Physicians' Academy for Cardiovascular Education

Non-coding variant in LPA gene associated with unexplained FH

News - May 30, 2023

Variants in LPA are associated with mutation negative FH: Genome Wide Association Study in the 100,000 Genomes Project

Presented at the EAS Congress 2023 by: Marta Futema, PhD - London, UK

Introduction and methods

Familial hypercholesterolemia (FH) is caused by pathogenic variants of the LDLR, APOB or PCSK9 genes which affects LDL-c clearance. However, the majority of patients with clinical FH (approximately 60%), do not have a mutation in the LDLR, APOB or PCSK9 genes.

The 100,000 Genomes Project was established in the UK to test the benefits of implementing genomic testing in the national health system. In a pilot study, FH was investigated in the 100,000 Genomes Project. Whole genome sequencing (WGS) was performed for 544 participants with clinical FH. This included 68 relatives. Participants were affected according to the Simon Broome criteria, but did not have mutations in known FH genes as confirmed with a FH genetic diagnostic test. WGS data of >70,000 individuals without FH (‘controls’) were available.

Main results


A Genome Wide Association Study in the 100,000 Genomes Project showed that a rare non-coding variant in the LPA gene is associated with mutation negative FH.

The current study was relatively small and there were no data on lipid profiles of the participants. In addition, replication is needed in non-European individuals. Marta Futema concluded that both Lp(a) and LDL-c measurements should be part of the differential diagnosis of FH.

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