Non-coding variant in LPA gene associated with unexplained FH

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

News - May 30, 2023

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

  • Rare pathogenic variants in known FH genes were found in 15% of the FH cohort. In 4% of participants with FH, a variant of unknown significance (VUS) was found.
  • To understand what causes clinical FH in the remaining individuals, a Genome Wide Association Study was performed, which compared variants from 404 FH mutation negative cases with 50,791 controls. A significant association was found between a rare non-coding variant in the LPA gene and unexplained FH. 8.7% of individuals in the FH mutation negative cohort were carrier of this variant (2 homozygotes and 33 heterozygotes).


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.

  • Our reporting is based on the information provided at the EAS Congress 2023 -

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