👤 Tadej Battelino

Lipoprotein(a) [Lp(a)] is a significant genetic risk factor for cardiovascular disease (CVD). Extremely high Lp(a) levels (153mg/dL), affecting about 1 in 100 individuals, can elevate low-density lipoprotein cholesterol (LDL-C) due to structural similarities between Lp(a) and LDL-C particles. This study assessed the role and impact of Lp(a) on LDL-C in children with hypercholesterolemia, a relationship that remains poorly understood. The study included 1,418 children (median age: 6.34 years) with hypercholesterolemia, identified by universal or cascade familial hypercholesterolemia (FH) screening in Slovenia. Participants were categorized as: 363 (25.6%) with definite FH (pathogenic variants in LDLR/APOB/PCSK9), 1,014 (71.5%) with possible FH (no FH pathogenic variant), and 41 (2.9%) definite non-FH (siblings of definite FH cases without FH pathogenic variant). Elevated Lp(a) levels (>30 mg/dL) were found in 25.1% of definite FH and 34.9% of possible FH cases (p=0.003). In definite FH, 32.7% of Lp(a) levels contributed to LDL-C levels, and 18.6% of Lp(a) levels contributed to Apolipoprotein B. The Lp(a) component of LDL-C varied widely (0-49.6%) and accounted for 10.3% of LDL-C variability. After adjusting for Lp(a), elevated LDL-C (>3.5 mmol/L) still persisted in 88.4% of definite FH and 30.4% of possible FH children. One in four children with FH and one in three children with polygenic hypercholesterolemia have elevated Lp(a) levels, contributing notably to LDL-C levels and ApoB. Modifiable CVD risk factors (elevated LDL-C and obesity) are already present in those children, highlighting the need for early, targeted evaluation and management. Show less

Thyroid hormones regulate lipoprotein metabolism-primarily by up-regulating the LDL receptor. Whether TSH relates to LDL-C in hypercholesterolemic children, and whether this depends on familial hypercholesterolemia (FH) status or the underlying defective gene, is uncertain. We evaluated TSH-lipid associations in prepubertal children and tested effect modification by FH status and, within FH, by gene with a pathogenic variant (LDLR vs APOB). We performed a cross-sectional study of prepubertal children referred to the Slovenian national tertiary center through the universal FH screening program or cascade screening. Eligibility required concurrent TSH and fasting lipid measurement and completed genetic testing (pathogenic/likely pathogenic variants in LDLR/APOB/PCSK9 vs polygenic hypercholesterolemia). Among 738 children, 182 (24.7%) were FH-positive (LDLR 132; APOB 50). In the pooled cohort, TSH did not correlate with age or lipids (all p ≥ 0.050). After sex stratification, TSH correlated with triglycerides only in males (ρ = 0.156; p = 0.012). In FH-positive children, TSH correlated with total cholesterol, LDL-cholesterol, and ApoB (ρ ~ 0.184-0.207; all p < 0.050), with no associations in FH-negative children. Interaction testing confirmed effect modification by FH (TSH × FH β = 0.141 mmol/L per mIU/L, p = 0.023). Within FH-positive children, a positive TSH-LDL-C slope was seen in LDLR carriers (β = 0.237, p = 0.004) but not in APOB carriers (β = -0.065, p = 0.655). TSH was positively associated with LDL-C only in FH due to LDLR variants, not in APOB carriers. These findings suggest that genetic background may shape hormonal sensitivity, and that attention to thyroid status could be particularly relevant in LDLR-FH. Show less

