Abstract 591: Genetic Risk Score Does Not Explain Hypercholesterolemic Phenotype in Children with Hypercholesterolemia of Unknown Genetic Origin

Abstract

Background: Autosomal Dominant Hypercholesterolemia (ADH) is caused by mutations in LDLR , APOB or PCSK9 . In our previous study, we identified a causative mutation in these genes in 255 (95%) out of 269 children with clinically defined ADH (vd Graaf Circulation 2011). In the current study we addressed whether these 14 ADH children were characterized by a polygenetic form of dyslipidemia, defined by the presence of an excessive number of LDL-C raising SNPs (gene risk score (GRS)). Methods: Upon reassessment of the molecular diagnosis and clinical phenotype in the 14 ADH children we excluded: 2 patients in whom a pathogenic ADH mutation was identified by re-sequencing, one patient in whom a secondary cause of hypercholesterolemia became evident, 2 patients in whom hypercholesterolemia was not identified anymore, and one patient who was lost to follow-up. In total, 8 index patients and their 24 first degree relatives (median[IQR] = 3[2-4] relatives/index case) were included. We genotyped all individuals for 15 SNPS with an effect on LDL-C levels (Teslovich Nature 2010) and created a GRS. Results: The GRS was 16.1±2.2 in the indices and 16.2±2.2 in their relatives, irrespective of their LDL-C levels (p=0.928) The GRSs did not differ between individuals with LDL-C levels above the 90 th percentile (n=21) and those with LDL-C levels below the 90 th percentile (n=11) (GRS 16.4±2.1 vs.15.7±2.3; p=0.399 and effect size LDL-C 1.15±0.15 vs. 1.18±0.20 mmol/L; p=0.616). Conclusions: In children with a definite clinical diagnosis of ADH, absence of mutations in known genes is very rare. In these individuals, we did not find a suggestion of a polygenetic cause for the phenotype, suggesting that other, as of yet unidentified ((epi)genetic) mechanisms might constitute the underlying cause of hypercholesterolemia in these patients. Further research is carried out to elucidate this mechanism.