Characteristics of Hospitalized COVID-19 Patients at Admission and Factors Associated with Clinical Severity in Low- and Middle-Income Countries: An Observational Study.

Despite the numerous articles published on the clinical characteristics and outcomes of COVID-19 with regard to high-income countries, little is known about patients in low- and middle-income countries (LMIC) in this context. The objective of this observational, prospective, hospital-based multicentric study was to describe clinical features and outcomes of laboratory-confirmed COVID-19 patients hospitalized in each of the participating centers in Bangladesh, Guinea, Ivory Coast, Lebanon, Madagascar, and Mali during the first year of the pandemic (March 5, 2020 to May 4, 2021). The study outcome was the clinical severity of COVID-19, defined as hospitalization in intensive care unit or death. Multivariate logistic regression models were performed to identify independent variables associated with disease severity. Overall, 1,096 patients were included. The median age was 49.0 years, ranging from 38.0 in Mali to 63.0 years in Guinea. The overall clinical severity of COVID-19 was 12.3%, ranging from 6.4% in Mali to 18.8% in Guinea. In both groups of patients <60 and ≥60 years old, cardiovascular diseases (adjusted odds ratio [aOR]: 1.99; 95% CI: 1.13-3.50, P = 0.02; aOR: 2.47; 95% CI: 1.33-4.57, P = 0.004) were independently associated with clinical severity, whereas in patients <60 years, diabetes (aOR: 2.13; 95% CI: 1.11-4.10, P = 0.02) was also associated with clinical severity. Our findings suggest that COVID-19-related severity and death in LMICs are mainly driven by older age. However, the presence of chronic diseases can also increase the risk of severity especially in younger patients.

Effect of Mediterranean Dietary Pattern on Cognitive Status in Community-Dwelling Older Adults.

Modifiable factors associated with cognitive decline (CD) require more attention, particularly dietary patterns. This study aimed to investigate the link between cognitive decline and associated factors, particularly dietary patterns (DPs), in community-dwelling older Lebanese of modest economic status. Our cross-sectional national study included 352 participants above 60 years old, from the medico-social centers of the ministry of social affairs all over the country. CD was screened based on literacy. Nutritional and dietary data were collected through a validated food frequency questionnaire. DPs were extracted by the K-mean cluster analysis. CD was found in 32.7% and 61.5% of literate and illiterate groups, respectively. Identified DPs included a Westernized type and Mediterranean type, with high and moderate food intakes. In the context of literacy, independent factors associated with CD were age above 80 years, living in Beirut, frailty, and adopting a Westernized (OR = 3.08, 95% CI: 1.22-7.8) and a high-intake Mediterranean DP (OR = 2.11, 95% CI: 1.05-4.22). In the context of illiteracy, the same factors were associated with CD, but not DP nor frailty, with an age cut-off at 78 years. In a Lebanese sample of older adults, factors associated with CD depend on the level of literacy, with DP only associated with CD in the context of literacy.

Identification of the specific molecular and functional signatures of pre-beta-HDL: relevance to cardiovascular disease.

While low concentrations of high-density lipoprotein-cholesterol (HDL-C) are widely accepted as an independent cardiovascular risk factor, HDL-C-rising therapies largely failed, suggesting the importance of both HDL functions and individual subspecies. Indeed HDL particles are highly heterogeneous, with small, dense pre-beta-HDLs being considered highly biologically active but remaining poorly studied, largely reflecting difficulties for their purification. We developed an original experimental approach allowing the isolation of sufficient amounts of human pre-beta-HDLs and revealing the specificity of their proteomic and lipidomic profiles and biological activities. Pre-beta-HDLs were enriched in highly poly-unsaturated species of phosphatidic acid and phosphatidylserine, and in an unexpectedly high number of proteins implicated in the inflammatory response, including serum paraoxonase/arylesterase-1, vitronectin and clusterin, as well as in complement regulation and immunity, including haptoglobin-related protein, complement proteins and those of the immunoglobulin class. Interestingly, amongst proteins associated with lipid metabolism, phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase were strongly enriched in, or restricted to, pre-beta-HDL. Furthermore, pre-beta-HDL potently mediated cellular cholesterol efflux and displayed strong anti-inflammatory activities. A correlational network analysis between lipidome, proteome and biological activities highlighted 15 individual lipid and protein components of pre-beta-HDL relevant to cardiovascular disease, which may constitute novel diagnostic targets in a pathological context of altered lipoprotein metabolism.

