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The genetic architecture of the familial hyperlipidaemia syndromes: rare mutations and common variants in multiple genes

Talmud, Philippa J.; Futema, Marta; Humphries, Steve E.

doi: 10.1097/MOL.0000000000000090
HYPERLIPIDAEMIA AND CARDIOVASCULAR DISEASE: Edited by Paul N. Durrington

Purpose of review: Genome-Wide Association Studies have provided robust identification of approximately 100 genetic loci determining plasma lipid parameters. Using these multiple common genetic lipid-determining variants in a ‘gene score’ has thrown new light on the mode of inheritance of familial lipid disorders.

Recent findings: Different hypertriglyceridaemia states have been explained by the polygenic coinheritance of triglyceride-raising alleles. Taking this gene score approach with 12 LDL-cholesterol-raising alleles, we reported that for patients with a clinical diagnosis of familial hypercholesterolaemia, but no identified rare mutation in the familial hypercholesterolaemia-causing genes, LDL receptor, apolipoprotein B and PCSK9, the most likely explanation for their elevated LDL-C levels was a polygenic, not a monogenic, cause of the disease.

Summary: These findings have wider implications for understanding complex disorders, and may very well explain the genetic basis of familial combined hyperlipidaemia, another familial lipid disorder in which the genetic cause(s) has remained elusive.

Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK

Correspondence to Philippa J. Talmud, PhD, DSc, Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, 5 University St, London WC1E 6JF, UK. Tel: +44 207679 6968; fax: +44 207 679 6212; e-mail: p.talmud@ucl.ac.uk

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins