Predicted deleterious variants in ABCA1, LPL, LPA and KIF6 are associated with statin response and adverse events in patients with familial hypercholesterolemia and disturb protein structure and stability

OBJECTIVES: This study explored the association of deleterious variants in pharmacodynamics (PD) genes with statin response and adverse effects in patients with familial hypercholesterolemia (FH) and analyzed their potential effects on protein structure and stability. METHODS: Clinical and laboratory data were obtained from 144 adult FH patients treated with statins. A panel of 32 PD genes was analyzed by exon-targeted gene sequencing. Deleterious variants were identified using prediction algorithms and their structural effects were analyzed by molecular modeling studies. RESULTS: A total of 102 variants were predicted as deleterious (83 missense, 8 stop-gain, 4 frameshift, 1 indel, 6 splicing). The variants ABCA1 rs769705621 (indel), LPA rs41267807 (p.Tyr2023Cys) and KIF6 rs20455 (p.Trp719Arg) were associated with reduced low-density lipoprotein cholesterol (LDLc) response to statins, and the LPL rs1801177 (p.Asp36Asn) with increased LDLc response (P < 0.05). LPA rs3124784 (p.Arg2016Cys) was predicted to increase statin response (P = 0.022), and ABCA1 rs769705621 to increase the risk of statin-related adverse events (SRAE) (P = 0.027). LPA p.Arg2016Cys and LPL p.Asn36Asp maintained interactions with solvent, LPA p.Tyr2023Cys reduced intramolecular interaction with Gln1987, and KIF6 p.Trp719Arg did not affect intramolecular interactions. DDMut analysis showed that LPA p.Arg2016Cys and p.Tyr2023Cys and LPL p.Asp36Asn caused energetically favorable changes, and KIF6 p.Trp719Arg resulted in unfavorable energetic changes, affecting protein stability. CONCLUSION: Deleterious variants in ABCA1, LPA, LPL and KIF6 are associated with variability in LDLc response to statins, and ABCA1 rs769705621 is associated with SRAE risk in FH patients. Molecular modeling studies suggest that LPA p.Tyr2023Cys and KIF6 p.Trp719Arg disturb protein conformational structure and stability.

Evinacumab: Mechanism of action, clinical, and translational science.

Homozygous familial hypercholesterolemia (HoFH) is a rare and serious genetic condition characterized by premature cardiovascular disease due to severely elevated low-density lipoprotein cholesterol (LDL-C). HoFH primarily results from loss-of-function (LOF) mutations in the LDL receptor (LDLR), reducing LDL-C clearance such that patients experience severe hypercholesterolemia, exacerbating the risk of developing cardiovascular events. Treatment options such as statins, lomitapide, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and apheresis help lower LDL-C; however, many patients with HoFH still fail to reach their target LDL-C levels and many of these lipid-lowering therapies are not indicated for pediatric use. Angiopoietin-like protein 3 (ANGPTL3) has been identified as a target to treat elevated LDL-C by acting as a natural inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL), enzymes involved in the hydrolysis of the triglyceride and phospholipid content of very low-density lipoproteins. Persons heterozygous for LOF mutations in ANGPTL3 were reported to have lower LDL-C than non-carriers and lower risk of coronary artery disease. Evinacumab is a first-in-class human monoclonal antibody that specifically binds to ANGPTL3 to prevent its inhibition of LPL and EL. In clinical trials, a 15 mg/kg intravenous dose every 4 weeks has shown a mean percent change from baseline in LDL-C of ~50% in adult, adolescent, and pediatric patients with HoFH. This mini review article describes the mechanism of action of evinacumab, evinacumab population PK and PD modeling, and clinical development history of evinacumab for the treatment of HoFH.

Resilient Older Subjects with Heterozygous Familial Hypercholesterolemia, Baseline Differences and Associated Factors.