Genetic and molecular architecture of familial hypercholesterolemia.

Atherosclerotic cardiovascular disease is the leading cause of death globally. Despite its important risk of premature atherosclerosis and cardiovascular disease, familial hypercholesterolemia (FH) is still largely underdiagnosed worldwide. It is one of the most frequently inherited diseases due to mutations, for autosomal dominant forms, in either of the LDLR, APOB, and PCSK9 genes or possibly a few mutations in the APOE gene and, for the rare autosomal forms, in the LDLRAP1 gene. The discovery of the genes implicated in the disease has largely helped to improve the diagnosis and treatment of FH from the LDLR by Brown and Goldstein, as well as the introduction of statins, to PCSK9 discovery in FH by Abifadel et al., and the very rapid availability of PCSK9 inhibitors. In the last two decades, major progress has been made in clinical and genetic diagnostic tools and the therapeutic arsenal against FH. Improving prevention, diagnosis, and treatment and making them more accessible to all patients will help reduce the lifelong burden of the disease.

The time is now: Achieving FH paediatric screening across Europe - The Prague Declaration.

Familial hypercholesterolaemia (FH) is the most common inherited metabolic disorder characterized by high cholesterol and if left untreated leads to premature cardiovascular disease, such as heart attacks. Treatment that begins early in life, particularly in childhood, is highly efficacious in preventing cardiovascular disease and cost-effective, thus early detection of FH is crucial. However, in Europe, less than 10% of people living with FH are diagnosed and even less receive life-saving treatment. The Prague Declaration is a call to action for national and European Union policymakers and decision-makers and a result of the Czech EU Presidency meeting on FH Paediatric Screening (early detection of inherited high cholesterol) at the Czech Senate in Prague on 6th September 2022. It builds on a considerable body of evidence which was discussed at the Technical Meeting under the auspices of the Slovenian EU Presidency in October 2021. The Prague meeting addressed the outstanding barriers to the systematic implementation of FH paediatric screening across Europe. In this article, we present the key points from the Prague meeting and concrete actions needed to move forward.

Low circulating PCSK9 levels in LPL homozygous children with chylomicronemia syndrome in a syrian refugee family in Lebanon.

Familial chylomicronemia syndrome is a rare autosomal recessive disorder of lipoprotein metabolism characterized by the presence of chylomicrons in fasting plasma and an important increase in plasma triglycerides (TG) levels that can exceed 22.58 mmol/l. The disease is associated with recurrent episodes of abdominal pain and pancreatitis, eruptive cutaneous xanthomatosis, lipemia retinalis, and hepatosplenomegaly. A consanguineous Syrian family who migrated to Lebanon was referred to our laboratory after perceiving familial chylomicronemia syndrome in two children. The LPL and PCSK9 genes were sequenced and plasma PCSK9 levels were measured. Sanger sequencing of the LPL gene revealed the presence of the p.(Val227Phe) pathogenic variant in exon 5 at the homozygous state in the two affected children, and at the heterozygous state in the other recruited family members. Interestingly, PCSK9 levels in homozygous carriers of the p.(Val227Phe) were ≈50% lower than those in heterozygous carriers of the variant (p-value = 0.13) and ranged between the 5th and the 7.5th percentile of PCSK9 levels in a sample of Lebanese children of approximately the same age group. Moreover, this is the first reported case of individuals carrying simultaneously an LPL pathogenic variant and PCSK9 variants, the L10 and L11 leucine insertion, which can lower and raise low-density lipoprotein cholesterol (LDL-C) levels respectively. TG levels fluctuated concomitantly between the two children, were especially high following the migration from a country to another, and were reduced under a low-fat diet. This case is crucial to raise public awareness on the risks of consanguineous marriages to decrease the emergence of inherited autosomal recessive diseases. It also highlights the importance of the early diagnosis and management of these diseases to prevent serious complications, such as recurrent pancreatitis in the case of familial hyperchylomicronemia.

Lipid Parameters and Proprotein Convertase Subtilisin/Kexin Type 9 in Healthy Lebanese Adults.

Background: High levels of non-HDL cholesterol (non-HDL-C), triglycerides (TG), lipoprotein (a) (Lp(a)), and Proprotein convertase subtilisin/kexin type 9 (PCSK9) as well as low levels of HDL-C are strongly associated with cardiovascular disease (CVD). Our study aims to estimate the prevalence of dyslipidemia and high Lp(a) in the Lebanese population and to study the relationship of these variables with gender, age, body mass index (BMI), and PCSK9. Methods: This cross-sectional study was carried out on a sample of healthy volunteers aged 18 to 65. Blood samples were drawn from volunteers for total cholesterol (TC), HDL-C, TG, PCSK9, and Lp(a) measurements. Non-HDL-C was calculated by subtracting HDL-C from TC. Results: In total, 303 volunteer subjects with an average age of 38.9 years were included in the study. Respectively, 44%, 29.8%, and 44% of men had high non-HDL-C and TG with low HDL-C versus 23.5%, 8%, and 37% in women. Non-HDL-C and TG were significantly higher in men than in women, while the reverse was observed for HDL-C (p < 0.0001 for the three comparisons). Non-HDL-C and TG were significantly correlated with age and BMI (p< 0.0001 for all correlations), while HDL-C was inversely correlated with BMI (p < 0.0001) but not with age. Abnormal Lp(a) levels (≥75 nmol/L) were found in 19.1% of the population, predominantly in women (24.1% versus 13.4% in men, p = 0.004). The median PCSK9 and its interquartile was 300 (254−382) ng/L with no gender difference (p = 0.18). None of the following factors: gender, age, BMI, non-HDL-C, HDL-C, or TG, were independently associated with Lp(a), while PCSK9 was significantly correlated with age, non-HDL-C, and TG in both men and women and inversely correlated with HDL-C in men. Dyslipidemia is very common in the Lebanese population and is associated with age, high BMI, and male sex. Lp(a) is higher in women without any correlation with the lipid profile, whereas PCSK9 is associated with non-HDL-C and TG. Further studies are needed to evaluate the potential role of Lp(a) and PCSK9 in predicting CVD in healthy populations.

Circulating PCSK9 Linked to Dyslipidemia in Lebanese Schoolchildren.

In adults, elevated levels of circulating Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) have been associated with increased Low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and worse cardiovascular outcomes. However, few studies analyzed the relation between PCSK9 and lipid parameters in pediatric populations. The aim of our study is to evaluate the distribution and the correlation of serum PCSK9 levels with lipid parameters in a sample of Lebanese school children. Using an immunofluorescence assay, we measured serum PCSK9 levels in 681 school children recruited from ten public and private Lebanese schools. We analyzed the association between PCSK9 and age, sex, Body Mass Index (BMI), and lipid parameters (total cholesterol (TC), LDL-C, TG, High-density lipoprotein cholesterol (HDL-C), non-HDL-C, and lipoprotein (a) (Lp(a)). Serum PCSK9 levels were significantly correlated with TC, LDL-C, and non-HDL-C (p value < 0.0001) but not with TG, HDL-C, and Lp(a). PCSK9 levels were also significantly higher in children with high TC, LDL-C, and non-HDL-C (p values = 0.0012, 0.0002, 0.001, respectively). No significant gender differences in PCSK9 were found. In addition, no significant associations between PCSK9 and both age and BMI percentiles were observed. In girls, no difference in PCSK9 values was observed according to menarche while in boys, testosterone levels were not significantly associated with PCSK9. Serum PCSK9 levels were significantly correlated with TC, LDL-C, and non-HDL-C levels. Further studies are needed to find if PCSK9 measurements have an additional value to predict future cardiovascular outcomes in pediatric populations.

Validity and reliability of a food frequency questionnaire for community dwelling older adults in a Mediterranean country: Lebanon.

