Epidemiological and Mendelian randomization studies have reported an inverse relationship between lipoprotein(a) [Lp(a)] concentration and type 2 diabetes (T2D), although findings have not been uniform across studies. We hypothesized that genetic variation at the LPA locus may contribute to T2D development beyond circulating Lp(a) concentration alone, and therefore aimed to investigate the association between common LPA variation and incident T2D. We analysed 5058 male participants from the Aragon Workers’ Health Study with approximately 15 years of follow-up. T2D was defined as the presence of antidiabetic treatment or HbA1c ≥ 6.5

Background and aims: Recent reports have shown that subjects with high high-density lipoprotein cholesterol (HDLc) levels are paradoxically at increased risk for all-cause and cardiovascular mortality. The aim was to study the association of HDLc concentration with mortality in subjects with high cholesterol. Methods: We analyzed total mortality, cardiovascular mortality, and non-cardiovascular mortality in a cohort of 2992 subjects with primary hypercholesterolemia, who were followed for 10.2 years (range 1-25 years), with a total of 30,602 subject-years of follow-up. Results: During follow-up, 168 subjects died, with 52 (13.7 %), 105 (4.80 %), and 11 (2.60 %) in the low, normal, and high HDLc groups, respectively (p < 0.001). The risk of death was 2.89 times higher (95 % confidence interval (CI), 1.50-5.57, p < 0.001) in subjects in the low HDLc group compared to those in the high HDLc group and 1.48 times higher (95 % CI 0.80-2.76, p = 0.214) in the normal HDLc group compared to the high HDLc group. However, HDLc concentration and HDLc groups based on HDLc concentration were not independently associated with mortality in Cox regression analysis. Cardiovascular and non-cardiovascular mortalities showed similar results. Conclusions: All types of mortality were lower in subjects with primary hypercholesterolemia and with high HDLc in univariate analysis. Elevated HDLc was not associated with total, cardiovascular, and non-cardiovascular mortality when adjusted for major cardiovascular risk factors.

Introducción y objetivos La frecuencia, las características clínicas y el riesgo de enfermedad cardiovascular ateroesclerótica (ECVA) de los diferentes tipos de hipercolesterolemia no están bien establecidos. Los criterios de valoración primarios y secundarios fueron establecer la causa de la hipercolesterolemia y si esta confiere un pronóstico diferente para la ECVA. Métodos El análisis incluyó a 3.474 probandos con hipercolesterolemia primaria, de los cuales 3.283 (94,8%) se siguieron durante 9,33±5,8 años para la ECVA. El análisis genético de los genes de la hipercolesterolemia familiar (HF), la puntuación de riesgo poligénico para la hipercolesterolemia y las concentraciones de lípidos, incluyendo la lipoproteína(a), se utilizaron para clasificar la hipercolesterolemia. Resultados Los diagnósticos fueron: HF heterocigota, n=400 (11,5%); hiperlipoproteinemia(a), n=181 (5,2%); hipercolesterolemia poligénica, n=434 (12,5%); hiperlipoproteinemia(a)+hipercolesterolemia poligénica, n=128 (3,7%); multifactorial, n=1.562 (45,0%), e idiopática, n=769 (22,1%). Al inicio, el colesterol unido a lipoproteínas de baja densidad fue mayor en la HF heterocigota, y la prevalencia de ECVA fue mayor en la hiperlipoproteinemia(a). Otras características clínicas y bioquímicas no difirieron entre los subgrupos de hipercolesterolemia. Los sujetos con hiperlipoproteinemia(a) mostraron una tasa de supervivencia menor que los otros grupos de hipercolesterolemia (p=0,001). Las variables asociadas independientemente con episodios de ECVA durante el seguimiento fueron la edad, el sexo masculino, la presencia de ECVA, diabetes o hipertensión al inicio, el tabaquismo, y las concentraciones de lipoproteína(a) y colesterol unido a lipoproteínas de alta densidad; estas últimas se asociaron inversamente con episodios de ECVA. La mortalidad total fue independiente del tipo de hipercolesterolemia. Conclusiones La hipercolesterolemia genética presenta un peor pronóstico para la ECVA que la hipercolesterolemia no genética. Entre ellas, las personas con valores elevados de lipoproteína(a) presentan el peor pronóstico. El tratamiento hipolipemiante convencional para el colesterol unido a lipoproteínas de baja densidad parece ser menos eficaz en la hipercolesterolemia debida a hiperlipoproteinemia(a) que en otras hipercolesterolemias.

