Monogenic Familial Hypercholesterolemia Research Articles

Abstract 068: Investigation Of Familial Hypercholesterolemia Subtypes In The UK Biobank

Familial hypercholesterolemia (FH) is an inherited disorder characterized by lifelong elevated low density lipoprotein cholesterol (LDL-C) and dramatically increased risk for premature atherosclerotic cardiovascular disease (ASCVD). FH diagnosis currently requires either the presence of a pathogenic variant in an FH gene, or phenotypic characteristics. However, genetic studies now suggest that FH encompasses four discrete subtypes: 1) presence of a monogenic FH variant, 2) a high LDL-C polygenic score, “polygenic FH,” 3) elevated lipoprotein(a), and 4) LDL-C > 190 mg/dl and a positive family history without an identifiable genetic cause, or true “phenotypic FH.” Here, we screened 134,444 unrelated white British individuals with exome sequences available in the UK Biobank for individuals with FH subtypes. We classified 358 individuals (1 in 376; 0.27%) with a pathogenic variant in their exome sequence as monogenic FH, 2,800 had polygenic FH (1 in 48; 2.1%), 2,246 had elevated lipoprotein (a) (1 in 60; 1.7%), and 3,146 had phenotypic FH (1 in 43; 2.3%). The remaining 125,894 samples without an FH subtype were classified as controls. We stratified the cohort into statin treated and untreated individuals. Those with an FH subtype were 2.8 times more likely to be prescribed a lipid lowering medication at the baseline interview compared to controls. In the statin treated group (n=21,875), those with monogenic FH were at the highest risk for 10-year incident ASCVD. We observed a 2.7 (95% confidence interval (95% CI): 1.6-4.3) fold higher ASCVD risk in monogenic FH compared to controls as measured by the hazard ratio (HR). Those with elevated lipoprotein (a) and phenotypic FH were also at increased risk for ASCVD (HR = 1.5 (95% CI: 1.1-2.1) and HR = 1.6 (95% CI: 1.3-2.1), respectively). In contrast, we do not observe elevated rates of incident ASCVD in those with polygenic FH relative to controls among treated individuals. In the untreated group (n=112,569), the risk of ASCVD in FH subtypes was more pronounced relative to controls. Individuals with elevated lipoprotein (a) were at the highest risk of incident ASCVD (HR = 2.9, 95% CI: 2.4-3.7) among the four subgroups. In conclusion, we observed differences in ASCVD risk among subtypes of FH. These findings demonstrate the importance of considering subtypes in ASCVD risk assessment for patients who present with the FH phenotype.

Cost-Effectiveness of Screening Algorithms for Familial Hypercholesterolaemia in Primary Care.

Although familial hypercholesterolemia (FH) screening within primary care is considered cost-effective, which screening approach is cost-effective has not been established. This study determines the cost-effectiveness of six case-finding strategies for screening of electronic health records to identify index patients who have genetically confirmed monogenic FH in English primary care. A decision tree was constructed to represent pathways of care for each approach (FH Case Identification Tool (FAMCAT) versions 1 and 2, cholesterol screening, Dutch Lipid Clinic Network (DLCN), Simon Broome criteria, no active screening). Clinical effectiveness was measured as the number of monogenic FH cases identified. Healthcare costs for each algorithm were evaluated from an NHS England perspective over a 12 week time horizon. The primary outcome was the incremental cost per additional monogenic FH case identified (ICER). FAMCAT2 was found to dominate (cheaper and more effective) cholesterol and FAMCAT1 algorithms, and extendedly dominate DLCN. The ICER for FAMCAT2 vs. no active screening was 8111 GBP (95% CI: 4088 to 14,865), and for Simon Broome vs. FAMCAT2 was 74,059 GBP (95% CI: −1,113,172 to 1,697,142). Simon Broome found the largest number of FH cases yet required 102 genetic tests to identify one FH patient. FAMCAT2 identified fewer, but only required 23 genetic tests.

Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia.

