of DBL (>90%), but they suffered from a very low positive predictive value (0.6%-15.4%). CONCLUSION: This study reported for the first time the prevalence of DBL in the UK Biobank according to genetic ancestry. Furthermore, we provided the first external validation of different diagnostic criteria for DBL in a large population-based cohort and highlighted the fact that these criteria should not be used to diagnose DBL alone but should rather be used as a first screening step to determine which individuals may benefit from genetic testing to confirm the diagnosis.

Two Cases of Sitosterolemia Falsely Diagnosed as Familial Hypercholesterolemia: Could Digging Deeper Have Avoided Harm?

Sitosterolemia is a rare monogenic lipid disease characterized by the excessive uptake of phytosterols and their accumulation in blood and tissues. Clinically, it can present with hypercholesterolemia and xanthomas, often causing it to be misdiagnosed as familial hypercholesterolemia (FH). The diagnosis of sitosterolemia can easily be confirmed and distinguished from FH with a sterol profile and genetic investigations. Here, we report a sibship of 2 sisters with sitosterolemia initially misdiagnosed as FH. This case report illustrates the importance of considering rare conditions, such as sitosterolemia, as a differential diagnosis in patients with hypercholesterolemia, xanthomas, and hematologic anomalies. It also emphasizes the underdiagnosis of sitosterolemia and the benefits of using sterol profiles and genetic testing in the diagnostic process to initiate the appropriate therapy and avoid harm to patients.

High hsCRP concentration is associated with acute pancreatitis in multifactorial chylomicronemia syndrome.

BACKGROUND: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). However, the risk of AP is very heterogenous in MCS. Previous studies suggested that inflammation might promote disease progression in hyperTG-induced AP. OBJECTIVE: To determine if low-grade inflammation is associated with AP in MCS. METHODS: This study included 102 subjects with MCS for which high-sensitivity C-reactive protein (hsCRP) concentration was measured at their first visit at the Montreal Clinical Research Institute. RESULTS: MCS subjects with a previous history of AP had a significant higher hsCRP concentration (4.62 mg/L vs. 2.61 mg/L; p=0.003) and high hsCRP concentration (≥3mg/L) was independently associated with AP prevalence (p<0.05). Up to 64% of the variability in AP prevalence was explained by the maximal TG concentration, hsCRP concentration, the presence of rare variants in TG-related genes, and fructose intake based on a stepwise multivariate regression model (p<0.0001). CONCLUSION: This retrospective study showed for the first time that hsCRP concentration is strongly associated with AP prevalence in MCS. It also suggests that low-grade inflammation may be a driver of AP in severe hypertriglyceridemia. Prospective studies could help determine the causality of this association and assess whether medication known to reduce low-grade inflammation could help prevent AP in individuals with severe hypertriglyceridemia.

High carrier frequency for abetalipoproteinemia and evidence of a founder variant in a French-Canadian population.

Abetalipoproteinemia (ABL) is a rare recessive genetic disease caused by bi-allelic pathogenic variants in the microsomal triglyceride transfer protein (MTTP) gene. This disease is characterized by a deficiency in the secretion of apolipoprotein B-containing lipoproteins. Patients with ABL present with neurological, hematological, and gastrointestinal symptoms due to fat malabsorption and a deficiency in liposoluble vitamins. In this report, we present a total of four ABL cases, including three new cases, all originating from the same French-Canadian founder population in Saguenay-Lac-Saint-Jean, Québec, Canada. These individuals are homozygous for the same pathogenic variant in the MTTP gene (c.419dup, p.Asn140Lysfs*2). We found that this variant is more common than anticipated in this population, with an estimated carrier frequency of 1:203. Early diagnosis is essential to initiate treatment known to prevent complications associated with ABL. Population carrier screening or newborn screening for ABL should be considered in this French-Canadian founder population.

Pancreatitis polygenic risk score is associated with acute pancreatitis in multifactorial chylomicronemia syndrome.