Despite elevated low-density lipoprotein (LDL) cholesterol levels, some older subjects with heterozygous familial hypercholesterolemia (HeFH) do not develop atherosclerotic cardiovascular disease (ACVD) during their lifetime. The factors related to this resilient state have not been fully established. The aim of this study was to evaluate differential characteristics between older HeFH subjects with and without ACVD and factors associated with the presence of ACVD. Subjects were part of the Spanish Atherosclerosis Society Dyslipidemia Registry, and those ≥ 70 years old and with HeFH were included. Baseline characteristics of these subjects with and without ACVD were compared. A multivariate analysis was performed to assess factors associated with the presence of ACVD. A total of 2148 subjects with HeFH were included. Resilient subjects were mostly female, younger and presented fewer comorbidities with respect to the ACVD group. Subjects without ACVD had higher baseline high-density lipoprotein (HDL) cholesterol (55.8 ± 17.1 vs. 47.9 ± 15.4 mg/dL; p < 0.001) and lower lipoprotein(a) [Lp(a)] (53.4 ± 67.9 vs. 66.6 ± 85.6 mg/dL; p < 0.001) levels with respect to those in the ACVD group. Lp(a) and the presence of ≥3 risk factors were associated with the presence of ACVD.

It is Time to Screen for Homozygous Familial Hypercholesterolemia in the United States.

Homozygous familial hypercholesterolemia (HoFH) is an ultra-rare inherited condition that affects approximately one in 300,000 people. The disorder is characterized by extremely high, life-threatening levels of low-density lipoprotein (LDL) cholesterol from birth, leading to significant premature cardiovascular morbidity and mortality, if left untreated. Homozygous familial hypercholesterolemia is severely underdiagnosed and undertreated in the United States (US), despite guidelines recommendations for universal pediatric lipid screening in children aged 9-11. Early diagnosis and adequate treatment are critical in averting premature cardiovascular disease in individuals affected by HoFH. Yet, an unacceptably high number of people living with HoFH remain undiagnosed, misdiagnosed, and/or receive a late diagnosis, often after a major cardiovascular event. The emergence of novel lipid-lowering therapies, along with the realization that diagnosis is too often delayed, have highlighted an urgency to implement policies that ensure timely detection of HoFH in the US. Evidence from around the world suggests that a combination of universal pediatric screening and cascade screening strategies constitutes an effective approach to identifying heterozygous familial hypercholesterolemia (HeFH). Nevertheless, HoFH and its complications manifest much earlier in life compared to HeFH. To date, little focus has been placed on the detection of HoFH in very young children and/or infants. The 2023 Updated European Atherosclerosis Society Consensus Statement on HoFH has recommended, for the first time, broadening pediatric guidelines to include lipid screening of newborn infants. Some unique aspects of HoFH need to be considered before implementing newborn screening. As such, insights from pilot studies conducted in Europe may provide some preliminary guidance. Our paper proposes a set of actionable measures that states can implement to reduce the burden of HoFH. It also outlines key research and policy gaps that need to be addressed in order to pave the way for universal newborn screening of HoFH in the US.

Analysis of the Correlation between FH and PCSK9 and APOB Gene Mutations in Han and Mongolian Populations of the Hulunbuir.