Introduction: Familial hypercholesterolaemia (FH) is a common autosomal dominant genetic condition, characterised by elevated LDL cholesterol (LDL-C), leading to premature cardiovascular disease (CVD). Early and accurate diagnosis, with implementation of preventative therapies, has a major impact on reducing premature CVD, morbidity and mortality. Genetic testing is recommended to confirm clinical diagnosis in the proband and enable cascade testing in relatives. There is growing evidence that the risk of CVD conferred by hypercholesterolaemia depends not only on monogenic causes but also on polygenic factors. GENinCode has developed a novel genomic testing system (Lipid inCode®) which we have assessed against an accredited National Health Service (NHS UK) genetic screening service in order to validate its diagnostic and clinical utility.Methods: DNA samples from 40 index cases who had been referred for FH testing in an ISO15189-accredited NHS genetic screening service, were retrospectively tested using the Lipid inCode® assay. The results were compared with those from NHS testing.Results: There was absolute concordance in variant detection between both diagnostic tests for monogenic and polygenic FH, the only difference being in the interpretation and classification of DNA variants based on ACMG guidelines, which did not differ by more than one classification class. The Lipid inCode® test was equivalent to the NHS test in providing comprehensive genetic analysis that included the assessment of both monogenic (FH) and polygenic determinants of blood cholesterol and including a pharmacogenomic assessment of predisposition to statin-related myopathy.Conclusion: The Lipid inCode® diagnostic test can be undertaken with rapid turnaround and gave the same results as those reported by standard NHS genetic laboratory testing. In addition to assessment of monogenic FH, the Lipid inCode® assay provides additional genetic data, such as polygenic factors contributing to hypercholesterolaemia, a polygenic risk score (PRS) for coronary artery disease (CAD), pharmacogenomic testing for statin myopathy, and genetic predisposition to raised Lp(a).

Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia

Introduction: Familial hypercholesterolaemia (FH) is a common autosomal dominant genetic condition, characterised by elevated LDL cholesterol (LDL-C), leading to premature cardiovascular disease (CVD). Early and accurate diagnosis, with implementation of preventative therapies, has a major impact on reducing premature CVD, morbidity and mortality.Genetic testing is recommended to confirm clinical diagnosis in the proband and enable cascade testing in relatives. There is growing evidence that the risk of CVD conferred by hypercholesterolaemia depends not only on monogenic causes but also on polygenic factors. GENinCode has developed a novel genomic testing system (Lipid inCode®) which we have assessed against an accredited National Health Service (NHS UK) genetic screening service in order to validate its diagnostic and clinical utility.Methods: DNA samples from 40 index cases who had been referred for FH testing in an ISO15189-accredited NHS genetic screening service, were retrospectively tested using the Lipid inCode® assay. The results were compared with those from NHS testing. Results: There was absolute concordance in variant detection between both diagnostic tests for monogenic and polygenic FH, the only difference being in the interpretation and classification of DNA variants based on ACMG guidelines, which did not differ by more than one classification class. The Lipid inCode® test was equivalent to the NHS test in providing comprehensive genetic analysis that included the assessment of both monogenic (FH) and polygenic determinants of blood cholesterol and including a pharmacogenomic assessment of predisposition to statin-related myopathy.Conclusion: The Lipid inCode® diagnostic test can be undertaken with rapid turnaround and gave the same results as those reported by standard NHS genetic laboratory testing. In addition to assessment of monogenic FH, the Lipid inCode® assay provides additional genetic data, such as polygenic factors contributing to hypercholesterolaemia, a polygenic risk score (PRS) for coronary artery disease (CAD), pharmacogenomic testing for statin myopathy, and genetic predisposition to raised Lp(a).