BACKGROUND: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia associated with an increased risk of acute pancreatitis (AP). The risk of AP is heterogenous and is associated with increased level of triglycerides (TG) and presence of rare variants in TG metabolism-related genes. OBJECTIVE: To determine if the accumulation of common variants in pancreatitis susceptibility genes, measured with a weighted polygenic risk score (PRS), is associated with AP in MCS patients. METHODS: A total of 114 patients with MCS underwent genetic testing for eight single nucleotide polymorphisms (SNPs) in known pancreatitis susceptibility genes (ABCG8, CLDN2, CTRB1/2, CTRC, PRSS1, PRSS2, SPINK1 and TWIST2). A weighted PRS was calculated to account for the phenotypic effect of each SNP locus. RESULTS: A high pancreatitis-PRS score (≥ 0.44) was associated with a 2.94-fold increase risk of AP (p = 0.02) among patients with MCS. MCS patients with a high pancreatitis-PRS and a rare variant in TG metabolism-related gene have a 9.50-fold increase risk of AP (p = 0.001), compared to those with a low-PRS and no rare variant. A multivariate analysis including the presence of rare variants, the maximal TG values and a high pancreatitis-PRS explained 26% of the variability in AP in MCS patients. CONCLUSION: This study shows for the first time that the accumulation of common variants in pancreatitis susceptibility genes is associated with AP in MCS patients. Pancreatitis-PRS could help clinicians to identify MCS patients who may be at higher risk of AP and who may benefit from more aggressive treatment.

Acute pancreatitis risk in multifactorial chylomicronemia syndrome depends on the molecular cause of severe hypertriglyceridemia.

BACKGROUND AND AIMS: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). Severe hyperTG is mainly polygenic in nature, either caused by the presence of heterozygous pathogenic variants (PVs) in TG-related metabolism genes or by accumulation of common variants in hyperTG susceptibility genes. This study aims to determine if the risk of AP is similar amongst MCS patients with different molecular causes of severe hyperTG. METHODS: This study included 114 MCS patients who underwent genetic testing for PVs in TG-related metabolism genes and 16 single nucleotide polymorphisms (SNPs) in hyperTG susceptibility genes. A weighted TG-polygenic risk score (TG-PRS) was calculated. A TG-PRS score ≥ 90th percentile was used to define a high TG-PRS. RESULTS: Overall, 66.7% of patients had severe hyperTG of polygenic origin. MCS patients with only a PV and those with both a PV and high TG-PRS were more prone to have maximal TG concentration ≥ 40 mmol/L (OR 5.33 (1.55-18.36); p = 0.008 and OR 5.33 (1.28-22.25); p = 0.02), as well as higher prevalence of AP (OR 3.64 (0.89-14.92); p = 0.07 and OR 11.90 (2.54-55.85); p = 0.002) compared to MCS patients with high TG-PRS alone. CONCLUSIONS: This is the first study to show that MCS caused by a high TG-PRS and a PV is associated with higher risk of AP, similar to what is seen in the monogenic form of severe hyperTG. This suggests that determining the molecular cause of severe hyperTG could be useful to stratify the risk of pancreatitis in MCS.

The 20-Year Diagnostic Odyssey of a Milder Form of Cerebrotendinous Xanthomatosis.

Tendinous xanthomas are usually a sign of genetic dyslipidemias and are said to be pathognomonic for familial hypercholesterolemia. However, the differential diagnosis must also include rarer forms of genetic dyslipidemias such as cerebrotendinous xanthomatosis (CTX). In this report, we present the diagnostic odyssey of a French-Canadian patient presenting with Achilles tendon xanthomas and an unusual mild to moderate hypercholesterolemia. Comprehensive biochemical and genetic investigations confirmed the diagnosis of CTX, 20 years after the onset of her first symptoms. We also describe a new variant in the CYP27A1 gene associated with this atypical case and expand the clinical phenotype of this rare genetic condition. CTX is thought to be underdiagnosed, and early diagnosis and treatment of this disease is essential as it has been shown to greatly improve the patient's symptoms and prognosis.