To assess whether the role of selenium on pre-diabetes is differential by age, given comorbidities and decreased β-cell function in older adults. We evaluated the cross-sectional association of blood selenium with the homeostatic model assessment for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) in middle-aged (Aragon Workers Health Study [AWHS], N = 1186), and older (Seniors ENRICA [Study on Nutrition and Cardiovascular Risk in Spain]-2 [SEN-2], N = 915) diabetes-free adults. A subsample of participants from AWHS (N = 571) and SEN-2 (N = 603) had glucose and insulin repeated measurements for longitudinal analysis. We validated the cross-sectional dose–response associations in the 2011–2018 National Health and Nutrition Examination Survey (NHANES, N = 1317 middle age and N = 960 older) participants. Selenium was measured in whole blood with ICP-MS in AWHS, SEN-2 and NHANES. The cross-sectional geometric mean ratios (95% confidence intervals) per two-fold selenium increase were 1.09 (1.01, 1.19) for HOMA-IR and 1.15 (1.06, 1.24) for HOMA-β in AWHS; and 1.13 (0.98, 1.31) and 1.03 (0.90, 1.18), in SEN-2. The cross-sectional dose-response associations were consistent in NHANES, with mostly increasingly positive trends for both HOMA endpoints in younger adults and a plateau at levels >~150 μg/L in older adults. The longitudinal dose–response consistently showed positive associations at high selenium dose for both HOMA endpoints in the younger, but not the older, study population. Increased blood selenium was associated with increased insulin resistance and β-cell function in middle-aged, but not in older individuals, especially for β-cell function. The results suggest that selenium-associated insulin resistance might induce compensatory increased β-cell function at younger ages, being this compensatory capacity decreased with aging.

BACKGROUND:Nuclear magnetic resonance (NMR) spectroscopy enables the characterisation of lipoprotein sub-particles, providing a more detailed lipid profile than the conventional lipid measurements, with potential clinical relevance, particularly in cardiovascular disease (CVD), which remains the leading cause of mortality worldwide. Nonetheless, for clinical implementation, it is essential to first determine the normal variation of lipoprotein parameters by age and sex. METHODS:This cross-sectional study analysed a large dataset of 31,275 serum or plasma samples from five different countries using the B.I.LISA™ NMR-based platform, quantifying 112 lipoprotein parameters, including subclass size and concentration. Lipoprotein parameters from specific cohorts were fitted to a Quantile Generalised Additive Model (QGAM) to calculate the different percentiles as a function of age and sex. FINDINGS:A sub-cohort of individuals belonging to non-oriented cohorts (27,470 individuals) showed that lipoprotein parameters exhibit distinct sex- and age-dependent patterns, with inflection points observed around 44 and 60 years in women and around 60 years in men, aligning with known ageing acceleration models. The sub-cohort of 3021 individuals showing cardiometabolic risk factors was used to evaluate the effect of obesity, hypertension and diabetes in the lipoprotein distribution. Finally, we analysed the lipoprotein parameters that align with SCORE2 (a well-known CVD risk predictor) in an age- and sex-dependent manner. Many NMR-derived parameters effectively distinguish between low and high/very high CVD risk profiles, with very low-density (VLDL)-associated parameters demonstrating the highest sensitivity across a broad age range. INTERPRETATION:Our findings provide reference values for NMR-derived lipoprotein parameters by age and sex, enabling their accurate interpretation in the context of cardiovascular disease risk stratification. FUNDING:The specific funding of this article is provided in the acknowledgements section.