Polygenic architecture and cardiovascular risk of familial combined hyperlipidemia

Background and aimsFamilial combined hyperlipidemia (FCHL) is one of the most common inherited lipid phenotypes, characterized by elevated plasma concentrations of apolipoprotein B-100 and triglycerides. The genetic inheritance of FCHL remains poorly understood. The goals of this study were to investigate the polygenetic architecture and cardiovascular risk associated with FCHL. Methods and resultsWe identified individuals with an FCHL phenotype among 349,222 unrelated participants of European ancestry in the UK Biobank using modified versions of 5 different diagnostic criteria. The prevalence of the FCHL phenotype was 11.44% (n = 39,961), 5.01% (n = 17,485), 1.48% (n = 5,153), 1.10% (n = 3,838), and 0.48% (n = 1,688) according to modified versions of the Consensus Conference, Dutch, Mexico, Brunzell, and Goldstein criteria, respectively. We performed discovery, case-control genome-wide association studies for these different FCHL criteria and identified 175 independent loci associated with FCHL at genome-wide significance. We investigated the association of genetic and clinical risk with FCHL and found that polygenic susceptibility to hypercholesterolemia or hypertriglyceridemia and features of metabolic syndrome were associated with greater prevalence of FCHL. Participants with an FCHL phenotype had a similar risk of incident coronary artery disease compared to participants with monogenic familial hypercholesterolemia (adjusted hazard ratio vs controls [95% confidence interval]: 2.72 [2.31–3.21] and 1.90 [1.30–2.78]). ConclusionsThese results suggest that, rather than being a single genetic entity, the FCHL phenotype represents a polygenic susceptibility to dyslipidemia in combination with metabolic abnormalities. The cardiovascular risk associated with an FCHL phenotype is similar to that of monogenic familial hypercholesterolemia, despite being ∼5x more common.

Polygenic contribution for familial hypercholesterolemia (FH).

The present review summarizes different polygenic risk scores associated with hypercholesterolemia applied to cohorts with a genetic diagnosis of familial hypercholesterolemia (FH). Several single-nucleotide polymorphisms associated with increased levels of LDL-C or Lp(a) have been genotyped in population cohorts with FH phenotype, to identify the cause of hypercholesterolemia in mutation negative individuals. In different studies, a large proportion of individuals without a monogenic causative variant (in low density lipoprotein receptor gene (LDLR), apolipoprotein B gene (APOB) or proprotein convertase subtilisin/kexin type 9 gene (PCSK9 genes) was considered to have a hypercholesterolemia with a polygenic basis. The heterogeneity in the phenotype of monogenic FH may also be explained by polygenic contributions to LDL-C. The elevated LDL-C genetic risk score (GRS) has been associated with increased risk of atherosclerotic cardiovascular disease in individuals with monogenic FH. Moreover, a poorer response to lipid lowering therapy has been associated with monogenic FH when compared to a polygenic basis. The reason why Lp(a) concentrations are raised in individuals with clinical FH is unclear, but it could be caused by a genetic variation in Lipoprotein(A) gene as a polygenic contribution. Polygenic risk scores have revealed to be important tools to define the cause of hypercholesterolemia in FH mutation-negative individuals and should be included in FH diagnosis strategies, although there is still space for more specific LDL-C GRS to be developed. The use of GRS may be used to refine cardiovascular risk prediction in FH patients and could lead to a personalized approach to therapy. The identification of the genetic status of an individual with FH phenotype (monogenic or polygenic) may have implications on their risk stratification, cascade screening of relatives, disease management and therapeutic measures.

Polygenic risk scores for low-density lipoprotein cholesterol and familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) and an increased risk of premature coronary artery disease (CAD). Recently, it has been shown that a high polygenic risk score (PRS) could be an independent risk factor for CAD in FH patients of European ancestry. However, it is uncertain whether PRS is also useful for risk stratification of FH patients in East Asia. We recruited and genotyped clinically diagnosed FH (CDFH) patients from the Kanazawa University Mendelian Disease FH registry and controls from the Shikamachi Health Improvement Practice genome cohort in Japan. We calculated PRS from 3.6 million variants of each participant (imputed from the 1000 Genome phase 3 Asian dataset) for LDL-C (PRSLDLC) using a genome-wide association study summary statistic from the BioBank Japan Project. We assessed the association of PRSLDLC with LDL-C and CAD among and within monogenic FH, mutation negative CDFH, and controls. We tested a total of 1223 participants (376 FH patients, including 173 with monogenic FH and 203 with mutation negative CDFH, and 847 controls) for the analyses. PRSLDLC was significantly higher in mutation negative CDFH patients than in controls (p = 3.1 × 10-13). PRSLDLC was also significantly linked to LDL-C in controls (p trend = 3.6 × 10-4) but not in FH patients. Moreover, we could not detect any association between PRSLDLC and CAD in any of the groups. In conclusion, mutation negative CDFH patients demonstrated significantly higher PRSLDLC than controls. However, PRSLDLC may have little additional effect on LDL-C and CAD among FH patients.

