The fine line between familial and polygenic hypercholesterolemia

Abstract

Evaluation of: Talmud PJ, Shah S, Whittall R et al. Use of low–density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic hypercholesterolaemia: a case–control study. Lancet 381(9874), 1293–1301 (2013). Familial hypercholesterolemia (FH) is a common disorder caused by mutations in LDLR, APOB and PCSK9. However, many subjects with primary hypercholesterolemia did not demonstratefunctionalmutationsinanyofthesegenes.Genome-wideassociationstudieshaveidentifiedsingle nucleotidepolymorphismsthatinfluencethevariabilityofLDL-Cconcentration.Talmudet al. have genotyped 12 common LDL cholesterol (LDL–C)–raising alleles in 640 patients with the clinical diagnosis of FH and in 3020 healthy subjects from the UK Whitehall II study. Approximately 50% of the FH patients did not possess a causative mutation andthemeanweightedLDL-Cgenescorewassignificantlyhigherthaninthecontrols,indicatingapolygeniccause fortheirdisorder.TheseresultsindicatethatclinicalcriteriausedforFHdiagnosisarepoorlyspecificforFH,largely overlapping with polygenic hypercholesterolemia. The 12 single nucleotide polymorphisms LDL–C gene score might be a good tool for distinguishing between monogenic and polygenic hypercholesterolemia.

Key Words:

• familial hypercholesterolemia
• LDL receptor gene
• polygenic hypercholesterolemia
• SNP gene score