Sex differences in the presentation, treatment and outcomes of patients with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal semi-dominant lipid metabolism disorder characterized by extremely high low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease. The objective of this study was to investigate sex-differences in the treatment and outcomes of patients with HoFH. METHODS: We examined clinical characteristics, lipid-lowering therapy (LLT), and cardiovascular events using descriptive statistics of patients in the Canadian HoFH registry. Major adverse cardiovascular events (MACE) were defined as the composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Sex differences between continuous and categorical variables were analyzed using Mann-Whitney U test and Fisher's Exact test, respectively. RESULTS: This study included 48 patients (27 (56%) female). The median age at diagnosis in females was 14.0 (interquartile range (IQR) 9.0-30.0) and in males was 8.0 (IQR 2.0-23.0) (p = 0.07). Baseline clinical characteristics were comparable between both sexes. The median baseline LDL-C was 12.7 mmol/L (10.0-18.3) in females and 15.3 (10.5-20.0) in males (p = 0.51). Follow up LDL-C levels were 7.6 mmol/L (IQR 4.8-11.0) in females and 6.3 (IQR 4.6-7.5) in males (p = 0.1). Most patients were taking 3 or more LLTs, with comparable proportions in both sexes (p = 0.26). Apheresis was similar in both sexes, 14 (51.8%) vs. 10 (47.6%) (p = 0.2). Over a mean of 10 years of follow-up, MACE occurred in 3 females (11.1%) and 4 males (19.1%) (p = 0.2). CONCLUSION: Lipid levels and treatment were similar between sexes. MACE occurred in similar proportions between sexes, indicating that HoFH offsets the inherently lower cardiovascular risk in pre-menopausal females. Further investigation into sex-differences in HoFH in larger sample sizes is warranted.

Homozygous Familial Hypercholesterolemia in Canada: An Observational Study.

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease characterized by very high levels of low-density lipoprotein cholesterol (LDL-C). Untreated patients present with extensive xanthomas and premature atherosclerosis. Lipid-lowering therapy is highly efficacious and has dramatically increased life expectancy of patients with HoFH. Objectives: The aim of the study was to obtain a comprehensive registry of HoFH in Canada, known to have several founder effect regions, and describe the clinical characteristics and cardiovascular outcomes of this population over time. Methods: Clinical and genetic data on patients with HoFH were collected via a standardized questionnaire sent to academic sites participating in the Familial Hypercholesterolemia Canada network. Results: A total of 48 patients with HoFH were enrolled. The median age at diagnosis was 12 years (interquartile range [IQR]: 5-24) and untreated LDL-C levels were 15.0 mmol/L (IQR: 10.5-18.6 mmol/L; 580 mg/dL IQR: 404-717 mg/dL). At last follow-up visit, median age was 40 years (IQR: 26-54 years). Treated LDL-C levels were 6.75 mmol/L (IQR: 4.73-9.51 mmol/L; 261 mg/dL IQR: 183-368 mg/dL) with 95.5% of patients on statins, 88.6% on ezetimibe, 34.1% on proprotein convertase subtilisin/kexin type 9 inhibitors, 27.3% on lomitapide, 13.6% on evinacumab, and 56.8% were treated with low-density lipoprotein apheresis or plasmapheresis. Deaths were reported in 7 (14.5%) and major adverse cardiovascular events were observed in 14.6% of patients with the average onset at 30 years (IQR: 20-36 years). Aortic stenosis was reported in one-half the patients (47.9%) and 10 (20.8%) underwent aortic valve replacement. Conclusions: This HoFH patient registry in Canada will provide important new health-related knowledge about the phenotypic manifestations and determinants of cardiovascular risk in this population, allowing for closer examination of quality of life and burden to the health care system.