Familial Hypercholesterolemia Phenotype Research Articles

Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol

Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified. To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults. A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023. LDL-C, cumulative past LDL-C, FH variant status. Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults. Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant. In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

Clinical profile of severe hypercholesterolemia in 156,000 adults in primary care

ObjectiveTo examine the frequency of severe hypercholesterolemia (HS) and its clinical profile, and the phenotype of familial hypercholesterolemia (FH), in the primary-care setting in a large health area of ​​the Community of Madrid (CAM). Material and methodsMulticenter study of subjects with a health card assigned to 69 health centers (Northwest/CAM area). HS was defined as cholesterol ≥ 300 mg/dL or LDL-cholesterol ≥ 220 mg/dL in any analysis performed (1-1-2018 to 12-30-2021); and FH phenotype as c-LDL ≥ 240 mg/dL (≥160 mg/dL if lipid-lowering treatment) with triglycerides < 200 mg/dL and TSH < 5 uIU/ml. Results156,082 adults ≥ 18 years with an available lipid profile were analyzed. 6187 subjects had HS (3.96% of the laboratory tests studied, 95%CI 3.87%–4.06%). The mean evolution time of the diagnosis of hyperlipidemia in the computerized clinical record was 10.8 years; 36.5% had hypertension; 9.5% diabetes and 62.9% overweight/obesity. 83.7% were taking lipid-lowering drugs (65,7% low/moderate and 28.6% high/very high intensity). 6.1% had cardiovascular disease (94.2% treated with lipid-lowering agents), with LDL-cholesterol <55, <70 and <100 mg/dl of 1.8%, 5.8% and 20.2%, respectively. (vs 1%, 2.3% and 11.2% if no cardiovascular disease). 1600 subjects had FH phenotype (1.03%, 0.98%–1.08%). ConclusionsFour out of 100 patients analyzed in primary care have HS, with high treatment level, but insufficient intensity, and poor achievement of treatment goals. One in 100 have the FH phenotype. The identification of both dyslipidemias by computerized records would allow their more precise and early detection and establish cardiovascular preventive strategies.

Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype

Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person’s treatment according to the affected pathway.

B-252 In Vitro Expression Analysis of Variants in the Upstream Region of Genes Related to Familial Hypercholesterolemia

Abstract Background Familial hypercholesterolemia (FH) is commonly described as an autosomal dominant disorder caused mainly by variants in genes LDLR, APOB, and PCSK9, resulting in severe hypercholesterolemia. However, the substantial number of individuals who are clinically diagnosed but negative for known FH-causing variants indicates that relevant variants outside of frequently analyzed regions might exist. Considering the increasing number of promoter variants reported as likely to cause FH and the relevance of in vitro expression assays in the pathogenicity evaluation of these variants, this work aimed to examine the functionality of variants LDLR rs36218923-T and APOB rs934197-T, identified in a Brazilian FH cohort. Methods Upstream fragments of LDLR (-861 bp to +85 bp) and APOB (-1460 bp to +127 bp) were PCR amplified from genomic DNA of two FH patients carrying LDLR rs36218923-T and APOB rs934197-T in heterozygosis and homozygosis, respectively. After linearization and PGK promoter removal of the pGL4.53 vector using Kpn I and Hind III restriction enzymes, fragments were cloned upstream of the Firefly Luciferase (luc2) coding region using the NEBuilder HiFi DNA Assembly Cloning Kit. Site-directed mutagenesis was also performed using partially overlapping primers with 3´-overhangs and Platinum SuperFi II DNA Polymerase to produce different constructs, including one containing LDLR rs879254375-G, which is a known FH-causing variant. All constructs were confirmed by Sanger sequencing. pGL4.53 constructs containing either wild type or variant alleles and pNL1.1.TK (control of transfection variation, expressing NanoLuc Luciferase) were co-transfected into HepG2 cells. Wild type constructs were considered positive controls, while promoterless pGL4.53 was considered negative control. Luciferase assays were carried out 48 h after transfection using the Nano-Glo Dual-Luciferase Reporter Assay System. After normalization of luminescence units of each assay (Firefly/Nanoluc), luciferase activity was determined as the mean of four transfections with the assay performed in triplicate. Results The construct carrying LDLR rs36218923-T variant caused a significant mean reduction of luciferase activity (75,4% ± 2,9% SEM) over the promoterless construct relative to LDLR wild type construct. However, the construct harboring the LDLR rs879254375-G variant caused a more substantial reduction of luciferase activity relative to the wild type construct (91,2% ± 0,9% SEM). This reduction was consistent with shown by the previous study that reported LDLR rs879254375-G as a functional variant, which corroborates the methods adopted in this study. APOB rs934197-T was previously reported as functional based on a CAT assay using constructs of two tandemly arranged 30 bp fragments of APOB promoter, but in our study, the construct carrying the entire APOB promoter sequence and harboring rs934197-T variant did not cause a significant difference in mean luciferase activity compared to APOB wild type construct (P = 0.564). It is important to mention that our APOB upstream constructs had the additional variants rs617314-G, rs1560357-T, rs1625764-A, and rs1800481-G, which are considered benign because they occur at high frequency in the general population (0.82-1). Conclusion Our results suggest that LDLR rs36218923-T is likely to contribute to FH phenotype and emphasize the importance of performing in vitro expression assays in determining relevant upstream variants for FH molecular characterization.