BACKGROUND: Food frequency questionnaires (FFQ) is an easy and inexpensive tool that can be used to evaluate nutrient and dietary trends of groups and individuals. Few studies in the East Mediterranean region tailored FFQs to describe dietary intakes of older adults. The purpose of the study is therefore to assess the validity and reproducibility of a FFQ, designed for use with older adults living in a Mediterranean Arabic speaking country, Lebanon. METHODS: The FFQ is composed of a list of 90 food items, commonly consumed by adults above 60 years of age. Validity of the FFQ was tested using the mean of two 24-hours dietary recalls (24HDR), and reproducibility, by repeating the questionnaire within a one-month period, along the second dietary recall. Our study included 42 and 76 participants, for the repoducibility and validity analysis respectively. Subjects were randomly selected from 2 of the 8 governorates in the country. RESULTS: FFQ reproducibility showed a mean relative difference of 1.03% without any significant difference between all paired components of nutrients. Intra class correlation (ICC) showed good and excellent reliability for caloric intake and all macronutrients, moderate to good reliability for all remaining nutrients, except for poly-unsaturated fatty acids, vitamins A, B12 and fibers. Correlation coefficients for all nutrients were fair to strong. Both administrations of the FFQ showed good internal validity. Validation of FFQ showed a mean relative difference between FFQ and mean 24HDR at 19.5%. Agreements between the 2 methods, for classifying individuals in the same or adjacent quartile, for nutrient intake and nutrient adequacy, were 80 and 78.2% respectively. Mean Kappa coefficient was 0.56 and energy-adjusted correlations were within the recommended values for all items except for vitamin A and B12. Adjusting for nutrient-dense food intake improved the agreement for theses 2 vitamins to 0.49 and 0.56, respectively. CONCLUSION: The proposed FFQ can be considered a valid tool to help describe nutrient intake of older individuals in an Arabic speaking Mediterranean country. It could serve for possible use in the East Mediterranean region for the evaluation of regular dietary intake of community-dwelling older adults.

APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia.

Primary hypercholesterolemia is characterized by elevated LDL-cholesterol (LDL-C) levels isolated in autosomal dominant hypercholesterolemia (ADH) or associated with elevated triglyceride levels in familial combined hyperlipidemia (FCHL). Rare APOE variants are known in ADH and FCHL. We explored the APOE molecular spectrum in a French ADH/FCHL cohort of 5743 unrelated probands. The sequencing of LDLR, PCSK9, APOB, and APOE revealed 76 carriers of a rare APOE variant, with no mutation in LDLR, PCSK9, or APOB. Among the 31 APOE variants identified here, 15 are described in ADH, 10 in FCHL, and 6 in both probands. Five were previously reported with dyslipidemia and 26 are novel, including 12 missense, 5 synonymous, 2 intronic, and 7 variants in regulatory regions. Sixteen variants were predicted as pathogenic or likely pathogenic, and their carriers had significantly lower polygenic risk scores (wPRS) than carriers of predicted benign variants. We observed no correlation between LDL-C levels and wPRS, suggesting a major effect of APOE variants. Carriers of p.Leu167del were associated with a severe phenotype. The analysis of 11 probands suggests that carriers of an APOE variant respond better to statins than carriers of a LDLR mutation. Altogether, we show that the APOE variants account for a significant contribution to ADH and FCHL.

Whole Exome/Genome Sequencing Joint Analysis of a Family with Oligogenic Familial Hypercholesterolemia.

Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in LDLR, APOB, PCSK9 and APOE genes. We sought to identify new candidate genes responsible for the ADH phenotype in patients without pathogenic variants in the known ADH-causing genes by focusing on a French family with affected and non-affected members who presented a high ADH polygenic risk score (wPRS). Linkage analysis, whole exome and whole genome sequencing resulted in the identification of variants p.(Pro398Ala) in CYP7A1, p.(Val1382Phe) in LRP6 and p.(Ser202His) in LDLRAP1. A total of 6 other variants were identified in 6 of 160 unrelated ADH probands: p.(Ala13Val) and p.(Aps347Asn) in CYP7A1; p.(Tyr972Cys), p.(Thr1479Ile) and p.(Ser1612Phe) in LRP6; and p.(Ser202LeufsTer19) in LDLRAP1. All six probands presented a moderate wPRS. Serum analyses of carriers of the p.(Pro398Ala) variant in CYP7A1 showed no differences in the synthesis of bile acids compared to the serums of non-carriers. Functional studies of the four LRP6 mutants in HEK293T cells resulted in contradictory results excluding a major effect of each variant alone. Within the family, none of the heterozygous for only the LDLRAP1 p.(Ser202His) variant presented ADH. Altogether, each variant individually does not result in elevated LDL-C; however, the oligogenic combination of two or three variants reveals the ADH phenotype.

