Clinical utility of the polygenic LDL-C SNP score in familial hypercholesterolemia

Futema, Marta; Bourbon, Mafalda; Williams, Maggie; Humphries, Steve E.

http://hdl.handle.net/10400.18/5647

Use this identifier to reference this record.

Name:	Description:	Size:	Format:
Clinical utility of the polygenic LDL-C SNP score in familial.pdf		580.56 KB	Adobe PDF	Download

Send Feedback

Authors

Abstract(s)

Mutations in any of three genes (LDLR, APOB and PCSK9) are known to cause autosomal dominant FH, but a mutation can be found in only ∼40% of patients with a clinical diagnosis of FH. In the remainder, a polygenic aetiology may be the cause of the phenotype, due to the co-inheritance of common LDL-C raising variants. In 2013, we reported the development of a 12-SNP LDL-C "SNP-Score" based on common variants identified as LDL-C raising from genome wide association consortium studies, and have confirmed the validity of this score in samples of no-mutation FH adults and children from more than six countries with European-Caucasian populations. In more than 80% of those with a clinical diagnosis of FH but with no detectable mutation in LDLR/APOB/PCSK9, the polygenic explanation is the most likely for their hypercholesterolaemia. Those with a low score (in the bottom two deciles) may have a mutation in a novel gene, and further research including whole exome or whole genome sequencing is warranted. Only in families where the index case has a monogenic cause should cascade testing be carried out, using DNA tests for an unambiguous identification of affected relatives. The clinical utility of the polygenic explanation is that it supports a more conservative (less aggressive) treatment care pathway for those with no mutation. The ability to distinguish those with a clinical diagnosis of FH who have a monogenic or a polygenic cause of their hypercholesterolaemia is a paradigm example of the use of genomic information to inform Precision Medicine using lipid lowering agents with different efficacy and costs.

Keywords

Familial Hypercholesterolemia LDL-C SNP-Score Polygenic Hyper-cholesterolemia Variants of Unknown Significance (VUS) Doenças Cardio e Cérebro-vasculares