Genetic testing strategy for familial high cholesterol questioned

By Helen Albert, Senior medwireNews Reporter

Current testing strategies for the families of patients with familial hypercholesterolemia (FH) may not be an efficient use of health resources, suggest study results published in The Lancet.

The authors found that while 50% (n=319) of the FH patients tested had a mutation in one of three known genes associated with the condition - LDLR (93.1%), APOB (5.0%), or PCSK9 (1.9%), the rest of the patients (n=321) did not have known mutations.

Notably, when the patients without a known FH mutation were genotyped for 12 genetic variants associated with increases in low-density lipoprotein (LDL) cholesterol in previous studies, they had a significantly higher combined risk allele score than the 3020 controls from the Whitehall II study, report Steve Humphries (University College London, UK) and co-investigators. This suggests that they may inherit the disorder in a polygenic fashion.

At present, UK National Institute for Health and Clinical Excellence (NICE) guidelines suggest cascade testing of family members of FH patients based on the principle that the disorder is autosomal dominant and inherited monogenically, therefore putting first generation relatives of FH patients at 50% risk for having the disorder.

Humphries and colleagues suggest this screening strategy should be restricted to FH patients with a known autosomal dominant mutation, as such screening is likely to have little value if patients inherit their condition in a polygenic fashion.

The 12 single nucleotide polymorphisms (SNPs) were given a score dependent on the Global Lipid Genetic Consortium weighted sum of the risk allele for each SNP. The per SNP score ranged from 0.014-0.180.

The mean LDL cholesterol gene score was strongly linked with LDL cholesterol concentration. FH patients without a known mutation had a significantly higher mean weighted gene score, at 1.0, than Whitehall II study controls, at 0.90. This difference was validated in a Belgian cohort (0.99 score for mutation negative individuals).

Mutation positive FH patients had higher gene scores than controls, but not as high as mutation negative FH patients, at 0.95 in the original UK cohort and 0.92 in the Belgian cohort.

Humphries and team suggest that "patients with a familial hypercholesterolemia phenotype and no such mutations could be given the clinical diagnosis of polygenic hypercholesterolemia, and not familial hypercholesterolemia."

"This should not, however, affect the treatment of these patients, but would influence the decision to undertake cascade testing in their relatives," they conclude.

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