Prevalence and Impact of Apolipoprotein E7 on LDL Cholesterol Among Patients With Familial Hypercholesterolemia.

Background: It has been suggested that a rare mutant apolipoprotein E7, APOE7 (p.Glu262Lys, p.Glu263Lys), has been identified to be associated with hyperlipoproteinemia in the general population. Moreover, its prevalence has been shown to be 0.005–0.06%. However, there are no prior data regarding its prevalence and impact on serum lipids in patients with familial hypercholesterolemia (FH).Methods: We recruited 1,138 patients with clinically diagnosed FH [mean age = 48, men = 512, median low-density lipoprotein (LDL) cholesterol = 231 mg/dl]. The coding regions of three FH genes (LDLR, APOB, and PCSK9) and apolipoprotein E (APOE) gene were sequenced. We investigated the prevalence and impact of APOE7 mutant on serum lipid levels in patients with FH.Results: We identified 29 patients (2.5 %) with a mutant APOE7 (heterozygote), which is apparently much higher than that of the general population. Moreover, when we focus on those without FH mutation (n = 540), we identified 21 patients (3.9 %) with a mutant APOE7. Patients with a mutant APOE7 exhibited significantly higher median LDL cholesterol and triglyceride levels compared with those without this rare mutant (249 vs. 218 mg/dl, p < 0.05, 216 vs. 164 mg/dl, p < 0.05, respectively). Moreover, LDL cholesterol levels in the APOE7-oligogenic FH individuals, with a pathogenic mutation in FH genes and APOE7 mutant, were significantly higher than that in monogenic FH patients (265 vs. 245 mg/dl, p < 0.05).Conclusion: We identified more patients with a mutant APOE7 than expected among those diagnosed with FH clinically, especially among those without FH-causing mutation. This implies a mutant APOE7 may be one of the causes FH, especially among those without FH mutations.

The clinical applicability of polygenic risk scores for LDL-cholesterol: considerations, current evidence and future perspectives.

Purpose of reviewThe current review describes the development, clinical relevance and potential caveats of polygenic risk scores (PRS) for LDL cholesterol (LDL-C).Recent findingsIn recent years, a large number of common variants have been shown to have a small effect on LDL-C levels. The aggregate effect of all of these variants on LDL-C levels can be captured in a PRS and an elevated number of LDL-C increasing common variants is considered to be a cause of high LDL-C levels in patients with familial hypercholesterolemia (FH) without a large effect, rare mutation. PRS do not only serve as a tool in diagnostics, but are also helpful in cardiovascular disease (CVD) risk prediction. Moreover, PRS modulate CVD risk even in patients without a monogenic FH. However, future larger scale PRS directly aimed at CVD risk may serve as more sensitive tools to identify individuals with severely increased CVD risk.SummaryLDL-C PRS help explain part of hypercholesterolemia in a proportion of dyslipidemic patients that do not have monogenic FH. Nevertheless, the CVD risk conferred by current PRS does not appear to match that of monogenic FH. LDL-C PRS are currently not widely used in clinical care.

Familial Hypercholesterolemia: A Narrative Review on Diagnosis and Management Strategies for Children and Adolescents.