Identification of a Variant in APOB Gene as a Major Cause of Hypobetalipoproteinemia in Lebanese Families.

Familial hypobetalipoproteinemia (FHBL) is a codominant genetic disorder characterized by reduced plasma levels of low-density lipoprotein cholesterol and apolipoprotein B. To our knowledge, no study on FHBL in Lebanon and the Middle East region has been reported. Therefore, we conducted genetic studies in unrelated families and probands of Lebanese origin presenting with FHBL, in order to identify the causes of this disease. We found that 71% of the recruited probands and their affected relatives were heterozygous for the p.(Arg490Trp) variant in the APOB gene. Haplotype analysis showed that these patients presented the same mutant haplotype. Moreover, there was a decrease in plasma levels of PCSK9 in affected individuals compared to the non-affected and a significant positive correlation between circulating PCSK9 and ApoB levels in all studied probands and their family members. Some of the p.(Arg490Trp) carriers suffered from diabetes, hepatic steatosis or neurological problems. In conclusion, the p.(Arg490Trp) pathogenic variant seems a cause of FHBL in patients from Lebanese origin, accounting for approximately 70% of the probands with FHBL presumably as a result of a founder mutation in Lebanon. This study is crucial to guide the early diagnosis, management and prevention of the associated complications of this disease.

Dietary Patterns and Risk Factors of Frailty in Lebanese Older Adults.

Factors associated with frailty, particularly dietary patterns, are not fully understood in Mediterranean countries. This study aimed to investigate the association of data-driven dietary patterns with frailty prevalence in older Lebanese adults. We conducted a cross-sectional national study that included 352 participants above 60 years of age. Sociodemographic and health-related data were collected. Food frequency questionnaires were used to elaborate dietary patterns via the K-mean cluster analysis method. Frailty that accounted for 15% of the sample was twice as much in women (20%) than men (10%). Identified dietary patterns included a Westernized-type dietary pattern (WDP), a high intake/Mediterranean-type dietary pattern (HI-MEDDP), and a moderate intake/Mediterranean-type dietary pattern (MOD-MEDDP). In the multivariate analysis, age, waist to height ratio, polypharmacy, age-related conditions, and WDP were independently associated with frailty. In comparison to MOD-MEDDP, and after adjusting for covariates, adopting a WDP was strongly associated with a higher frailty prevalence in men (OR = 6.63, 95% (CI) (1.82-24.21) and in women (OR = 11.54, 95% (CI) (2.02-65.85). In conclusion, MOD-MEDDP was associated with the least prevalence of frailty, and WDP had the strongest association with frailty in this sample. In the Mediterranean sample, a diet far from the traditional one appears as the key deleterious determinant of frailty.

Phospholipid transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis is directly correlated with HDL-cholesterol levels and is not associated with cardiovascular risk.

