Sorting the Wheat from the Chaff in Familial Hypercholesterolemia

[摘要] Familial hypercholesterolemia (FH)5 is classically a monogenic disorder that delays the hepatic catabolism of LDL particles, resulting in a marked increase in the plasma concentration of LDL cholesterol (LDL-C) and accelerated coronary artery disease (CAD) (1). Heterozygous FH may be as prevalent as 1 in 200 in the population (2), and treatment with statins mitigates the risk of CAD (1, 2). The genetic causes of FH and related autosomal-dominant hypercholesterolemias include mutations in LDLR (low density lipoprotein receptor),6 of which >1200 have hitherto been described, and less commonly mutations in APOB (apolipoprotein B) and PCSK9 (proprotein convertase subtilisin/kexin type 9) (1, 2). In certain countries (1), but not the US (3), DNA testing is recommended to confirm a diagnosis of FH in an index patient and to cascade-screen families to identify new cases of FH. This is supported by health economic evaluations and by the fact that the clinical expression of the disorder can be diminished, particularly in the young, leading to false reassurance and undertreatment of at-risk family members (1, 2). However, in up to 30% of phenotypically frank FH, a pathogenic mutation cannot be detected (1, 2). These individuals may well carry single mutations in known or unknown FH genes that cannot be detected by conventional methods, but it is more likely that a significant proportion have polygenic hypercholesterolemia (PHC). That is, they have inherited a greater-than-average number of common, cholesterol-raising genetic variants that, collectively, have a large effect on the plasma concentration of LDL-C (4).But how can PHC be diagnosed, and is it important to distinguish it from FH? In this issue of Clinical Chemistry , Futema et al. describe a simplified LDL-C gene score to assist in the diagnosis of PHC (5). They studied 7 replication cohorts of …

[学科分类] 过敏症与临床免疫学