Familial hypercholesterolemia (FH) is a relatively common inherited disorder caused by deleterious mutation(s) in the low-density lipoprotein (LDL) receptor or its associated genes. Given its nature as a heritable disease, any useful screening scheme, including universal, and cascade screening, allows for the early identification of patients with FH. Another important aspect to note is that early diagnosis associated with appropriate treatment can promote better prognosis. However, most clinical diagnostic criteria for adults have adopted clinical elements, such as physical xanthomas and family history, both of which are usually obscure and/or difficult to obtain in children and adolescents. Moreover, LDL cholesterol levels fluctuating considerably during adolescence, hindering the timely diagnosis of FH. In addition, recent advancements in human genetics have revealed several types of FH, including conventional monogenic FH, polygenic FH caused by common single nucleotide variations (SNV) accumulation associated with elevated LDL cholesterol, and oligogenic FH with multiple deleterious genetic variations leading to substantially elevated LDL cholesterol. The aforementioned findings collectively suggest the need for amassing information related to genetics and imaging, in addition to classical clinical elements, for the accurate diagnosis of FH in this era of personalized medicine. The current narrative review summarizes the current status of the clinical and genetic diagnosis of FH in children and adolescents, as well as provide useful management strategies for FH in children and adolescents based on currently available clinical evidence.

Monogenic versus polygenic familial hypercholesterolemia: genetic risk score and response to treatment

Background and Aims: Background: A polygenic background can be recognized in part of patients with clinically diagnosed familial hypercholesterolemia (FH). The phenotypical distinction between monogenic (due to causative mutations in major LDLR, APOB or PCSK9 genes) and polygenic FH is not completely clarified. Aims: We aimed to compare the clinical phenotype and response to treatment in monogenic vs. polygenic FH

Higher responsiveness to rosuvastatin in polygenic versus monogenic hypercholesterolaemia: a propensity score analysis

Abstract Background The underlying monogenic defect in familial hypercholesterolemia (FH) can be detected in ∼40% of cases. The majority of mutation-negative patients have a polygenic cause of high LDL-cholesterol (LDL-C) due to having inherited a greater than average number of common LDL-C raising single nucleotide polymorphisms (SNPs). Purpose We sought to investigate, whether the monogenic or polygenic defect in FH is associated with the response to rosuvastatin. Methods Individuals with a clinical diagnosis of FH were tested for mutations in LDLR and APOB genes. A previously established LDL-C-specific polygenic risk score (PRS) was used to examine the possibility of polygenic hypercholesterolemia in mutation negative patients. The propensity score analysis was performed to evaluate the variables associated with the response to rosuvastatin. The type of hypercholesterolemia (polygenic or monogenic) and following variables: age, gender, LDL-baseline, statin intolerance, ezetimibe use, rosuvastatin dose, diabetes and cardiovascular disease (CVD), were examined to minimize the bias of this observational study. Results LDLR/APOB mutation was found in 47 (42%) patients, whereas polygenic hypercholesterolemia was diagnosed in 65 (58%) of patients. Mean age was comparable in both groups (54±13 vs 51±13, p=0.134). CVD was diagnosed in ≈26% of individuals in both cohorts (p=0.343). There was no difference in the distribution of CV risk factors, such as arterial hypertension, smoking, diabetes, body mass index and in rate of statin intolerance. Monogenic subjects had higher baseline LDL-C compared to polygenic (Table 1). Adjusted model showed a lower percentage of change in LDL-C after rosuvastatin treatment in monogenic vs. polygenic subjects (46% vs 55%, p&amp;lt;0.001) (Figure 1). The probability of achieving LDL-C targets in monogenic FH was lower than in polygenic subjects (0.075 vs. 0.245, p=0.004). Polygenic patients were more likely to achieve LDL-C goals, compared to mutation-positive patients (OR 3.28; 95% CI:1.23–8.72). Conclusion Our findings indicate an essentially higher responsiveness to rosuvastatin in patients with a polygenic cause, as compared to those carrying monogenic mutations. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): 1. Polish Ministry of Science and Higher Education European Regional Development Fund under the Programme Innovative Economy 2007–2013 (POIG.01.01.02-22-079/09). 2. British Heart Foundation (PG 08/008). 3. The National Institute for Health Research, University College London Hospitals, Biomedical Research Centre. 4. The Foundation Leducq Transatlantic Networks of Excellence Program grant (no. 14 CVD03)

