Familial hypercholesterolaemia is characterised by substantially raised plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and is associated with a risk of coronary heart disease that is five to eight times higher than average. One charity has estimated a saving of £378.7 million from cardiovascular events avoided if all relatives of index cases were identified and treated optimally over 55 years of age.

The disease is inherited in an autosomal-dominant fashion and is thought to be monogenic, however no mutations are detected in about 60% of patients with the clinical phenotype who are tested. A proportion of these cases of familial hypercholesterolaemia could be polygenic, due to the inheritance of a greater than average number of common LDL-C-rasing alleles. Identification of those individuals with polygenic hyperlipidaemia could improve the efficacy of a testing programme.

Talmud et al. assembled patients with familial hypercholesterolaemia from three UK sources and compared them with a control sample from the UK Whitehall II (WHII) study. Patients from a Belgian lipid clinic were also studied for validation analysis. Participants were genotyped for 12 common LDL-C-raising alleles and a weighted LDL-C-raising gene score was constructed.

The mean weighted LDL-C gene score of the control (Whitehall) participants (0.90) was strongly associated with LDL-C concentration. Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1.0) than did WHII controls, as did the mutation negative Belgian patients (0.99). The score was also higher in UK (0.95) and Belgian (0.92) mutation-positive patients when compared to Whitehall study controls.

Conclusions:

A substantial number of patients with familial hypercholesterolaemia have no known mutation, and this study suggests that in these patients the raised LDL-C concentrations have a polygenic cause. This finding may explain the variable penetrance of the disease, and has implications for genetic testing strategies.

• Talmud PJ, Shah S, Whittall R et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet 2013;381:1291-1301.