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. 2024 Nov 12:zwae371.
doi: 10.1093/eurjpc/zwae371. Online ahead of print.

Variants in LPA are associated with Familial Hypercholesterolaemia: whole genome sequencing analysis in the 100,000 Genomes Project

Martin Bird  1 , Antoine Rimbert  2 , Alan M Pittman  3 , Steve E Humphries  4 , Marta Futema  1   4
Affiliations

Variants in LPA are associated with Familial Hypercholesterolaemia: whole genome sequencing analysis in the 100,000 Genomes Project

Martin Bird et al. Eur J Prev Cardiol. .

Abstract

Background: Familial Hypercholesterolaemia (FH) is an inherited disease of high LDL-cholesterol (LDL-C) caused by defects in LDLR, APOB, APOE and PCSK9 genes. A pathogenic variant cannot be found in ∼60% of clinical FH patients. Using whole genome sequencing (WGS) we examined genetic determinants of FH.

Methods: WGS data generated by the 100,000 Genomes Project (100KGP) included 536 FH patients diagnosed using the FH Simon Broome criteria. Rare variants in known FH genes were analysed. Genome-wide association study (GWAS) between 443 FH variant-negative unrelated FH cases and 77,275 control participants of the 100KGP was run using high coverage WGS data. Polygenic risk scores for LDL-C (LDL PRS) and lipoprotein(a) (Lp(a) PRS) were computed.

Results: An FH-causing variant was found in 17.4% of FH cases. GWAS identified the LPA gene locus being significantly associated (p<1x10-8). FH variant-negative participants had higher LDL and Lp(a) PRSs in comparison to the controls (p<1.0×10-16 and p<4.09×10-6, respectively). Similar associations were found in the monogenic FH with both LDL and Lp(a) PRSs being higher than in controls (p<4.03×10-4 and p<3.01x10-3, respectively). High LDL PRS was observed in 36.4% of FH variant-negative cases, whereas high Lp(a) PRS in 18.5%, with 7.0% having both high LDL and Lp(a) PRSs.

Conclusions: This genome-wide analysis of monogenic and polygenic FH causes confirms a complex and heterogenous architecture of hypercholesterolaemia, with the LPA gene playing a significant role. Both Lp(a) and LDL-C should be measured for precision FH diagnosis. Specific therapies to lower Lp(a) should be targeted to those who will benefit most.

Keywords: LPA; Familial hypercholesterolaemia; Lp(a); genome wide association study; whole genome sequencing.

Plain language summary

Familial Hypercholesterolaemia (FH) is a genetic condition that causes very high levels of "bad" cholesterol (LDL-C), which increases the risk of heart disease. This study used advanced genetic testing (whole genome sequencing) to better understand the genetic causes behind high cholesterol in people with FH. Key Findings: FH is caused by both rare and common genetic changes. Many small changes in DNA combine to increase a person's overall risk, which is measured through what’s called a "polygenic risk score." Polygenic score for LDL-C and Lp(a) are higher in FH individuals.The gene (LPA) that determines the blood amount of lipoprotein(a), or Lp(a), plays an important role in FH affected individuals. High levels of Lp(a) are a known risk factor for heart disease, separate from LDL-C. This means that Lp(a) levels should be checked in FH patients to better manage their condition and prevent heart disease.

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