Polygenic Causes of Hypercholesterolaemia Minimize Effectiveness of Cascade Testing
Familial hypercholesterolaemia can be caused by an accumulation of common small-effect alleles instead of a dominant monogenic mutation, which could compromise the efficiency of cascade testing, according to a study published online Feb. 22 in Lancet. The authors suggest such cascade testing should be restricted to patients positive for one of three known dominant autosomal […]
Familial hypercholesterolaemia can be caused by an accumulation of common small-effect alleles instead of a dominant monogenic mutation, which could compromise the efficiency of cascade testing, according to a study published online Feb. 22 in Lancet. The authors suggest such cascade testing should be restricted to patients positive for one of three known dominant autosomal mutations, rather than those with polygenic causes of hypercholesterolaemia. Patients with familial hypercholesterolaemia typically have significantly escalated low-density lipoprotein cholesterol (LDL-C) and a five to eight times increased risk of early coronary heart disease. However, there is no single accepted criterion for the diagnosis of the condition. Clinical diagnosis misses significant numbers of patients, and genetic testing is complicated by the polygenetic nature of the condition. A strategy of cascade testing of first-degree relatives of an index patient with DNA-confirmed hypercholesterolaemia is employed in several European nations and New Zealand, but the effectiveness of this strategy may be compromised with these findings of polygenic causes of the condition. “The inclusion of probands with polygenic rather than monogenic cause of hypercholesterolaemia would reduce the efficiency of any cascade screening program, since much less than the expected 50 percent of first-degree relatives would be affected,” write the authors, led by Philippa Talmud, D.Sc., from University College London (United Kingdom). “Therefore, identification and exclusion of individuals with polygenic hyperlipidaemia would enhance and enrich any cascade testing program.” Mutations in one of three genes are known to cause familial hypercholesterolaemia (LDLR, APOB, and PCSK9) but are onlydetected in 40 percent of patients suspected of the disorder, the authors say. In the Lancet study data from a sample of 640 U.K. patients with familial hypercholesterolaemia (321 mutation-negative and 319 mutation-positive patients) were compared to a sample of 3,020 healthy controls. For validation analyses 451 mutation-negative and 273 mutation-positive Belgian patients were assessed. All participants were genotyped for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and a weighted LDL-C-raising gene score was constructed. The researchers found the mean weighted LDL-C gene score of the controls was strongly associated with LDL-C concentration. Controls in decile 10 of the LDL-C score distribution had a much higher likelihood than those in decile 1 of having LDL-C concentrations above the diagnostic threshold of 4.9 mmol/L. In primary analysis, mutation-negative patients with hypercholesterolaemia had a significantly higher mean weighted LDL-C score controls, as did the mutation-negative patients in validation analyses. Twenty percent of these patients had a score that fell within decile 10 of the controls’ LDL-C score distribution, 52 percent had a score within deciles 7 to 10, and 11 percent had a score within deciles 1 to 3. This suggests, the authors say, that a substantial proportion of the mutation-negative familial hypercholesterolaemia group’s raised LDL-C concentrations can be explained by coinheritance of common LDL-C-raising single nucleotide polymorphisms. Mutation-positive patients, both in primary and validation analyses, also had significantly higher LDL-C scores than controls, suggesting that even in patients with a detected causative mutation, their raised LDL-C concentrations have an additional polygenic component.