POLYGENIC CONTRIBUTION TO LOW-DENSITY LIPOPROTEIN CHOLESTEROL LEVELS AND CARDIOVASCULAR RISK IN MONOGENIC FAMILIAL HYPERCHOLESTEROLEMIA

Familial hypercholesterolemia (FH) is the most common autosomal dominant genetic disorder, and causes elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of atherosclerotic cardiovascular disease (ASCVD). Even among patients with monogenic FH, there is substantial interindividual variability in LDL-C levels and risk of ASCVD. We assessed the influence of an LDL-C polygenic score on levels of LDL-C and risk of ASCVD for individuals with monogenic FH.

Polygenic Markers in Patients Diagnosed of Autosomal Dominant Hypercholesterolemia in Catalonia: Distribution of Weighted LDL-c-Raising SNP Scores and Refinement of Variant Selection.

Familial hypercholesterolemia (FH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes. A pathological variant has not been identified in 30–70% of clinically diagnosed FH patients, and a burden of LDL cholesterol (LDL-c)-raising alleles has been hypothesized as a potential cause of hypercholesterolemia in these patients. Our aim was to study the distribution of weighted LDL-c-raising single-nucleotide polymorphism (SNP) scores (weighted gene scores or wGS) in a population recruited in a clinical setting in Catalonia. The study included 670 consecutive patients with a clinical diagnosis of FH and a prior genetic study involving 250 mutation-positive (FH/M+) and 420 mutation-negative (FH/M−) patients. Three wGSs based on LDL-c-raising variants were calculated to evaluate their distribution among FH patients and compared with 503 European samples from the 1000 Genomes Project. The FH/M− patients had significantly higher wGSs than the FH/M+ and control populations, with sensitivities ranging from 42% to 47%. A wGS based only on the SNPs significantly associated with FH (wGS8) showed a higher area under the receiver operating characteristic curve, and higher diagnostic specificity and sensitivity, with 46.4% of the subjects in the top quartile. wGS8 would allow for the assignment of a genetic cause to 66.4% of the patients if those with polygenic FH are added to the 37.3% of patients with monogenic FH. Our data indicate that a score based on 8 SNPs and the75th percentile cutoff point may identify patients with polygenic FH in Catalonia, although with limited diagnostic sensitivity and specificity.

Polygenic Contribution to Low-Density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is a common autosomal codominant genetic disorder, which causes elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Even among individuals with monogenic FH, there is substantial interindividual variability in LDL-C levels and risk of ASCVD. We assessed the influence of an LDL-C polygenic score on levels of LDL-C and risk of ASCVD for individuals with monogenic FH. We constructed a weighted LDL-C polygenic score, composed of 28 single-nucleotide variants, for individuals with monogenic FH from the British Columbia FH (n=262); Nutrition, Metabolism and Atherosclerosis Clinic (n=552); and UK Biobank cohorts (n=306). We assessed the association between LDL-C polygenic score with LDL-C levels and ASCVD risk using linear regression and Cox-proportional hazard models, respectively. ASCVD was defined as myocardial infarction, coronary or carotid revascularization, transient ischemic attack, or stroke. The results from individual cohorts were combined in fixed-effect meta-analyses. Levels of LDL-C were significantly associated with LDL-C polygenic score in the Nutrition, Metabolism and Atherosclerosis Clinic cohort, UK Biobank cohort, and in the meta-analysis (β [95% CI]=0.13 [0.072-0.19] per a 20% increase in LDL-C polygenic score percentile, P<0.0001). Additionally, an elevated LDL-C polygenic score (≥80th percentile) was associated with a trend towards increased ASCVD risk in all 3 cohorts individually. This association was statistically significant in the meta-analysis (hazard ratio [95% CI]=1.48 [1.02-2.14], P=0.04). Polygenic contributions to LDL-C explain some of the heterogeneity in clinical presentation and ASCVD risk for individuals with FH.