Perfil clínico de la hipercolesterolemia severa en 156.000 adultos en atención primaria

ObjectiveTo examine the frequency of severe hypercholesterolemia (HS) and its clinical profile, and the phenotype of familial hypercholesterolemia (FH), in the primary-care setting in a large health area of the Community of Madrid (CAM). Material and methodsMulticenter study of subjects with a health card assigned to 69 health centers (Northwest/CAM area). HS was defined as cholesterol ≥300mg/dL or LDL-cholesterol ≥220mg/dL in any analysis performed (1-1-2018 to 12-30-2021); and FH phenotype as c-LDL ≥240mg/dL (≥160mg/dL if lipid-lowering treatment) with triglycerides <200mg/dL and TSH <5μIU/mL. Results156,082 adults ≥18years with an available lipid profile were analyzed. 6187 subjects had HS (3.96% of the laboratory tests studied, 95%CI: 3.87-4.06%). The mean evolution time of the diagnosis of hyperlipidemia in the computerized clinical record was 10.8years, 36.5% had hypertension, 9.5% diabetes and 62.9% overweight/obesity. 83.7% were taking lipid-lowering drugs (65.7% low/moderate and 28.6% high/very high intensity). 6.1% had cardiovascular disease (94.2% treated with lipid-lowering agents), with LDL-cholesterol <55, <70 and <100mg/dL of 1.8%, 5.8% and 20.2%, respectively (vs. 1%, 2.3% and 11.2% if no cardiovascular disease). 1600 subjects had FH phenotype (95%CI: 1.03%, 0.98-1.08%). ConclusionsFour out of 100 patients analyzed in primary care have HS, with high treatment level, but insufficient intensity, and poor achievement of treatment goals. One in 100 have the FH phenotype. The identification of both dyslipidemias by computerized records would allow their more precise and early detection and establish cardiovascular preventive strategies.

Searching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learning.