BACKGROUND: The goal of the study was to provide an individual and precise genetic and molecular biological basis for the early prevention, diagnosis, and treatment of local FH by analyzing the risk factors for the development of FH in Han and Mongolian patients in the Hulunbuir, comparing the lipid levels of FH patients of the two ethnicities, and assessing differences in mutations to two genes between the two ethnic groups. METHODS: Twenty cases each of Han Chinese and Mongolian healthy controls and fifty patients who each met the inclusion criteria from November 2021 to December 2022 in five general hospitals in Hulunbuir were selected. Multifactor logistic analysis was used to analyze the risk factors associated with the development of FH. We used t-tests to analyze statistical differences in lipid levels between the groups, and Sanger sequencing to detect the dis-tribution of common mutation sites of PCSK9 and APOB in all study subjects. The mutation rates and differences between regions and ethnic groups were summarized and compared. RESULTS: 1) Gender, age, alcohol consumption, dietary status, and a family history of FH were risk factors associated with the development of FH. 2) TC, LDL-C, and APOB were significantly higher in Mongolian cases than Han cases (p < 0.05). sdLDL-C was not statistically different between the two ethnicities (p > 0.05). 3) We detected four (8%) heterozygous mutations at the PCSK9 gene E670G mutation site in the Han case group and a total of nine (18%) mutations at this site in the Mongolian cases, including one (2%) homozygous and eight (16%) heterozygous mutations. One case of a heterozygous mutation was detected in the Mongolian control group. We detected a total of ten (20%) mutations at the APOB gene rs1367117 mutation site in the Han case group, including eight (16%) heterozygous and two (4%) homozygous mutations, 11 cases (22%) of heterozygous mutations in the Mongolian case group, two cases of heterozygous mutations in the Han control group, and one case of a heterozygous mutation in the Mongolian control group. 4) The D374Y and S127R mutation sites of PCSK9 and the R3500Q mutation site of APOB were not detected in any of the study subjects. CONCLUSIONS: The mutation sites of the PCSK9 and APOB genes in FH patients in Hulunbuir are different from other regions, and the mutation rate is higher than in other regions. Therefore, we recommend that the mutation sites of the PCSK9 and APOB genes described herein be used as clinical detection indicators to assist the diagnosis of FH in this region.

Algorithm for detection and screening of familial hypercholesterolemia in Lithuanian population.

BACKGROUND: Familial hypercholesterolemia (FH) is one of the most common autosomal dominant diseases. FH causes a lifelong increase in low-density lipoprotein cholesterol (LDL-C) levels, which in turn leads to atherosclerotic cardiovascular disease. The incidence of FH is widely underestimated and undertreated, despite the availability and effectiveness of lipid-lowering therapy. Patients with FH have an increased cardiovascular risk; therefore, early diagnosis and treatment are vital. To address the burden of FH, several countries have implemented national FH screening programmes. The currently used method for FH detection in Lithuania is mainly based on opportunistic testing with subsequent cascade screening of index cases' first-degree relatives. METHODS: A total of 428 patients were included in this study. Patients with suspected FH are referred to a lipidology center for thorough evaluation. Patients who met the criteria for probable or definite FH according to the Dutch Lipid Clinic Network (DLCN) scoring system and/or had LDL-C > = 6.5 mmol/l were subjected to genetic testing. Laboratory and instrumental tests, vascular marker data of early atherosclerosis, and consultations by other specialists, such as radiologists and ophthalmologists, were also recorded. RESULTS: A total of 127/428 (30%) patients were genetically tested. FH-related mutations were found in 38.6% (n = 49/127) of the patients. Coronary artery disease (CAD) was diagnosed in 13% (n = 57/428) of the included patients, whereas premature CAD was found in 47/428 (11%) patients. CAD was diagnosed in 19% (n = 9/49) of patients with FH-related mutations, and this diagnosis was premature for all of them. CONCLUSIONS: Most patients in this study were classified as probable or possible FH without difference of age and sex. The median age of FH diagnosis was 47 years with significantly older females than males, which refers to the strong interface of this study with the LitHir programme. CAD and premature CAD were more common among patients with probable and definite FH, as well as those with an FH-causing mutation. The algorithm described in this study is the first attempt in Lithuania to implement a specific tool which allows to maximise FH detection rates, establish an accurate diagnosis of FH, excluding secondary causes of dyslipidaemia, and to select patients for cascade screening initiation more precisely.

Evinacumab and Cardiovascular Outcome in Patients With Homozygous Familial Hypercholesterolemia.

BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) remain at very high cardiovascular risk despite the best standard of care lipid-lowering treatment. The addition of evinacumab, an angiopoietin-like protein 3 monoclonal antibody, more than halves low-density lipoprotein cholesterol in short-term studies. This study evaluated whether the evinacumab response was durable in the long term and improved cardiovascular outcome. METHODS: The OLE ELIPSE HoFH (Open-Label Extension to Evinacumab Lipid Studies in Patients With HoFH) study included newly diagnosed patients and those completing the ELIPSE HoFH trial, on stable lipid-lowering therapy including lipoprotein apheresis but not lomitapide. All patients received evinacumab (15 mg/kg intravenously) every 4 weeks, with no change in concomitant lipid-lowering treatment during the first 6 months. The primary efficacy end points were the mean absolute and percentage changes in low-density lipoprotein cholesterol from baseline to 6 months. A key secondary end point was cardiovascular event-free survival, which was compared with a control HoFH cohort not treated with evinacumab or lomitapide and matched for age, sex, and lipoprotein apheresis, derived from French Registry of Familial hypercholesterolemia. RESULTS: Twelve patients, 5 women and 7 men (12-57 years), were enrolled in 3 centers in France. At 6 months, the mean low-density lipoprotein cholesterol reduction with evinacumab was 3.7 mmol/L or 56% (from 6.5 mmol/L at baseline to 2.8 mmol/L; P<0.0001) and was sustained over the median 3.5-year follow-up. No patients on evinacumab experienced cardiovascular events versus 13 events for 5/21 (24%) over 4 years in the control cohort (likelihood P=0.0267). CONCLUSIONS: Real-life, long-term evinacumab adjunctive to lipid-lowering therapy including lipoprotein apheresis led to sustained low-density lipoprotein cholesterol lowering and improved cardiovascular event-free survival of patients with HoFH.

Implementation of a primary-tertiary shared care model to improve the detection of familial hypercholesterolaemia (FH): a mixed methods pre-post implementation study protocol.

INTRODUCTION: Familial hypercholesterolaemia (FH) is an autosomal dominant inherited disorder of lipid metabolism and a preventable cause of premature cardiovascular disease. Current detection rates for this highly treatable condition are low. Early detection and management of FH can significantly reduce cardiac morbidity and mortality. This study aims to implement a primary-tertiary shared care model to improve detection rates for FH. The primary objective is to evaluate the implementation of a shared care model and support package for genetic testing of FH. This protocol describes the design and methods used to evaluate the implementation of the shared care model and support package to improve the detection of FH. METHODS AND ANALYSIS: This mixed methods pre-post implementation study design will be used to evaluate increased detection rates for FH in the tertiary and primary care setting. The primary-tertiary shared care model will be implemented at NSW Health Pathology and Sydney Local Health District in NSW, Australia, over a 12-month period. Implementation of the shared care model will be evaluated using a modification of the implementation outcome taxonomy and will focus on the acceptability, evidence of delivery, appropriateness, feasibility, fidelity, implementation cost and timely initiation of the intervention. Quantitative pre-post and qualitative semistructured interview data will be collected. It is anticipated that data relating to at least 62 index patients will be collected over this period and a similar number obtained for the historical group for the quantitative data. We anticipate conducting approximately 20 interviews for the qualitative data. ETHICS AND DISSEMINATION: Ethical approval has been granted by the ethics review committee (Royal Prince Alfred Hospital Zone) of the Sydney Local Health District (Protocol ID: X23-0239). Findings will be disseminated through peer-reviewed publications, conference presentations and an end-of-study research report to stakeholders.

Current US prevalence of myocardial injury patterns and clinical outcomes among hospitalised patients with familial hypercholesterolaemia: insight from the National Inpatient Sample-a retrospective cohort study.

