(HealthDay News) – For patients with familial hypercholesterolemia who do not have any of the known mutations, their high low-density lipoprotein cholesterol (LDL-C) levels may have a polygenic cause, and for those with a detected mutation, the difference in disease penetrance may be explained by a polygenic contribution, according to a study published online Feb. 22 in The Lancet.

Noting that about 60% of patients with familial hypercholesterolemia do not have mutations in any of the three genes currently linked to the disorder, Philippa J. Talmud, DSc, from the University College London, and colleagues performed genotyping for 12 common LDL-C-raising alleles in 321 mutation-negative patients with familial hypercholesterolemia, 319 mutation-position patients with familial hypercholesterolemia, and 3,020 healthy controls.

As determined by a mean weighted LDL-C gene score based on the number of risk-associated gene copies inherited, the researchers found that the gene score in healthy controls was strongly linked to LDL-C concentration. The gene score was significantly higher in both mutation-negative and mutation-positive patients compared with healthy controls. The results were confirmed in an independent group of 724 similar patients.

“In a substantial proportion of patients with familial hypercholesterolemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing,” Talmud and colleagues conclude. “In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease.”

The study was partly funded by Pfizer, AstraZeneca, Schering-Plough, and Unilever.

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