Article Dans Une Revue Atherosclerosis Plus Année : 2024

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

Résumé

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 phenotype. Material and 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 FH variant-negative unrelated FH cases and 50,109 control participants of the 100KGP was run using high coverage WGS data. Polygenic risk scores for LDL-C (LDL PRS) and lipoprotein(a) (LPA PRS) were computed. Results: An FH-causing rare variant was found in 17.4% of FH participants. GWAS of the FH variant-negative participants identified the LPA gene locus being significantly associated (p< 3.56x10-9). FH variant-negative participants had significantly higher LDL and LPA PRSs in comparison to the controls (p =1.43×10-28 and p=1.41×10-6, respectively). High LDL PRS was observed in 36.3% of FH variant-negative cases, whereas high LPA PRS in 18.5%, with 6.5% having both high LDL and LPA PRSs. Conclusions: This genome-wide analysis of monogenic and polygenic FH causes confirms a complex and heterogenous genetic architecture of hypercholesterolaemia, with LPA genotype playing a significant role. Both Lp(a) and LDL-C measurements should be included in the precision diagnosis and treatment of FH. Specific therapies to lower Lp(a) should be targeted to those who will benefit most.

Dates et versions

hal-05594877 , version 1 (17-04-2026)

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Martin Bird, Antoine Rimbert, Alan Pittman, Steve Humphries, Marta Futema. Variants in LPA are associated with mutation-negative Familial Hypercholesterolaemia: whole genome sequencing analysis in the 100,000 Genomes Project. Atherosclerosis Plus, 2024, 57, pp.2. ⟨10.1016/j.athplu.2024.08.015⟩. ⟨hal-05594877⟩
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