BACKGROUND: Familial hypercholesterolaemia (FH) increases propensity for premature atherosclerotic disease. Knowledge of inpatient outcomes among patients with FH admitted with acute myocardial injury (AMI) is limited. OBJECTIVES: Our study aimed to identify myocardial injury types, including type 1 myocardial infarction (MI), type 2 MI and takotsubo cardiomyopathy, assess lesion severity and study adverse short-term inpatient outcomes among patients with FH admitted with AMI. SETTING: Our study retrospectively queried the US National Inpatient Sample from 2018 to 2020. POPULATION: Adults admitted with AMI and dichotomised based on the presence of FH. STUDY OUTCOMES: We evaluated myocardial injury types and complexity of coronary revascularisation. Primary outcome of all-cause mortality and other clinical secondary outcomes were studied. RESULTS: There were 3 711 765 admissions with AMI including 2360 (0.06%) with FH. FH was associated with higher odds of ST-elevation MI (STEMI) (adjusted OR (aOR): 1.62, p<0.001) and non-ST-elevation MI (NSTEMI) (aOR: 1.29, p<0.001) but lower type 2 MI (aOR: 0.39, p<0.001) and takotsubo cardiomyopathy (aOR: 0.36, p=0.004). FH was associated with higher multistent percutaneous coronary interventions (aOR: 2.36, p<0.001), multivessel coronary artery bypass (aOR: 2.65, p<0.001), higher odds of intracardiac thrombus (aOR: 3.28, p=0.038) and mechanical circulatory support (aOR: 1.79, p<0.001). There was 50% reduction in odds of all-cause mortality (aOR: 0.50, p=0.006) and lower odds of mechanical ventilation (aOR: 0.37, p<0.001). There was no difference in rate of ventricular tachycardia, cardioversion, new implantable cardioverter defibrillator implantation, cardiogenic shock and cardiac arrest. CONCLUSION: Among patients hospitalised with AMI, FH was associated with higher STEMI and NSTEMI, lower type 2 MI and takotsubo cardiomyopathy, higher number of multiple stents and coronary bypasses, and mechanical circulatory support device but was associated with lower all-cause mortality and rate of mechanical ventilation.

Human In Vitro Oxidized Low-Density Lipoprotein (oxLDL) Increases Urinary Albumin Excretion in Rats.

Hypercholesterolemia-associated oxidative stress increases the formation of oxidized low-density lipoprotein (oxLDL), which can affect endothelial cell function and potentially contribute to renal dysfunction, as reflected by changes in urinary protein excretion. This study aimed to investigate the impact of exogenous oxLDL on urinary excretion of albumin and nephrin. LDL was isolated from a patient with familial hypercholesterolemia (FH) undergoing lipoprotein apheresis (LA) and was oxidized in vitro with Cu (II) ions. Biochemical markers of LDL oxidation, such as TBARS, conjugated dienes, and free ε-amino groups, were measured. Wistar rats were treated with a single intraperitoneal injection of PBS, LDL, or oxLDL (4 mg of protein/kg b.w.). Urine was collected one day before and two days after the injection. We measured blood lipid profiles, urinary protein excretion (specifically albumin and nephrin), and markers of systemic oxidative stress (8-OHdG and 8-iso-PGF2α). The results showed that injection of oxLDL increased urinary albumin excretion by approximately 28% (310 ± 27 µg/24 h vs. 396 ± 26 µg/24 h, p = 0.0003) but had no effect on nephrin excretion. Neither PBS nor LDL had any effect on urinary albumin or nephrin excretion. Additionally, oxLDL did not affect systemic oxidative stress. In conclusion, hypercholesterolemia may adversely affect renal function through oxidatively modified LDL, which interferes with the renal handling of albumin and leads to the development of albuminuria.

Familial hypercholesterolemia.

Familial hypercholesterolemia is a common genetic disorder of autosomal inheritance associated with elevated LDL-cholesterol. It is estimated to affect 1:250 individuals in general population roughly estimated to be 5 million in India. The prevalence of FH is higher in young CAD patients (<55 years in men; <60 years in women). FH is underdiagnosed and undertreated. Screening during childhood and Cascade screening of family members of known FH patients is of utmost importance in order to prevent the burden of CAD. Early identification of FH patients and early initiation of the lifelong lipid lowering therapy is the most effective strategy for managing FH. FH management includes pharmaceutical agents (statins and non statin drugs) and lifestyle modification. Inspite of maximum dose of statin with or without Ezetimibe, if target levels of LDL-C are not achieved, Bempedoic acid, proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibitors/Inclisiran can be added.