Context: Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by the presence of 2 pathogenic variants in the LDLR, APOB, PCSK9, or LDLRAP1 genes, which cause very high levels of LDL-cholesterol and premature atherosclerotic cardiovascular disease (ASCVD). Objective: To analyze the current situation regarding diagnosis, cardiovascular disease, lipid-lowering treatment, and degree of control of lipids in patients with HoFH in the National Dyslipidemia Registry of the Spanish Atherosclerosis Society. Methods: Subjects with HoFH, confirmed by the presence of 2 pathogenic variants in the genes mentioned above, included in the registry from 2013 to June 2023 with an updated review were analyzed. Results: Of 71 included subjects with HoFH, 40.8% were women, aged 52 [24-62] years, 57 adults and 13 children. The median follow-up was 7 [4-13] years. Age of diagnosis was 14 [2-26] years, with 10% of ASCVD at diagnosis and 27% of current ASCVD at 40.6 (13.4) years of age; 38% were on PCSK9 inhibitors, 9 patients on lomitapide, 9 on LDL apheresis, and 1 patient on evinacumab. Subjects with more than 4 therapies achieved >80% reduction in LDLc. In the last visit, the median LDLc was 139.3 [89.4-204.2] mg/dL. ASCVD was strongly associated with male sex and family history of ASCVD, relative risk 5.26 (1.53-18.10) and 2.53 (1.03-6.26), P < .05, respectively. Only 18% and 10% meet the recommended LDLc goal in primary and secondary prevention respectively. Conclusion: The current situation of HoFH in Spain is better than expected, with marked reductions in LDLc levels with new treatments. In this population, recommended LDLc goals are difficult to achieve despite maximum lipid-lowering therapy. ASCVD has been reduced and delayed by 2 decades.

Understanding potential determinants of selenium biomarkers can help to unravel selenium health effects. We evaluated the contribution of non-genetic (sociodemographic and lifestyle) and genetic factors to serum selenium biomarkers and selenium species (quantified as selenium) including selenium in glutathione peroxidase (GPx), selenoprotein P (SeP), selenoalbumin (SeAlb) and total selenometabolites (Se-metabolites) in the Aragon Workers Health Study (AWHS), a predominantly male cohort of car assembly factory workers in Spain. Total serum selenium and selenium species were measured by HPLC/ICP-QQQ-MS in 1624 AWHS participants. Blood and urine selenium, measured by ICP-MS, were available in a subset. A Healthy Lifestyle Score (HLS) included Mediterranean diet, physical activity, smoking, BMI and alcohol intake. Candidate gene and genome-wide discovery analyses (CGA and GDA, respectively) were based on TOPMed imputed SNPs. In sex and age-adjusted models, overall HLS, physical activity, and specific foods intake showed positive associations with serum total selenium, SeAlb and Se-metabolites concentrations. The associations between smoking status and BMI with total serum selenium; age, smoking status, BMI and meat intake with SeAlb; and smoking status with Se-metabolites, were inverse. In the GDA, we identified 20, 24, 21, 26, 16, 20 and 68 independent genetic loci for serum total selenium, GPx, SeP, SeAlb, Se-metabolites, and total blood and urine selenium, respectively, with some overlapping genes also relevant in the CGA. Enrichment analysis pointed to biological pathways including circadian rhythm regulation, immune system processes, signaling and receptor- and transporter-related pathways. The explained variability of selenium markers ranged from 15 % for SeP to 21 % for SeAlb and from 0.2 % for SeP to 3.5 % for SeAlb in environmental determinants-adjusted models with and without the specific selenium biomarker polygenic score, respectively. While the genetic contribution is substantial, selenium status might be influenced by reinforced healthy lifestyle interventions. Follow-up genetic studies to evaluate selenium health consequences are granted.

