Founder mutations in the Netherlands: geographical distribution of the most prevalent mutations in the low-density lipoprotein receptor and apolipoprotein B genes

Background In the Netherlands, a screening programme was set up in 1994 in order to identify all patients with familial hypercholesterolaemia (FH). After 15 years of screening, we evaluated the geographical distribution, possible founder effects and clinical phenotype of the 12 most prevalent FH gene mutations. Methods Patients who carried one of the 12 most prevalent mutations, index cases and those identified between 1994 and 2009 through the screening programme and whose postal code was known were included in the study. Low-density lipoprotein cholesterol (LDL-C) levels at the time of screening were retrieved. The prevalence of identified patients in each postal code area was calculated and visualised in different maps. Results A total of 10,889 patients were included in the study. Mean untreated LDL-C levels ranged from 4.4 to 6.4 mmol/l. For almost all mutations, a region of high prevalence could be observed. In total, 51 homozygous patients were identified in the Netherlands, of which 13 true homozygous for one of the 12 most prevalent mutations. The majority of them were living in high-prevalence areas for that specific mutation. Conclusions Phenotypes with regard to LDL-C levels varied between the 12 most prevalent FH mutations. For most of these mutations, a founder effect was observed. Our observations can have implications with regard to the efficiency of molecular screening and physician's perception of FH and to the understanding of the prevalence and distribution of homozygous patients in the Netherland

Assessment of practical applicability and clinical relevance of a commonly used LDL-C polygenic score in patients with severe hypercholesterolemia

Background and aims: Low-density lipoprotein cholesterol (LDL-C) levels vary in patients with familial hypercholesterolemia (FH) and can be explained by a single deleterious genetic variant or by the aggregate effect of multiple, common small-effect variants that can be captured in a polygenic score (PS). We set out to investigate the contribution of a previously published PS to the inter-individual LDL-C variation and coronary artery disease (CAD) risk in patients with a clinical FH phenotype. Methods: First, in a cohort of 628 patients referred for genetic FH testing, we evaluated the distribution of a PS for LDL-C comprising 12 genetic variants. Next, we determined its association with coronary artery disease (CAD) risk using UK Biobank data. Results: The mean PS was higher in 533 FH-variant-negative patients (FH/M-) compared with 95 FH-variant carriers (1.02 vs 0.94, p < 0.001). 39% of all patients had a PS equal to the top 20% from a population-based reference cohort and these patients were less likely to carry an FH variant (OR 0.22, 95% CI 0.10–0.48) compared with patients in the lowest 20%. In UK Biobank data, the PS explained 7.4% of variance in LDL-C levels and was associated with incident CAD. Addition of PS to a prediction model using age and sex and LDL-C did not increase the c-statistic for predicting CAD risk. Conclusions: This 12-variant PS was higher in FH/M- patients and associated with incident CAD in UK Biobank data. However, the PS did not improve predictive accuracy when added to the readily available characteristics age, sex and LDL-C, suggesting limited discriminative value for CAD

A retrospective observational study to determine baseline characteristics and early prescribing patterns for patients receiving Alirocumab in UK clinical practice

Background Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) and has been previously shown, in the phase III ODYSSEY clinical trial program, to provide significant lowering of lowdensity lipoprotein cholesterol (LDL-C) and reduction in risk of major adverse cardiovascular events. However, real-world evidence to date is limited. Objective The primary objective was to describe baseline characteristics, clinical history, and prior lipid-lowering therapy (LLT) use of patients initiated on alirocumab in UK clinical practice following publication of health technology appraisal (HTA) body recommendations. Secondary objectives included description of alirocumab use and lipid parameter outcomes over a 4-month follow-up period. Methods In this retrospective, single-arm, observational, multicenter study, data were collected for 150 patients initiated on alirocumab. Results Mean (standard deviation; SD) age of patients was 61.4 (10.5) years and baseline median (interquartile range; IQR) LDL-C level was 4.8 (4.2–5.8) mmol/l. Alirocumab use occurred predominantly in patients with heterozygous familial hypercholesterolemia (HeFH) (n = 100/150, 66%) and those with statin intolerance (n = 123/150, 82%). Most patients started on alirocumab 75 mg (n = 108/150 [72%]) and 35 (23.3%) were up-titrated to 150 mg. Clinically significant reductions in atherogenic lipid parameters were observed with alirocumab, including LDL-C (median [IQR] change from baseline, − 53.6% [− 62.9 to − 34.9], P < 0.001). Conclusion This study highlights the unmet need for additional LLT in patients with uncontrolled hyperlipidemia and demonstrates the clinical utility of alirocumab in early real-world practice, where dosing flexibility is an important attribute of this therapeutic option

Patients’ Perceptions and Experiences of Familial Hypercholesterolemia, Cascade Genetic Screening and Treatment

Background: Familial hypercholesterolemia (FH) is a serious genetic disorder affecting approximately 1 in every 300 to 500 individuals and is characterised by excessively high low-density lipoprotein (LDL) cholesterol levels, substantially increased risk of early-onset coronary heart disease (CHD) and premature mortality. If FH is untreated, it leads to a greater than 50 % risk of CHD in men by the age of 50 and at least 30 % in women by the age of 60. FH can be diagnosed through genetic screening and effectively managed through pharmacological treatment and lifestyle changes. Purpose: Familial hypercholesterolemia (FH) is a genetic health condition that increases the risk of cardiovascular disease. Although FH can be effectively managed with appropriate pharmacological and dietary interventions, FH detection rate through genetic screening remains low. The present study explored perceptions and experiences of FH patients (N = 18) involved in a genetic cascade screening programme. Methods: Face-to-face interviews were conducted to assess patients’ knowledge and understanding of FH, explore factors linked to adherence to health-protective behaviours and examine perceptions of genetic screening. Results: Thematic analysis of interviews revealed four themes: disease knowledge, severity of FH, lifestyle behavioural change and barriers to cascade screening and treatment. Participants recognised FH as a permanent, genetic condition that increased their risk of CHD and premature mortality. Many participants dismissed the seriousness of FH and the importance of lifestyle changes because they perceived it to be effectively managed through medication. Despite positive attitudes toward screening, many participants reported that relatives were reluctant to attend screening due to their relatives’ ‘fatalistic’ outlook or low motivation. Participants believed that they had insufficient authority or control to persuade family members to attend screening and welcomed greater hospital assistance for contact with relatives. Conclusions: Findings support the adoption of direct methods of recruitment to cascade screening led by medical professionals, who were perceived as having greater authority. Other implications included the need for clinicians to provide clear information, particularly to those who are asymptomatic, related to the seriousness of FH and the necessity for adherence to medication and lifestyle changes