Role of statins in the management of dyslipidaemia.

Blood cholesterol has firmly been established as a crucial risk factor for the development of atherosclerotic cardiovascular disease (ASCVD) by elegant epidemiological studies. Naturally, means to reduce blood cholesterol level took the centerstage of research in this field. After initial lukewarm results with nicotinic acid, fibrates and some other agents, statins emerged as the most effective class of medicine to reduce blood cholesterol; in particular, the most atherogenic low density lipoprotein cholesterol (LDL-C). Also, they are very safe and well tolerated. As ASCVD comes in various stages, statins have also been tried in different settings, e.g., primary prevention, secondary prevention, as part of coronary intervention strategy, familial hypercholesterolemia, etc. Almost in all clinical scenarios, statins proved themselves to impart clinical benefit. Though side effects of statins are outweighed by their benefits, nonetheless clinicians should detect the side effects early to avoid major problems.

A machine-learning algorithm using claims data to identify patients with homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is an underdiagnosed and undertreated ultra-rare disease. We utilized claims data from the Komodo Healthcare Map database to develop a machine-learning model to identify potential HoFH patients. We tokenized patients enrolled in MyRARE (patient support program for those prescribed evinacumab-dgnb in the United States) and linked them with their Komodo claims. A true positive HoFH cohort (n = 331) was formed by including patients from MyRARE and patients with prescriptions for evinacumab-dgnb or lomitapide. The negative cohort (n = 1423) comprised patients with or at risk for cardiovascular disease. We divided the cohort into an 80% training and 20% testing set. Overall, 10,616 candidate features were investigated; 87 were selected due to clinical relevance and importance on prediction performance. Different machine-learning algorithms were explored, with fast interpretable greedy-tree sums selected as the final machine-learning tool. This selection was based on its satisfactory performance and its easily interpretable nature. The model identified four useful features and yielded precision (positive predicted value) of 0.98, recall (sensitivity) of 0.88, area under the receiver operating characteristic curve of 0.98, and accuracy of 0.97. The model performed well in identifying HoFH patients in the testing set, providing a useful tool to facilitate HoFH screening and diagnosis via healthcare claims data.

Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolaemia: An expert consensus statement from ERKNet and ESPN.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

Gene expression profiling in elderly patients with familial hypercholesterolemia with and without coronary heart disease.

BACKGROUND AND AIMS: Elderly familial hypercholesterolemia (FH) patients are at high risk of coronary heart disease (CHD) due to high cholesterol burden and late onset of effective cholesterol-lowering therapies. A subset of these individuals remains free from any CHD event, indicating the potential presence of protective factors. Identifying possible cardioprotective gene expression profiles could contribute to our understanding of CHD prevention and future preventive treatment. Therefore, this study aimed to investigate gene expression profiles in elderly event-free FH patients. METHODS: Expression of 773 genes was analysed using the Nanostring Metabolic Pathways Panel, in peripheral blood mononuclear cells (PBMCs) from FH patients ≥65 years without CHD (FH event-free, n = 44) and with CHD (FH CHD, n = 39), and from healthy controls ≥70 years (n = 39). RESULTS: None of the genes were differentially expressed between FH patients with and without CHD after adjusting for multiple testing. However, at nominal p < 0.05, we found 36 (5%) differentially expressed genes (DEGs) between the two FH groups, mainly related to lipid metabolism (e.g. higher expression of ABCA1 and ABCG1 in FH event-free) and immune responses (e.g. lower expression of STAT1 and STAT3 in FH event-free). When comparing FH patients to controls, the event-free group had fewer DEGs than the CHD group; 147 (19%) and 219 (28%) DEGs, respectively. CONCLUSIONS: Elderly event-free FH patients displayed a different PBMC gene expression profile compared to FH patients with CHD. Differences in gene expression compared to healthy controls were more pronounced in the CHD group, indicating a less atherogenic gene expression profile in event-free individuals. Overall, identification of cardioprotective factors could lead to future therapeutic targets.