In contrast to extensively studied hypercholesterolemia, knowledge of hypocholesterolemia is limited. This study aims to assess the prevalence, clinical characteristics, and genetics of children and adolescents with hypocholesterolemia. This national prospective cross-sectional cohort study was part of Slovenia's universal opt-out cholesterol screening program. The first part assessed hypocholesterolemia prevalence among 3538 children aged 5 years, randomly selected at the mandatory check-up. The second part included analysis of demographic and clinical data and genetic testing of 71 individuals with suspected hypocholesterolemia (total cholesterol [TC] < 3.0 mmol/L [116.0 mg/dL]) referred to the Lipid Clinic of University Children's Hospital Ljubljana. The prevalence of hypocholesterolemia among 3538 children was 2.66 % (95 % CI: 2.13-3.19 %). Among the 71 genetically tested individuals with suspected hypocholesterolemia, those with pathogenic variants had lower TC (2.58 ± 0.44 mmol/L vs. 2.85 ± 0.42 mmol/L [99.77 ± 17.02 mg/dL vs. 110.20 ± 16.24 mg/dL]; p = 0.037) and low-density lipoprotein cholesterol (1.00 ± 0.40 mmol/L vs. 1.33 ± 0.40 mmol/L [38.67 ± 15.47 mg/dL vs. 51.43 ± 15.47 mg/dL]; p = 0.014) compared to those without such variants. Genetic testing identified pathogenic alterations in 15 subjects, including 4 novel loss-of-function variants in the APOB gene. All but one subject were asymptomatic. This study provides new clinical and genetic insights into hypocholesterolemia. Asymptomatic patients with hypocholesterolemia may not require further evaluation, but additional research is needed to understand hypocholesterolemia better. Show less

Hypertriglyceridemia (HTG) is a complex disorder caused by genetic and environmental factors that frequently results from loss-of-function variants in the gene encoding lipoprotein lipase (LPL). Heterozygous patients have a range of symptoms, while homozygous LPL deficiency presents with severe symptoms including acute pancreatitis, xanthomas, and lipemia retinalis. We described the clinical characteristics of three Slovenian patients (an 8-year-old female, an 18-year-old man, and a 57-year-old female) and one Pakistani patient (a 59-year-old male) with LPL deficiency. We performed next-generation sequencing (NGS) targeting all coding exons and intron-exon boundaries of the Two Slovenian patients with a heterozygous pathogenic variant NM₀₀₀₂₃₇.3:c.984G>T (p.Met328Ile) were diagnosed within the first three years of life and had triglyceride (TG) values of 16 and 20 mmol/L. An asymptomatic Pakistani patient with TG values of 36.8 mmol/L until the age of 44 years, was identified as heterozygous for a pathogenic variant NM₀₀₀₂₃₇.3:c.724G>A (p.Asp242Asn). His TG levels dropped to 12.7 mmol/L on dietary modifications and by using fibrates. A Slovenian patient who first suffered from pancreatitis at the age of 18 years with a TG value of 34 mmol/L was found to be homozygous for NM₀₀₀₂₃₇.3:c.337T>C (p.Trp113Arg). Patients with LPL deficiency had high TG levels at diagnosis. Homozygous patients had worse outcomes. Good diet and medication compliance can reduce severity. Show less

Monogenic obesity is a severe, genetically determined disorder that affects up to 1/1000 newborns. Recent reports on potential new therapeutics and innovative clinical approaches have highlighted the need for early identification of individuals with rare genetic variants that can alter the functioning of the leptin-melanocortin signalling pathway, in order to speed up clinical intervention and reduce the risk of chronic complications. Therefore, next-generation DNA sequencing of central genes in the leptin-melanocortin pathway was performed in 1508 children and adolescents with and without obesity, aged 2-19 years. The recruited cohort comprised approximately 5% of the national paediatric population with obesity. The model-estimated effect size of rare variants in the leptin-melanocortin signalling pathway on longitudinal weight gain between carriers and non-carriers was derived. In total, 21 (1.4%) participants had known disease-causing heterozygous variants (DCVs) in the genes under investigation, and 62 (4.1%) participants were carriers of rare variants of unknown clinical significance (VUS). The estimated frequency of potential genetic variants associated with obesity (including rare VUS) ranged between 1/150 (VUS and DCV) and 1/850 (DCV) and differed significantly between participants with and without obesity. On average, the variants identified would result in approximately 7.6 kg (7.0-12.9 kg at the 95th percentile of body weight) (girls) and 8.4 kg (8.2-14.4 kg) (boys) of additional weight gain in carriers at age 18 years compared with subjects without obesity. In conclusion, children with a genetic predisposition to obesity can be promptly identified and may account for more than 6% of obesity cases. Early identification of genetic variants in the Show less

Proopiomelanocortin (POMC) deficiency is an extremely rare inherited autosomal recessive disorder characterized by severe obesity, adrenal insufficiency, skin hypopigmentation, and red hair. It is caused by pathogenic variants in the Show less