Prevalence Of familial hypercholeSTerolaemia (FH) in Italian Patients with coronary artERy disease: The POSTER study

Background and aimsFamilial hypercholesterolaemia (FH) is a powerful risk factor for cardiovascular (CV) events. High levels of low-density lipoprotein cholesterol (LDL-C) since birth are linked to the early onset of atherosclerotic disease. A genetic mutation determining FH is present in about one subject out of 250; FH should be more represented among subjects with a documented diagnosis of coronary artery disease (CAD). The POSTER Study evaluated the prevalence of FH in Italian patients with a recent CAD event. MethodsEighty-two cardiology centres enrolled patients with a documented CAD event; CV risk profile, drug therapy and biochemical parameters were collected. Dutch Lipid Clinic Network (DLCN) criteria were used to define patients with a potential FH diagnosis (score ≥6); these patients underwent molecular testing for genetic diagnosis of FH. ResultsOverall, 5415 patients were enrolled and the main index events were myocardial infarction with ST-elevation, non ST-elevation acute coronary syndrome (ACS), or a recent coronary revascularization (34.8%, 37.2%, and 28% respectively). Mean age was 66 ± 11 years, men were 78%; about 40% were already treated with statins, proportion that increased after the acute event (96.5%). Based on the DLCN score, the prevalence of potential FH was 5.1%, 0.9% of them had a diagnosis of definite FH (score >8). These patients were younger than patients with a score <6 (56 ± 10 vs 66 ± 11, p < 0.001), and LDL-C levels were in most of them (~87%) >190 mg/dL. FH was genetically confirmed in 42 subjects (15.9%); genetic diagnosis was defined as not conclusive for FH in 63 patients (23.9%). Finally, in 159 subjects (60.2%) no pathogenic mutations in the tested genes were identified, defining them as negative for monogenic familial hypercholesterolemia. ConclusionsResults underscore a relatively high prevalence of potential FH in patients with a recent CAD event. Therefore, an early identification of these subjects may help improve the management of their high CV risk and, by cascade screening, identify possible FH relatives.

Cholesterol metabolism in mice models of genetic hypercholesterolemia.

Monogenic familial hypercholesterolemia is characterized by impaired cellular uptake of apolipoprotein B containing lipoproteins. However, its consequences on whole-body cholesterol metabolism are unclear. We investigated cholesterol metabolism in wild-type mice (control) and in knockout (KO) mice for the low-density lipoprotein receptor (LDLR-KO) and for apolipoprotein E (apoE-KO) containing the genetic basis of the C57BL/6J mice, under a cholesterol-free diet. Cholesterol and "non-cholesterol" sterols (cholestanol, desmosterol, and lathosterol) were measured in plasma, tissues, as well as in feces as cholesterol and its bacterial modified products (neutral sterols) using gas chromatography/mass spectrometry, and bile acids were measured by an enzymatic method. Compared to controls, LDLR-KO mice have elevated plasma and whole-body cholesterol concentrations, but total fecal sterols are not modified, characterizing unaltered body cholesterol synthesis together with impaired body cholesterol excretion. ApoE-KO mice presented the highest concentrations of plasma cholesterol, whole-body cholesterol, cholestanol, total fecal sterols, and cholestanol, compatible with high cholesterol synthesis rate; the latter seems attributed to elevated body desmosterol (Bloch cholesterol synthesis pathway). Nonetheless, whole-body lathosterol (Kandutsch-Russel cholesterol synthesis pathway) decreased in both KO models, likely explaining the diminished fecal bile acids. We have demonstrated for the first time quantitative changes of cholesterol metabolism in experimental mouse models that explain differences between LDLR-KO and apoE-KO mice. These findings contribute to elucidate the metabolism of cholesterol in human hypercholesterolemia of genetic origin.

Familial hypercholesterolemia: is it time to separate monogenic from polygenic familial hypercholesterolemia?