INTRODUCTION AND OBJECTIVES:The frequency, clinical characteristics and risk of atherosclerotic cardiovascular disease (ASCVD) of the different types of hypercholesterolemia are not well established. The primary and secondary objectives of this study were to determine the cause of hypercholesterolemia and whether the cause confers a different ASCVD prognosis. METHODS:The analysis included 3474 probands with primary hypercholesterolemia, of whom 3283 (94.8%) were followed up for 9.33± 5.8 years for ASCVD. Genetic analysis of familial hypercholesterolemia (FH) genes, polygenic risk score for hypercholesterolemia, and lipid concentrations, including lipoprotein(a), were used to classify hypercholesterolemia. RESULTS:The diagnoses were heterozygous FH, n=400 (11.5%); hyperlipoproteinemia(a), n=181 (5.2%); polygenic hypercholesterolemia, n=434 (12.5%); hyperlipoproteinemia(a) plus polygenic hypercholesterolemia, n=128 (3.7%); multifactorial, n=1562 (45.0%); and idiopathic, n=769 (22.1%). At baseline, low-density lipoprotein cholesterol levels were higher in heterozygous FH, and the prevalence of ASCVD was higher in hyperlipoproteinemia(a). Other clinical and biochemical characteristics did not differ among hypercholesterolemia subgroups. The survival rate was lower in participants with hyperlipoproteinemia(a) than in the other hypercholesterolemia groups (P=.001). Variables independently associated with ASCVD events during follow-up were age, male sex, the presence of ASCVD, diabetes or hypertension at baseline, current smoking, lipoprotein(a) concentration, and high-density lipoprotein cholesterol concentration, the latter being inversely associated with ASCVD events. Total mortality was independent of the type of hypercholesterolemia. CONCLUSIONS:Genetic hypercholesterolemia has a worse prognosis for ASCVD than nongenetic hypercholesterolemia. Among individuals with genetic hypercholesterolemia, those with elevated lipoprotein(a) have the worst prognosis. Conventional lipid-lowering treatment for low-density lipoprotein cholesterol appears to be less effective in hypercholesterolemia due to hyperlipoproteinemia(a) than in other forms of hypercholesterolemia.

Aims:Familial hypercholesterolaemia (FH) is the most prevalent autosomal dominant disorder, affecting about 1 in 200-250 individuals. It is the leading cause of early and aggressive coronary artery disease. Methods and results:We analysed patients with genetically confirmed FH or a score >8 on the Dutch Lipid Clinics Network criteria from the National Registry of the Spanish Atherosclerosis Society, including individuals enrolled from January 2010 to December 2017. The model utilized a dataset incorporating family history, clinical characteristics, laboratory results, genetic data, imaging studies, and lipid-lowering treatment details. Eighty per cent of the population was allocated for training the AI algorithm and 20% was used for testing. A Histogram-based Gradient Boosting Classification Tree was used. The stability of the AI system was assessed using K-fold cross-validation. Shapley additive explanations methodology analysed the influence of different variables by sex. Youden's J statistic established the optimal cut-off point. A total of 1764 patients were included (51.8% women), among whom 264 experienced major adverse cardiovascular events (MACEs), with 8% being women. The final model incorporated 82 variables, achieving metrics of precision for MACE accuracy (0.92), recall (0.89), F1-score (0.91), and receiver operating characteristic (0.88; 95% confidence interval, 0.85-0.90). In the model, age, gamma-glutamyl transferase levels, and subclinical disease significantly impacted risk for women, while year of birth, age at initiation of statin treatment, and HbA1c levels were more influential for men. The optimal risk threshold was 0.25. Conclusion:Artificial intelligence-machine learning algorithms are promising tools for enhancing vascular risk stratification, revealing critical sex-based differences.

