Abstract 17666: Polygenic Familial Hypercholesterolemia Does Not Exist: Data from 1430 Referred Children
Introduction: Autosomal Dominant Hypercholesterolemia (ADH) is caused by mutations in LDLR, APOB or PCSK9. However, a mutation in one of these three genes is not found in a proportion of individuals with an ADH phenotype, and some hypothesize that these individuals are affected by a polygenic form of dyslipidaemia. In the current study we addressed whether children with a clinical ADH diagnosis but without an ADH genotype could indeed be characterized by a polygenic form of dyslipidemia, defined as the presence of a high number of LDL-C raising SNPs (gene risk score (GRS)).
Methods: 1430 index cases were referred to our paediatric lipid clinic; 269 had a true ADH phenotype based on strict criteria and a family work-up. A causative ADH mutation was found in 255 (95%) of these children (vd Graaf Circulation 2011). Upon reassessment of the molecular diagnosis and clinical phenotype in the remaining 14 ADH kindreds, we excluded 6 children (retest: 2 mutations upon re-sequencing, 1 secondary dyslipidemia, 2 not dyslipidemic, 1 lost to follow-up). Eight index cases and their 26 first degree relatives were included. All individuals were genotyped for both APOE and 15 SNPs with a proven effect on LDL-C (Teslovich Nature 2010). We created a GRS by counting the SNPs (maximum score of 30) and a second GRS was created based on the described effect sizes.
Results: The numerical GRS was 16.1±2.2 in indices and 16.0±2.3 in their relatives, irrespective of their LDL-C levels (p=0.892). The numerical GRS and weighted GRS did not differ between individuals with LDL-C levels above the 90th percentile (n=23) and those with LDL-C levels below the 90th percentile (n=11) (GRS 16.2±2.2 vs.15.7±2.3; p=0.094 and effect size 1.10±0.17 vs. 1.17±0.19; p=0.155), after adjusting for potential confounders.
Conclusions: A causal mutation in one of the three ADH genes can be identified in almost all children with a definite clinical diagnosis of ADH. In the small group without a mutation, we did not find a suggestion of a polygenic cause for this phenotype, suggesting that other, as of yet unidentified ((epi)genetic) mechanisms might constitute the underlying cause of hypercholesterolemia in these individuals. Our study also emphasizes the importance of a thorough clinical assessment in the diagnosis of ADH.
Author Disclosures: B. Sjouke: None. S.W. Fouchier: None. M.W. Tanck: None. A. Wiegman: None. B.A. Hutten: None. J.J. Kastelein: Consultant/Advisory Board; Modest; Genzyme, Aegerion, Sanofi, Regeneron, Amgen, Eli Lilly, Catabasis, Dezima Pharmaceuticals. Consultant/Advisory Board; Significant; Isis Pharmaceuticals. G. Hovingh: Honoraria; Modest; Pfizer, Sanofi, Regeneron, Synageva, Amgen, Roche, and Genzyme.
- © 2014 by American Heart Association, Inc.