This review explores the concepts of monogenic and the so-called polygenic familial hypercholesterolemia and how the identification of familial hypercholesterolemia as a monogenic condition and its separation from polygenic primary hypercholesterolemia may have implications for clinical practice. Through genetic testing, a mutation in any of the three known autosomal dominant familial hypercholesterolemia-causing genes is found in 60-80% of cases with a clinical diagnosis of definite familial hypercholesterolemia. As individuals with a polygenic basis for their hypercholesterolemia do not follow the same inheritance pattern observed in monogenic familial hypercholesterolemia, the use of family-based cascade screening in individuals with a polygenic origin is not recommend, as only 30% of relatives have an elevated LDL-C compared to the 50% in monogenic families. The presence of a causative monogenic mutation associates the highest cardiovascular risk vs. not having a mutation or having a polygenic background, providing prognostic information independent of LDL-C. It may also help assess intensity of interventions. Treatment adherence also seems to be higher after monogenic confirmation of hypercholesterolemia. Knowledge about the genetic status of an individual with clinical familial hypercholesterolemia (monogenic vs. polygenic) can provide a more informed understanding to evaluating risk, managing disease and opportunities for screening strategies.

Higher Responsiveness to Rosuvastatin in Polygenic versus Monogenic Hypercholesterolaemia: A Propensity Score Analysis.

Background: The monogenic defect in familial hypercholesterolemia (FH) is detected in ∼40% of cases. The majority of mutation-negative patients have a polygenic cause of high LDL-cholesterol (LDL-C). We sought to investigate whether the underlying monogenic or polygenic defect is associated with the response to rosuvastatin. Methods: FH Individuals were tested for mutations in LDLR and APOB genes. A previously established LDL-C-specific polygenic risk score (PRS) was used to examine the possibility of polygenic hypercholesterolemia in mutation-negative patients. All of the patients received rosuvastatin and they were followed for 8 ± 2 months. A propensity score analysis was performed to evaluate the variables associated with the response to treatment. Results: Monogenic subjects had higher mean (±SD) baseline LDL-C when compared to polygenic (7.6 ± 1.5 mmol/L vs. 6.2 ± 1.2 mmol/L; p < 0.001). Adjusted model showed a lower percentage of change in LDL-C after rosuvastatin treatment in monogenic patients vs. polygenic subjects (45.9% vs. 55.4%, p < 0.001). The probability of achieving LDL-C targets in monogenic FH was lower than in polygenic subjects (0.075 vs. 0.245, p = 0.004). Polygenic patients were more likely to achieve LDL-C goals, as compared to those monogenic (OR 3.28; 95% CI: 1.23–8.72). Conclusion: Our findings indicate an essentially higher responsiveness to rosuvastatin in FH patients with a polygenic cause, as compared to those carrying monogenic mutations.

Verification of Underlying Genetic Cause in a Cohort of Russian Patients with Familial Hypercholesterolemia Using Targeted Next Generation Sequencing.

Russian patients with familial hypercholesterolemia (FH) were screened for pathogenic mutations using targeted next generation sequencing. Genetic testing was performed in 52 probands with definite or probable FH based on the Dutch lipid clinic network criteria (DLCN score ≥ 6). Blood samples were studied by massive parallel sequencing (Illumina HiSeq 1500 platform) using a custom capture library related to dyslipidemia and premature atherosclerosis. Mutations considered to be responsible for monogenic FH were identified in 48% of the probands: 24 with mutations in the LDLR gene and two with a mutation in the APOB gene. There were 22 pathogenic/likely pathogenic mutations in LDLR, eight of which have not been previously described in the literature. Four patients with a clinical picture of homozygous FH had two heterozygous LDLR mutations. Although mutation-negative patients had highly elevated total cholesterol and low-density lipoprotein cholesterol levels, only half of them had a family history of hypercholesterolemia. With respect to heterozygous FH, mutation-positive patients had higher maximum total cholesterol levels (p = 0.01), more severe carotid atherosclerotic lesions, and a higher percentage of premature peripheral artery disease (p = 0.03) than mutation-negative ones. However, the number of patients who suffered from myocardial infarction was similar between the two groups.