Impact of 12-SNP and 6-SNP Polygenic Scores on Predisposition to High LDL-Cholesterol Levels in Patients with Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) comprises high LDL-cholesterol (LDL-c) levels and high cardiovascular disease risk. In the absence of pathogenic variants in causative genes, a polygenic basis was hypothesized. METHODS: In a population of 418 patients (excluding homozygotes) with clinical suspicion of FH, the FH-causative genes and the regions of single nucleotide polymorphisms (SNPs) included in 12-SNP and 6-SNP scores were sequenced by next-generation sequencing, allowing for the detection of pathogenic variants (V+) in 220 patients. To make a comparison, only patients without uncertain significance variants (V-/USV-) were considered (n = 162). RESULTS: Higher values of both scores were observed in V+ than in V-. Considering a cut-off leading to 80% of V-/USV- as score-positive, a lower prevalence of patients positive for both 12-SNP and 6-SNP scores was observed in V+ (p = 0.010 and 0.033, respectively). Mainly for the 12-SNP score, among V+ patients, higher LDL-c levels were observed in score-positive (223 mg/dL -IQR 187-279) than in negative patients (212 mg/dL -IQR 162-240; p = 0.006). Multivariate analysis confirmed the association of scores and LDL-c levels independently of age, sex, and presence of pathogenic variants and revealed a greater association in children. CONCLUSIONS: The 12-SNP and 6-SNP polygenic scores could explain hypercholesterolemia in patients without pathogenic variants as well as the variability of LDL-c levels among patients with FH-causative variants.

Family cascade screening for equitable identification of familial hypercholesterolemia: study protocol for a hybrid effectiveness-implementation type III randomized controlled trial.

BACKGROUND: Familial hypercholesterolemia (FH) is a heritable disorder affecting 1.3 million individuals in the USA. Eighty percent of people with FH are undiagnosed, particularly minoritized populations including Black or African American people, Asian or Asian American people, and women across racial groups. Family cascade screening is an evidence-based practice that can increase diagnosis and improve health outcomes but is rarely implemented in routine practice, representing an important care gap. In pilot work, we leveraged best practices from behavioral economics and implementation science-including mixed-methods contextual inquiry with clinicians, patients, and health system constituents-to co-design two patient-facing implementation strategies to address this care gap: (a) an automated health system-mediated strategy and (b) a nonprofit foundation-mediated strategy with contact from a foundation-employed care navigator. This trial will test the comparative effectiveness of these strategies on completion of cascade screening for relatives of individuals with FH, centering equitable reach. METHODS: We will conduct a hybrid effectiveness-implementation type III randomized controlled trial testing the comparative effectiveness of two strategies for implementing cascade screening with 220 individuals with FH (i.e., probands) per arm identified from a large northeastern health system. The primary implementation outcome is reach, or the proportion of probands with at least one first-degree biological relative (parent, sibling, child) in the USA who is screened for FH through the study. Our secondary implementation outcomes include the number of relatives screened and the number of relatives meeting the American Heart Association criteria for FH. Our secondary clinical effectiveness outcome is post-trial proband cholesterol level. We will also use mixed methods to identify implementation strategy mechanisms for implementation strategy effectiveness while centering equity. DISCUSSION: We will test two patient-facing implementation strategies harnessing insights from behavioral economics that were developed collaboratively with constituents. This trial will improve our understanding of how to implement evidence-based cascade screening for FH, which implementation strategies work, for whom, and why. Learnings from this trial can be used to equitably scale cascade screening programs for FH nationally and inform cascade screening implementation efforts for other genetic disorders. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05750667. Registered 15 February 2023-retrospectively registered, https://clinicaltrials.gov/study/NCT05750667 .