Key result
Polygenic rather than monogenic causes primarily drive elevated LDL-C in clinical FH lacking rare mutations.
Why the study?
The genetic basis of familial lipid disorders, including familial hypercholesterolaemia without rare mutations and familial combined hyperlipidaemia, remains incompletely understood.
Many cases of clinically diagnosed familial hypercholesterolaemia without known monogenic mutations are likely driven by polygenic inheritance of multiple LDL-C-raising alleles.
Supports polygenic scoring in mutation-negative clinical FH; leaves open prospective validation before changing management.
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.
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Talmud et al. (2014) conducted a review in Familial hyperlipidaemia syndromes. Polygenic gene score was evaluated. For patients with clinical familial hypercholesterolaemia lacking rare mutations in known genes, elevated LDL-C levels are most likely explained by a polygenic rather than monogenic cause.
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