Clinical utility of the polygenic LDL-C SNP score in familial hypercholesterolemia. (October 2018)

• Record Type: Journal Article
• Authors: Futema, Marta; Bourbon, Mafalda; Williams, Maggie; Humphries, Steve E.
• Is Part Of: Atherosclerosis. Volume 277(2018)
• Page Start: 457
• Page End: 463
• Publication Date: 2018-10
• Subjects: Familial hypercholesterolemia -- LDL-C SNP-Score -- Polygenic hyper-cholesterolemia -- Variants of unknown significance (VUS); Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2018.06.006
• Languages: English
• ISSNs: 0021-9150

Abstract

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. Highlights: A mutation in LDLR/APOB/PCSK9 is found in only ∼40% of patients with clinical familial hypercholesterolaemia (FH). At least 80% of these no-mutation patients have a high LDL-C "SNP-Score". Atherosclerosis and CHD risk are lower in polygenic patients than in monogenic FH. Monogenic FH requires more aggressive lipid lowering than polygenic hypercholesterolaemia. This is a paradigm example of the use of genomic data to inform precision medicine.