One of the most common congenital metabolic disorders is familial hypercholesterolemia. Familial hypercholesterolemia is a condition caused by a type of genetic defect leading to a decreased rate of removal of low-density lipoproteins from the bloodstream and a pronounced increase in the blood level of total cholesterol. This disease leads to the early development of cardiovascular diseases of atherosclerotic etiology. Familial hypercholesterolemia is a monogenic disease that is predominantly autosomal dominant. Rare pathogenic variants in the LDLR gene are present in 75-85 % of cases with an identified molecular genetic cause of the disease, and variants in other genes (APOB, PCSK9, LDLRAP1, ABCG5, ABCG8, and others) occur at a frequency of < 5 % in this group of patients. A negative result of genetic screening for pathogenic variants in genes of the low-density lipoprotein receptor and its ligands does not rule out a diagnosis of familial hypercholesterolemia. In 20-40 % of cases, molecular genetic testing fails to detect changes in the above genes. The aim of this work was to search for new genes associated with the familial hypercholesterolemia phenotype by modern high-tech methods of sequencing and machine learning. On the basis of a group of patients with familial hypercholesterolemia (enrolled according to the Dutch Lipid Clinic Network Criteria and including cases confirmed by molecular genetic analysis), decision trees were constructed, which made it possible to identify cases in the study population that require additional molecular genetic analysis. Five probands were identified as having the severest familial hypercholesterolemia without pathogenic variants in the studied genes and were analyzed by whole-genome sequencing on the HiSeq 1500 platform (Illumina). The whole-genome sequencing revealed rare variants in three out of five analyzed patients: a heterozygous variant (rs760657350) located in a splicing acceptor site in the PLD1 gene (c.2430-1G>A), a previously undescribed single-nucleotide deletion in the SIDT1 gene [c.2426del (p.Leu809CysfsTer2)], new missense variant c.10313C>G (p.Pro3438Arg) in the LRP1B gene, and single-nucleotide deletion variant rs753876598 [c.165del (p.Ser56AlafsTer11)] in the CETP gene. All these variants were found for the first time in patients with a clinical diagnosis of familial hypercholesterolemia. Variants were identified that may influence the formation of the familial hypercholesterolemia phenotype.

Additive effect of APOE rare variants on the phenotype of familial hypercholesterolemia

Additive effect of APOE rare variants on the phenotype of familial hypercholesterolemia

Comparing heterozygous familial hypercholesterolemia phenotype to genotype in an Irish cohort

Comparing heterozygous familial hypercholesterolemia phenotype to genotype in an Irish cohort

Genetic background of FH: Variants of uncertain clinical significance in severe FH phenotype

Genetic background of FH: Variants of uncertain clinical significance in severe FH phenotype

Lipoprotein (a) as a marker of hereditary lipid metabolism disorders in patients with early manifestation of coronary artery disease

Background: The clinical phenotype of familial hypercholesterolemia (FH) combined with the classical genetic defects of this disease increase the risk of coronary artery disease (CAD) in the case of a high level of lipoprotein (a) (Lp(a)). Aim: To assess the association of hereditary disorders of lipid metabolism with a high level of Lp(a) in the case of an early manifestation of CAD in the absence of the FH phenotype. Methods: We studied 81 patients with premature CAD (at the age up to 55 years in men and up to 60 years in women). Lp(a) was measured in the blood serum by the immunoturbidimetric method. We performed the molecular genetic testing, using massively parallel sequencing, which included the following panel of genes: ABCA1, ABCG1, ABCG5, ABCG8, ANGPTL3, APOA1, APOA2, APOA4, APOA5, APOB, APOC1, APOC2, APOC3, APOE, APOH, CETP, CH25H, CIDEC, CREB3L3, GPD1, GPIHBP1, LCAT, LDLR, LDLRAP1, LIPA, LIPC, LIPE, LIPG, LMF1, LPA, LPL, MTTP, MYLIP, NPC1, NPC1L1, NPC2, PCSK9, PLTP, PPP1R17, SAR1B, SCARB1, STAP1. Results: 24 (29.6%) patients had Lp(a) 30 mg/dl and were more likely to have a family history of CAD (70.8% vs 42.1%, p=0.05). In patients with a confirmed FH phenotype, there were no pathogenic variants associated with hereditary disorders of lipid metabolism. 4 patients with Lp(a) 30 mg/dl without a confirmed FH phenotype appeared to be carriers of pathogenic variants in the genes of lipid metabolism (LDLR p.Glu763Asp, ABCA1 p.Arg1128His, APOA5 p.His321Le), as well as of a not previously registered variant in the LIPE gene NM_005357.4:c. 2312TC. Conclusions: Lp(a) can be an appropriate marker for revealing pathogenic variants in the genes of the lipid metabolism system in patients without the clinical FH phenotype with an early CAD manifestation.

Yield of Familial Hypercholesterolemia Genetic and Phenotypic Diagnoses After Electronic Health Record and Genomic Data Screening.

