Use of Low-Density Lipoprotein Cholesterol Gene Score to Distinguish Patients With Polygenic and Monogenic Familial Hypercholesterolaemia: A Case-Control Study

Study Questions:

To what extent is familial hypercholesterolemia (FHC) a polygenic disease?


Genotyping for 12 common low-density lipoprotein cholesterol (LDL-C)-raising alleles was performed in patients with FHC from three United Kingdom (UK)-based sources and compared to healthy control samples from the UK Whitehall II (WHII) study. A weighted LDL-C-raising gene score was compared among patients with FHC with no confirmed mutation, those with an identified mutation, and controls from the WHII study.


A total of 321 mutation negative (-), 319 mutation positive (+), and 3,020 controls were evaluated. The mean LDL gene score of the controls (0.9 ± 0.23) was strongly associated with LDL concentration (p = 1.4 × 10–77). Mutation (-) patients had a higher LDL score (1.0 ± 0.21) than did controls (p = 4.5 × 10−16). The score was also higher in mutation (+) (0.95 ± 0.20; p = 1.6 × 10−5) patients than in controls; 167 (52%) of 321 mutation (-) patients had a score within the top three deciles of the WHII-weighted LDL gene score distribution, and only 35 (11%) fell within the lowest three deciles.


The authors concluded that in a substantial proportion of patients with FHC without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease.


Familial HC has traditionally been thought to be due to mutations involving the LDL receptor, although other genes such as APOB and PCSK9 are involved less frequently. However, a causative mutation was only identified in about 40% of patients with a clinical diagnosis of FHC. This is consistent with previous studies, suggesting that most cases of suspected FHC are polygenic. Even if causal mutations are found, disease expression is often influenced by other loci. These findings highlight the limitations of genetic cascade screening for this disease. Since the cardiovascular risk of FHC is associated with LDL levels, and low-cost effective treatment is available (statins), maybe lipid levels should be used as the primary tool to screen and treat patients with HC. As our understanding of additional pathways involved in lipid metabolism increases and new therapies for lowering LDL become available, genomic analyses may become more useful in the future towards personalized treatment strategies.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Mutation, Lipoproteins, LDL, Great Britain, Lipid Metabolism, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Cardiovascular Diseases, Genetic Testing

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