BACKGROUND:The APOE p.(Leu167del) variant has been identified as a rare cause of autosomal dominant hypercholesterolemia. A comprehensive phenotypic profile of carriers remains undefined, and its frequency has not been systematically studied. OBJECTIVE:To characterize the phenotypic differences between p.(Leu167del) carriers among individuals with primary hypercholesterolemia and those with familial hypercholesterolemia (FH), and to estimate the variant's frequency in different populations. MEDTHODS:Phenotypic differences were assessed from the Lipid Unit cohort of the Hospital Universitario Miguel Servet (HUMS, n = 6489). The allele frequency of the p.(Leu167del) variant was estimated using data from the HUMS and Aragon Workers Health Study (AWHS, n = 5678), a cohort of working adults, and international cohorts: GnomAD (n ≈ 807,162), TOPMed (n ≈ 180,000), 100 K Genomes Project (n ≈ 85,000). To characterize the profile of carriers, data from the HUMS cohort and a systematic review of the published literature were also used. RESULTS:Carriers showed significantly higher high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and non-HDL cholesterol and lower lipoprotein(a) [Lp(a)] concentrations compared to noncarriers with primary hypercholesterolemia. In comparison with FH patients carrying LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) variants, carriers displayed higher triglycerides and HDL cholesterol but lower LDL cholesterol and Lp(a). The APOE p.(Leu167del) frequency is approximately 1 in 12,000 individuals in the general population and about 2.5% of FH. CONCLUSION:The study confirmed the association of APOE p.(Leu167del) with hypercholesterolemia but with lower LDL cholesterol than subjects with FH. These findings support p.(Leu167del) as a cause of FH and its inclusion in the genetic screening for FH, particularly in Caucasian populations.

BACKGROUND:Rare variants in SCARB1, which encodes the high-density lipoprotein (HDL) receptor scavenger receptor class B type 1 (SR-B1), are hypothesized to drive unexplained extreme levels of plasma HDL cholesterol (HDL-C). OBJECTIVE:We sequenced and phenotypically correlated SCARB1 by analyzing individuals with extreme HDL-C levels and characterizing the functional consequences of rare identified variants. METHODS:SCARB1 was Sanger-sequenced in 96 unrelated participants with extreme HDL-C levels. Clinical, biochemical, and anthropometric data were compared between groups. Bioinformatic tools were used to predict the functional impact of all detected variants. Familial analyses of predicted damaging in silico or not previously described variants was assessed, and HDL uptake was quantified by flow cytometry in HEK293 cells expressing rare SCARB1 variants showing a suggestive pattern of familial segregation. RESULTS:Compared with the high-HDL-C group, low-HDL-C subjects exhibited lower low-density lipoprotein cholesterol and total cholesterol but higher triglycerides, higher body mass index, and a greater frequency of atherosclerotic cardiovascular disease events. Twenty-five SCARB1 variants were identified; 4 of them, c.-177G>T, p.(Thr118Ser), c.843-982G>A and p.(Thr378Met), were predicted to be deleterious. The missense changes p.(Thr118Ser) and p.(Thr378Met) showed a suggestive pattern of segregation with high HDL-C in available pedigrees. Cells expressing p.(Thr378Met) SCARB1 variant showed a reduction in HDL uptake vs wild-type. CONCLUSION:Rare predicted damaging in silico variant in SCARB1, p.(Thr378Met), impairs SR-B1-mediated HDL uptake and associates with high HDL-C levels, highlighting SCARB1 as a candidate gene for genetic screening in dyslipidemic patients.

PURPOSE OF REVIEW:Autosomal dominant hypercholesterolemia is a common cause of cardiovascular disease. In addition to the classic genes that cause hypercholesterolemia, LDLR, APOB and PCSK9 , a new locus has emerged as a candidate to be the cause of this hyperlipidemia, the p.(Leu167del) mutation in the APOE gene. RECENT FINDINGS:Various studies have demonstrated the involvement of the p.(Leu167del) mutation in the APOE gene in hypercholesterolemia: Studies of family segregation, lipoprotein composition by ultracentrifugation and proteomic techniques, and functional studies of VLDL-carrying p.(Leu167del) internalization with cell cultures have demonstrated the role of this mutation in the cause of hypercholesterolemia. The phenotype of individuals carrying the p.(Leu167del) in APOE is indistinguishable from familial hypercholesterolemia individuals with mutations in the classic genes. However, a better response to lipid-lowering treatment has been demonstrated in these APOE mutation carrier individuals. SUMMARY:Therefore, APOE gene should be considered a candidate locus along with LDLR, APOB , and PCSK9 to be investigated in the genetic diagnosis of familial hypercholesterolemia.