Background Data mining of electronic health records to identify patients suspected of familial hypercholesterolemia (FH) has been limited by absence of both phenotypic and genomic data in the same cohort. Methods and Results Using the Geisinger MyCode Community Health Initiative cohort (n=130 257), we ran 2 screening algorithms (Mayo Clinic [Mayo] and flag, identify, network, deliver [FIND] FH) to determine FH genetic and phenotypic diagnostic yields. With 29 243 excluded by Mayo (for secondary causes of hypercholesterolemia, no lipid value in electronic health records), 52 034 excluded by FIND FH (insufficient data to run the model), and 187 excluded for prior FH diagnosis, a final cohort of 59 729 participants was created. Genetic diagnosis was based on presence of a pathogenic or likely pathogenic variant in FH genes. Charts from 180 variant-negative participants (60 controls, 120 identified by FIND FH and Mayo) were reviewed to calculate Dutch Lipid Clinic Network scores; a score ≥5 defined probable phenotypic FH. Mayo flagged 10 415 subjects; 194 (1.9%) had a pathogenic or likely pathogenic FH variant. FIND FH flagged 573; 34 (5.9%) had a pathogenic or likely pathogenic variant, giving a net yield from both of 197 out of 280 (70%). Confirmation of a phenotypic diagnosis was constrained by lack of electronic health record data on physical findings or family history. Phenotypic FH by chart review was present by Mayo and/or FIND FH in 13 out of 120 versus 2 out of 60 not flagged by either (P<0.09). Conclusions Applying 2 recognized FH screening algorithms to the Geisinger MyCode Community Health Initiative identified 70% of those with a pathogenic or likely pathogenic FH variant. Phenotypic diagnosis was rarely achievable due to missing data.

Familial Hypercholesterolemia: How Far Should We Go?

Familial hypercholesterolemia (FH) is a common inherited disorder, yet the diagnosis methods and management are still challenging. The heterozygous FH (known as FH) is more common than the homozygous form, yet a mutation only found in only about 40% of patients with the phenotype of FH. In fact, most cases are most likely caused by polygenic aetiology with less severe clinical presentations than monogenic FH. Therefore, understanding FH is essential, so that the diagnosis methods and management, particularly the patients’ preventive measures of the patients can be improved. This review aims to describe and discuss the type of FH, including the clinical and lipid presentation, molecular pathogenesis of monogenic FH, and further discussion on how polygenic FH should be diagnosed and managed. Keywords: hypercholesterolemia, SNP, DNA testing

LDLR gene’s promoter region hypermethylation in patients with familial hypercholesterolemia

Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein cholesterol (LDL-C) levels and a high risk of early coronary heart disease. Structural alterations in the LDLR, APOB, and PCSK9 genes were not found in 20–40% of patients diagnosed using the Dutch Lipid Clinic Network (DCLN) criteria. We hypothesized that methylation in canonical genes could explain the origin of the phenotype in these patients. This study included 62 DNA samples from patients with a clinical diagnosis of FH according to the DCLN criteria, who previously tested negative for structural alterations in the canonical genes, and 47 DNA samples from patients with normal blood lipids (control group). All DNA samples were tested for methylation in the CpG islands of the three genes. The prevalence of FH relative to each gene was determined in both groups and the respective prevalence ratios (PRs) were calculated. The methylation analysis of APOB and PCSK9 was negative in both groups, showing no relationship between methylation in these genes and the FH phenotype. As the LDLR gene has two CpG islands, we analyzed each island separately. The analysis of LDLR-island1 showed PR = 0.982 (CI 0.33–2.95; χ2 = 0.001; p = 0.973), also suggesting no relationship between methylation and the FH phenotype. Analysis of LDLR-island2 showed a PR of 4.12 (CI 1.43–11.88; χ2 = 13,921; p = 0.00019), indicating a possible association between methylation on this island and the FH phenotype.

