Welcome to the EAS 2023 Interactive Program

Background and Aims

We aimed at assessing the impact of family history of coronary heart disease (CHD) and genetic predisposition in predicting the individual lifetime risk of major coronary events (MCE).

Methods

Using adjusted Cox proportional hazard models, we estimated the lifetime risk of MCE associated with parental family history of CHD and individual genetic predisposition (estimated through a polygenic score).

Results

A total of 445,744 UK-Biobank participants were selected (mean age 57 years; 54.3% females). Having one parent with a history of CHD increased the lifetime risk of MCE by 75% (HR 1.75, 95%CI 1.70-1.82, p-value<0.0001). Having both parents with a history of CHD further increased the risk (HR 2.78, 95%CI 2.64-2.92, p-value<0.0001) Similarly, a dose-dependent step-wise increase in MCE risk was observed moving from the lowest to the highest decile of the polygenic score. Compared to subjects without family history of CHD and with average level of the polygenic score, having a parental history of CHD determined an increase in lifetime risk of MCE (HR 1.90, 95%CI 1.82-1.98, p-value<0.0001) comparable to belonging to the highest decile of the polygenic score (HR 1.89, 95%CI 1.76-2.02, p-value<0.0001). However, if subjects present both parents with family history of CHD and a very high polygenic predisposition, the risk was even higher (HR 3.54, 95%CI 3.34-3.75, p-value<0.0001), suggesting an additive contribution.

Conclusions

We described the additive impact of family history of CHD and individual polygenic predisposition in predicting lifetime risk of MCE. Therefore, it is essential to retrieve information about both these hereditary components to identify subjects at higher risk.

Background and Aims

Globally, heterozygous familial hypercholesterolaemia (HeFH) presents in 6.4 million children/adolescents. Early identification enables the opportunity for timely intervention, but population efforts have largely focused on detecting adults to identify children. With screening for FH in children/adolescents increasingly discussed worldwide, we aimed to understand the current unmet need across the FH diagnostic pathway globally, as required resources for detection may vary across health systems and by country-income status.

Methods

Cross-sectional analyses at registry entry of <18-year-old children/adolescents with clinical and/or genetic diagnosis of HeFH from 48 countries. Homozygous FH individuals were excluded. Countries were classified by high- and non-high-income status in accordance to 2022 World Bank definition.

Results

11,848 children/adolescents were included in the analyses (96.4% from high-income; 50% girls); characteristics of participants are in table. 92.7% and 48.0% children/adolescents had a genetically confirmed diagnosis in high- and non-high-income regions respectively (p<0.001). Presence of corneal arcus, xanthomas, and coronary artery disease (CAD) were 2.8-times, 7.6-times, and 38-times higher in non-high-vs. high-income regions. LDL-C not on lipid-lowering medications (LLM) were 0.89 mmol/L higher in non-high-vs. high-income regions (p<0.001). The odds of having LDL-C not on LLM (>7.80 mmol/L) was 72% lower in high-income-regions.

Conclusions

Identification of FH across non-high-vs. high-income-regions is much lower. Genetic diagnosis in non-high-income regions is used less frequently (likely, at least partly, due to unavailability and/or inaccessibility of genetic testing), hence there is a higher reliance on clinical criteria among non-high-income-regions which leads to higher odds of children/adolescents being detected with a more severe phenotype (namely physical signs, CAD and LDL-C).

Background and Aims

Background: Lipoprotein(a) may be implicated in peripheral arterial disease (PAD) and abdominal aortic aneurysms (AAA), yet data from general population studies are limited, and large studies are needed to determine risk in individuals with the highest levels and associated risk of major adverse limb events (MALE).

Aims: To test whether high lipoprotein(a) levels associate with increased risk of PAD, AAA, and MALE, and to provide genetic evidence of causality using LPA genotypes.

Methods

Methods: We included 108,146 individuals from the contemporary Copenhagen General Population Study (CGPS). During follow-up, 2,450 developed PAD, 1,251 AAA, and 489 MALE. We used the historic Copenhagen City Heart Study (CCHS, N=10,960) to replicate findings for MALE (N=116).

Results

Results: High lipoprotein(a) levels and corresponding LPA risk genotypes associated with increased risk of PAD and AAA in the CGPS (Figure 1). For individuals with lipoprotein(a) levels >99^th percentile (≥143mg/dL,≥306nmol/L), multivariable adjusted hazard ratios were 2.99(95% confidence interval:2.09-4.30) for PAD and 2.22(1.21-4.07) for AAA compared to individuals with levels <50^th percentile (≤9mg/dL,≤17nmol/L). Corresponding hazard ratios for MALE were 2.70(1.67-4.37) in the CGPS and 8.12(3.56-18.55) in the CCHS. Absolute 10-year risks of PAD and/or AAA were 11% and 29% in smoking women aged 70-79 years with lipoprotein(a) <50^th vs. >99^th percentile. Equivalent values in men were 19% and 47%. The percentage of events attributable to lipoprotein(a) >50^th percentile was 9.5% and 12.3% for PAD and AAA.

Conclusions

Conclusion: High lipoprotein(a) levels increased risk of PAD, AAA, and MALE in the general population, opening opportunities for prevention given future lipoprotein(a) lowering therapies.

Background and Aims

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.

Methods

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 (ASCVD) were compared between the LDLR+APOE carriers (n=21) and the carriers of the same LDLR causative variants alone (n=22).

Results

The prevalence of LDLR+APOE carriers in this French ADH cohort is 0.4%. Overall, LDL-C concentrations were 23% higher in LDLR+APOE patients than in LDLR patients (mean ±SD: 9.14±2.51 versus 7.43±1.59 mmol/L, p<0.05). When only deleterious or probably deleterious variants were considered, the LDL-C concentrations were 46% higher in LDLR+APOE carriers than in LDLR carriers (mean±SD: 10.83±3.45 versus 7.43±1.59 mmol/L, p<0.05). Two patients exhibited a homozygous FH phenotype (LDL-C>13 mmol/L). Premature ASCVD were more common in LDLR+APOE patients than in LDLR carriers (85% vs 33%, p<0.01).

Conclusions

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.

Background and Aims

Introduction: Sitosterolemia is an autosomal recessive disorder caused by variants in ABCG5/8 genes and is characterized by severely elevated plasma plant sterols, causing xanthomas and premature cardiovascular disease. The aim of this study is to present 12 clinical cases of sitosterolemia in Iberoamerican countries.

Methods

Methods: We report seven index cases, and five relatives identified by cascade screening. Clinical and laboratory characteristics were determined in different countries. All individuals were sequenced for the ABCG5/8 genes either by sanger or next generation sequencing. Whenever possible sterols chromatography was performed.

Results

Results: All index children and 2 index adults presented xanthomas and children had a mean LDL of 570 mg/dL. The geographical distribution of the 12 cases is as follows: five from Spain (four compound heterozygous and one true homozygous, all in ABCG8); three from Portugal (all true homozygous, two in ABCG8 and one in ABCG5); one from Argentina (true homozygous in ABCG8) and three from Uruguay (all true homozygous in ABCG8). Six index cases present variants in ABCG8 gene (two missense and four nonsense variants) and only one presents a homozygosity in the ABCG5 gene (frameshift variant). Six cases (4 index and 2 relatives) (50%) were diagnosed in childhood, the remaining were identified as adults.

Conclusions

Conclusions: There is a genetic heterogeneity of sitosterolemia in Iberoamerican countries. The treatment for sitosterolemia is specific and completely different from the other types of hypercholesterolemia, so a correct and timely diagnosis is crucial to avoid delays in treatment that could lead to poor clinical outcomes.