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

Futema, M; Bourbon, M; Williams, M; Humphries, SE; (2018) Clinical utility of the polygenic LDL-C SNP score in familial hypercholesterolemia. Atherosclerosis , 277 pp. 457-463. 10.1016/j.atherosclerosis.2018.06.006. Green open access

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Abstract

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.

Type: Article
Title: Clinical utility of the polygenic LDL-C SNP score in familial hypercholesterolemia
Location: Ireland
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.atherosclerosis.2018.06.006
Publisher version: https://doi.org/10.1016/j.atherosclerosis.2018.06....
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Familial hypercholesterolemia, LDL-C SNP-Score, Polygenic hyper-cholesterolemia, Variants of unknown significance (VUS)
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Clinical Science
URI: https://discovery.ucl.ac.uk/id/eprint/10057963
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