Cardiometabolic risk factors in young adults diagnosed with acute myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: None. Background/introduction Morbidity and mortality associated with atherosclerotic cardiovascular diseases are prevalent in young patients. Meanwhile, traditional cardiovascular risk calculators underestimate disease risk in young adults. Purpose To characterize cardiometabolic risk factors and lipid levels in young adults with acute myocardial infarction. Setting: A multicenter, population-based analysis of patients diagnosed at our hospitals in Arizona, as well as our clinic health system spanning Minnesota and Wisconsin. Methods This is a retrospective cohort study including patients 18 to 50 years old diagnosed with acute myocardial infarction from October 1, 2015, to December 31, 2018. Parameters obtained included: Age, sex, ethnicity, body mass index, tobacco use, comorbid medical conditions, fasting blood glucose, hemoglobin A1c, lipid levels, and prescribed lipid-lowering therapy. Results Among 553 young patients diagnosed with acute myocardial infarction, the mean age at the time was 44.4 years, with men accounting for 69.1% of cases. The mean body mass index was 32.2 kg/m2. Hypertension, diabetes mellitus, and tobacco use were present in 64.7%, 25.9%, and 36.2% of patients. Insulin resistance, elevated triglycerides, and low HDL-C were present in 29.8%, 51.0%, and 62.8% of patients, respectively. Approximately 61.3% of patients within this cohort met World Health Organization criteria for diagnosis of metabolic syndrome. Mean LDL-C was 116 mg/dL and mean triglycerides were 190 mg/dL. Statin therapy was prescribed to 92 (16.6%) of patients prior to diagnosis of acute myocardial infarction, whereas 359 (67.3%) of patients met ACC/AHA criteria for lipid-lowering therapy. Within this subgroup receiving statin therapy, the mean serum LDL-C was 101 mg/dl, 26.1% had levels below 70 mg/dL, and 56.5% had LDL-C levels below 100 mg/dL. Thirty-four patients (6.1%) with LDL-C levels greater than 190 mg/dL, and 29 (85.3%) were not on lipid-lowering therapy. Conclusions and Relevance Multiple treatable risk factors were present in most young adults with acute myocardial infarction, including many with LDL-C levels below 100 mg/dL. Being overweight or obese was the most prevalent risk factor, while elevated non-HDL cholesterol was the most common lipid panel abnormality. In addition to known cardiometabolic risk factors, these findings build upon a growing body of evidence implicating triglyceride-rich lipoproteins in non-HDL and remnant cholesterol as an independent risk factor of ASCVD, which were common in this cohort of young patients presenting with myocardial infarction. In this cohort, lipid-lowering therapy was underutilized in young patients with known cardiometabolic risk factors, elevated estimated 10-year ASCVD risk, and individuals with phenotypic Familial Hypercholesterolemia.

Additive Effect of APOE Rare Variants on the Phenotype of Familial Hypercholesterolemia.

Autosomal dominant hypercholesterolemia (ADH) is due to deleterious variants in LDLR, APOB, or PCSK9 genes. Double heterozygote for these genes induces a more severe phenotype. More recently, a new causative variant of heterozygous ADH was identified in APOE. Here we study the phenotype of 21 adult patients, double heterozygotes for rare LDLR and rare APOE variants (LDLR+APOE) in a national wide French cohort. LDLR, APOB, PCSK9, and APOE genes were sequenced in 5743 probands addressed for ADH genotyping. The lipid profile and occurrence of premature atherosclerotic cardiovascular diseases were compared between the LDLR+APOE carriers (n=21) and the carriers of the same LDLR causative variants alone (n=22). The prevalence of LDLR+APOE carriers in this French ADH cohort is 0.4%. Overall, LDL (low-density lipoprotein)-cholesterol concentrations were 23% higher in LDLR+APOE patients than in LDLR patients (9.14±2.51 versus 7.43±1.59 mmol/L, P=0.0221). When only deleterious or probably deleterious variants were considered, the LDL-cholesterol concentrations were 46% higher in LDLR+APOE carriers than in LDLR carriers (10.83±3.45 versus 7.43±1.59 mmol/L, P=0.0270). Two patients exhibited a homozygous familial hypercholesterolemia phenotype (LDL-cholesterol >13 mmol/L). Premature atherosclerotic cardiovascular disease was more common in LDLR+APOE patients than in LDLR carriers (70% versus 30%, P=0.026). Although an incomplete penetrance should be taken into account for APOE variant classification, these results suggest an additive effect of deleterious APOE variants on ADH phenotype highlighting the relevance of APOE sequencing.

