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The apolipoprotein epsilon4 allele confers additional risk in children with familial hypercholesterolemia
Albert Wiegman1, Eric J G Sijbrands, Jessica Rodenburg
1Emma Children's Hospital/Academic Medical Center, University of Amsterdam, The Netherlands. a.wiegman@amc.uva.nl
Insights
Familial hypercholesterolemia (FH) shows varied LDL cholesterol in children. The apolipoprotein E4 (apoE4) allele is linked to lower HDL cholesterol in FH children, indicating an added risk.
Area of Science:
- Genetics
- Pediatrics
- Cardiovascular Disease
Background:
- Children with familial hypercholesterolemia (FH) display significant variability in LDL cholesterol levels.
- Previous studies included family members, potentially introducing bias; this study focuses on unrelated children and affected sib-pairs to mitigate this.
- Classical FH diagnosis is based on LDL cholesterol exceeding the 95th percentile for age and gender.
Purpose of the Study:
- To investigate phenotypic variations in LDL cholesterol among unrelated children with FH and affected sib-pairs.
- To examine the influence of apolipoprotein (apo) E genotypes, specifically the epsilon4 allele, on lipid profiles in children with FH.
- To determine if the apoE4 allele contributes to increased cardiovascular risk in pediatric FH.
Main Methods:
- Phenotypic analysis of 450 unrelated children with FH and 154 affected sib-pairs.
- Diagnosis of FH based on plasma LDL cholesterol levels above age- and gender-specific 95th percentiles.
- Analysis of apolipoprotein E genotypes and their association with LDL and HDL cholesterol levels, utilizing an affected sib-pair model for enhanced accuracy.
Main Results:
- Girls with FH exhibited higher LDL cholesterol levels compared to boys (p = 0.002).
- HDL cholesterol increased with age in girls (p for trend = 0.005), but not in boys.
- The epsilon4 allele of apoE was significantly associated with lower HDL cholesterol levels in the affected sib-pair analysis (p = 0.003), explaining 72.4% of the variance.
Conclusions:
- The epsilon4 allele of apolipoprotein E is associated with reduced HDL cholesterol levels in children with FH.
- This finding suggests that apoE4 significantly influences HDL cholesterol in pediatric FH.
- The presence of apoE4 may confer an additional disadvantage and increased cardiovascular risk for children diagnosed with FH.
Abstract:
Children with familial hypercholesterolemia (FH) exhibit substantial variance of LDL cholesterol. In previous studies, family members of children with FH were included, which may have influenced results. To avoid such bias, we studied phenotype in 450 unrelated children with FH and in 154 affected sib-pairs. In known families with classical FH, diagnosis was based on plasma LDL cholesterol above the age- and gender-specific 95th percentile. Girls had 0.47 +/- 0.15 mmol/L higher LDL cholesterol, compared with boys (p = 0.002). Also in girls, HDL cholesterol increased by 0.07 +/- 0.03 mmol/L per 5 y (pfor trend = 0.005); this age effect was not observed in boys. The distribution of apolipoprotein (apo) E genotypes was not significantly different between probands, their paired affected siblings, or a Dutch control population. Carriers with or without one epsilon4 allele had similar LDL and HDL cholesterol levels. Within the affected sib-pairs, the epsilon4 allele explained 72.4% of the variance of HDL cholesterol levels (-0.15 mmol/L, 95% confidence interval -0.24 to -0.05, p = 0.003). The effect of apoE4 on HDL cholesterol differed with an analysis based on probands or on affected sib-pairs. The affected sib-pair model used adjustment for shared environment, type of LDL receptor gene mutation, and a proportion of additional genetic factors and may, therefore, be more accurate in estimating effects of risk factors on complex traits. We conclude that the epsilon4 allele was associated with lower HDL cholesterol levels in an affected sib-pair analysis, which strongly suggests that apoE4 influences HDL cholesterol levels in FH children. Moreover, the strong association suggests that apoE4 carries an additional disadvantage for FH children.
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