BACKGROUND AND AIMS: While low concentrations of high-density lipoprotein-cholesterol (HDL-C) represent a well-established cardiovascular risk factor, extremely high HDL-C is paradoxically associated with elevated cardiovascular risk, resulting in the U-shape relationship with cardiovascular disease. Free cholesterol transfer to HDL upon lipolysis of triglyceride-rich lipoproteins (TGRL) was recently reported to underlie this relationship, linking HDL-C to triglyceride metabolism and atherosclerosis. In addition to free cholesterol, other surface components of TGRL, primarily phospholipids, are transferred to HDL during lipolysis. It remains indeterminate as to whether such transfer is linked to HDL-C and cardiovascular disease. METHODS AND RESULTS: When TGRL was labelled with fluorescent phospholipid 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), time- and dose-dependent transfer of DiI to HDL was observed upon incubations with lipoprotein lipase (LPL). The capacity of HDL to acquire DiI was decreased by -36% (p<0.001) in low HDL-C patients with acute myocardial infarction (n = 22) and by -95% (p<0.001) in low HDL-C subjects with Tangier disease (n = 7), unchanged in low HDL-C patients with Type 2 diabetes (n = 17) and in subjects with high HDL-C (n = 20), and elevated in subjects with extremely high HDL-C (+11%, p<0.05) relative to healthy normolipidemic controls. Across all the populations combined, HDL capacity to acquire DiI was directly correlated with HDL-C (r = 0.58, p<0.001). No relationship of HDL capacity to acquire DiI with both overall and cardiovascular mortality obtained from epidemiological studies for the mean HDL-C levels observed in the studied populations was obtained. CONCLUSIONS: These data indicate that the capacity of HDL to acquire phospholipid from TGRL upon LPL-mediated lipolysis is proportional to HDL-C and does not reflect cardiovascular risk in subjects widely differing in HDL-C levels.

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm.

PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. METHODS: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. RESULTS: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. CONCLUSION: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.

Identification of the first Tangier disease patient in Lebanon carrying a new pathogenic variant in ABCA1.

BACKGROUND: The Middle East region is characterized by low levels of high-density lipoprotein cholesterol (HDL-C). To date, no genetic study has investigated the cause of low HDL-C in the Lebanese population. OBJECTIVE: Our objective was to study the genetic causes for hypoalphalipoproteinemia in a Lebanese family with extremely low HDL-C levels. METHODS: We sequenced the ABCA1 gene and evaluated cholesterol efflux, inflammatory, and metabolic profiles in the proband and his family. RESULTS: We identified the first Lebanese pathogenic variant in ABCA1 gene causing Tangier disease in a consanguineous family. The proband carried a novel homozygous pathogenic variant p.Gly592Asp in exon 14 of ABCA1, which segregated with the disease in the family. Functional study of the p.Gly592Asp pathogenic variant revealed that lipid-free apolipoprotein A-I-dependent cholesterol efflux was completely abolished in cholesterol-loaded human monocytes-derived macrophages isolated from the proband when compared to controls. Systemic inflammatory and metabolic assessments showed that plasma cytokines (MCP-1, MIP-1α, IL-6, CRP, TNF-α), adhesion molecules (ICAM-1, VCAM-1, E-selectin), inflammatory soluble receptors (sIL-6r, sTNFRI, sTNFRII), and metabolic markers (Insulin, C-peptide) were elevated in the proband when compared to controls. Noninvasive cardiovascular investigation revealed the presence of premature artery lesions in the proband. CONCLUSIONS: It is the first case of Tangier disease reported in Lebanon harboring a novel pathogenic variant in ABCA1. Further genetic research is needed in the Middle East where the consanguinity rate is elevated, to understand the cause of the highly prevalent dyslipidemia. This will help guiding the early diagnosis, management, and prevention of cardiovascular complications.

Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).

BACKGROUND AND AIMS: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries. METHODS: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management. RESULTS: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60% countries, although access is limited. CONCLUSIONS: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed.

New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia.

Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated LDL-C levels leading to coronary heart disease. Four genes are implicated in ADH: LDLR, APOB, PCSK9 and APOE. Our aim was to identify new mutations in known genes, or in new genes implicated in ADH. Thirteen French families with ADH were recruited and studied by exome sequencing after exclusion, in their probands, of mutations in the LDLR, PCSK9 and APOE genes and fragments of exons 26 and 29 of APOB gene. We identified in one family a p.Arg50Gln mutation in the APOB gene, which occurs in a region not usually associated with ADH. Segregation and in-silico analysis suggested that this mutation is disease causing in the family. We identified in another family with the p.Ala3396Thr mutation of APOB, one patient with a severe phenotype carrying also a mutation in PCSK9: p.Arg96Cys. This is the first compound heterozygote reported with a mutation in APOB and PCSK9. Functional studies proved that the p.Arg96Cys mutation leads to increased LDL receptor degradation. This work shows that Next-Generation Sequencing (exome, genome or targeted sequencing) are powerful tools to find new mutations and identify compound heterozygotes, which will lead to better diagnosis and treatment of ADH.