Genotype-phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease (CVD). Both the heterozygous form and the very severe homozygous form can be diagnosed by genetic testing and by clinical criteria. Genetic testing can discern FH in a form caused by complete absence of the LDL-receptors, the negative variant and a form leading to reduced activity of the LDL receptors, the defective variant. The aim of this study is to provide more insight in the genotype-phenotype correlation in children and adolescents diagnosed with heterozygous FH (HeFH) and with homozygous FH (HoFH), specifically in relation to the clinical and therapeutic consequences of the negative and defective variant of FH. Data of 5904 children with a tentative diagnosis of FH referred to our center for genetic testing were collected. A lipid-profile was present in 3494 children, who became the study cohort. In this large cohort of children, which includes 2714 HeFH and 41 HoFH patients, it is shown that receptor negative variants are associated with significant higher LDL-C levels in HeFH patients than receptor defective variants (6.0 versus 4.9 mmol/L; p < 0.001). A negative/negative variant is associated with a significant higher LDL-C level jn HoFH patients than a negative/defective variant, which in itself has a higher LDL-C level than a defective/defective variant. Significantly more premature CVD is present in close relatives of children with HeFH with negative variants compared to close relatives of HeFH children with defective variants (75% vs 59%; p < 0.001). Performing genetic testing and identifying the type of underlying genetic variant is of added value in order to distinguish between pediatric patients with higher risks of premature CVD and to identify those that will benefit most from new types of lipid-lowering therapies. Since in children the phenotype of FH is less affected by environmental factors, the study substantiates the genotype-phenotype correlation in this large pediatric population.

Possibilities of lipid clinics in identifying patients with familial hypercholesterolemia

Aim. To assess the detection rate of familial hypercholesterolemia among outpa­tients visiting a lipidologist.Material and methods. We analyzed the causes and nature of lipid metabolism disorders in patients of the Adult Lipidology Center as follows: 1233 people aged 18-84, including 777 women (63,02%) and 456 men (36,98%). Biomaterial samples from 421 patients with the phenotype of definite, possible or probable familial hypercholesterolemia were studied by massive parallel sequencing using a panel of 5 genes associated with familial hypercholesterolemia (LDLR, LDLRAP1, APOB, APOE, PCSK9). For statistical processing, descriptive statistics methods were used.Results. Working-age patients apply 1,56 times more often than patients of the older age group (60,91% vs 39,09%), and the vast majority of them were referred by a primary care physician based on data from periodic health examinations. The mean level of total cholesterol and low-density lipoprotein cholesterol in the lipidology center was 7,58 and 4,8, respectively. Out of 421 samples, 127 patients (10,3% of the total number of patients and 30,16% of the number of biosamples) had previously described variants of the LDLR, APOB and/or PCSK9 genes associated with familial hypercholesterolemia.Conclusion. The detection rate of definite familial hypercholesterolemia ranges from 5,51 to 8,43% of outpatients visiting a lipidologist, while the proportion of verified carriers of gene mutations related to familial hypercholesterolemia is 10,3%. The diagnosis should not be rejected with a formally low probability according to the S. Broom and DLCN criteria, as well as when identifying data suggestive of secondary lipid metabolism disorders.

Women with familial hypercholesterolemia phenotype are undertreated and poorly controlled compared to men

Familial hypercholesterolemia (FH) is an autosomal dominant disease that has a prevalence of approximately 1/250 inhabitants and is the most frequent cause of early coronary heart disease (CHD). We included 1.343.973 women and 1.210.671 men with at least one LDL-c measurement from the Catalan primary care database. We identified 14.699 subjects with Familial hypercholesterolemia-Phenotype (FH-P) based on LDL-c cut-off points by age (7.033 and 919 women, and 5.088 and 1659 men in primary and secondary prevention, respectively). Lipid lower therapy (LLT), medication possession ratio (MPR) as an indicator of adherence, and number of patients that reached their goal on lipid levels were compared by sex. In primary and secondary prevention, 69% and 54% of women (P = 0.001) and 64% and 51% of men (P = 0.001) were on low-to-moderate-potency LLT. Adherence to LLT was reduced in women older than 55 years, especially in secondary prevention (P = 0.03), where the percentage of women and men with LDL-c > 1.81 mmol/L were 99.9% and 98.9%, respectively (P = 0.001). Women with FH-P are less often treated with high-intensity LLT, less adherent to LLT, and have a lower probability of meeting their LDL-c goals than men, especially in secondary prevention.

Cardiovascular Outcomes in Patients With Both Diabetes and Phenotypic Familial Hypercholesterolemia: A Nationwide Register-Based Cohort Study.

Patients with diabetes or familial hypercholesterolemia (FH) have an increased incidence of cardiovascular diseases compared with the population, but whether this risk is exacerbated in patients with combined traits is unknown. In this Swedish nationwide, register-based cohort study, patients with diabetes were included between 2002 and 2020. Adjusted Cox proportional hazards models were used to assess the risk of cardiovascular events in patients with or without phenotypic FH (≥6 points for phenotypic FH according to Dutch Lipid Clinic Network criteria) compared with general population control subjects without diabetes as reference. A total of 45,585 patients with type 1 diabetes (227,923 control subjects) and 655,250 patients with type 2 diabetes (655,250 control subjects) were followed for a median of 14.1 and 7.9 years, respectively. Of those, 153 and 7,197, respectively, had phenotypic FH. Compared with control subjects, patients with diabetes and phenotypic FH had higher risk of cardiovascular mortality (type 1: hazard ratio 21.3 [95% CI 14.6-31.0]; type 2: 2.40 [2.19-2.63]) and of a cardiovascular event (type 1: 15.1 [11.1-20.5]; type 2: 2.73 [2.58-2.89]). Further, patients with diabetes and phenotypic FH had higher LDL-cholesterol levels during observation (P < 0.05) and increased risk of all major cardiovascular outcomes (P < 0.0001) than patients with diabetes but without FH. The proportion receiving lipid-lowering treatment was higher in patients with phenotypic FH (P < 0.0001). Patients with both diabetes and phenotypic FH are more at risk for adverse cardiovascular outcomes and have higher LDL-cholesterol levels despite receiving intensified lipid-lowering therapy.

Abstract 9822: Yield of a Familial Hypercholesterolemia Genetic Diagnosis After Electronic Health Record and Genomic Data Screening

Background: Data mining of electronic health records (EHR) has been used as a strategy to identify patients with undiagnosed familial hypercholesterolemia (FH). Most studies have been limited by the absence of both phenotypic and genotypic data in the same cohort. Methods: Using a subset of the Geisinger MyCode Community Health Initiative (MyCode) cohort with both exome sequencing and EHR data (n=130,257), we ran two FH screening algorithms to determine genetic and phenotypic diagnostic yields: the Mayo Clinic algorithm (Mayo), which identifies those with LDL-C levels &gt; 190 mg/dL, and FIND FH®, the Family Heart Foundation’s machine learning model, to identify individuals with phenotypes suggestive of FH. With 29,243 excluded by Mayo (for secondary causes of hypercholesterolemia, no lipid value in EHR), 52,034 excluded by FIND-FH (insufficient data to run the model), and 187 excluded for prior FH diagnosis, a final cohort of 59,729 participants screened by both algorithms was created. Genetic diagnosis was based on the presence of a pathogenic or likely pathogenic (P/LP) variant in 3 genes implicated in FH via genomic screening. Charts from 180 variant negative participants (60 controls; 120 identified by FIND FH and/or Mayo) were reviewed to calculate Dutch Lipid Clinic Network scores; a score &gt; 5 defined probable or definite FH. Results: Mayo flagged 10,415 subjects; 164 (1.6%) had an FH P/LP variant. FIND-FH flagged 573; 28 (4.9%) had an FH P/LP variant giving a net yield from both algorithms of 167/240 (70%). Confirmation of a phenotypic diagnosis was constrained by lack of EHR data on physical findings or family history (high cholesterol, premature atherosclerotic disease) required for score calculation. Phenotypic FH by chart review was present by Mayo and/or FIND-FH in 13/120 vs 2/60 not flagged by either (p&lt; 0.09). Conclusion: After excluding those with a prior FH diagnosis, applying two recognized phenotypic FH screening algorithms to the eligible MyCode cohort identified 70% of those with a P/LP FH variant. Limitations to this approach include participant exclusions for each algorithm, a low yield of positive genomic screening for Mayo, and a low yield of participants for FIND FH. Phenotypic diagnosis was rarely achievable due to missing data.