This article is more than 5 years old. Information may no longer be current.
Efficacy of genetic testing for familial hypercholesterolemia questioned
Click Here to Manage Email Alerts
New data published in The Lancet suggest that elevated LDL in a significant number of patients diagnosed with familial hypercholesterolemia may have polygenic rather than monogenic causes.
Guidelines recommending DNA-based cascade, or family, screening for familial hypercholesterolemia rest on the assertion that the disease is caused by a large-effect mutation in a single gene (monogenic) instead of a combination of small-effect changes in several genes (polygenic). These study results, however, may alter how cascade testing for this disorder is viewed.
Polygenic vs. monogenic hypercholesterolemia
In November 2011, Steve E. Humphries, PhD, of the University College London in the United Kingdom, and colleagues genotyped patients with familial hypercholesterolemia from three U.K. cohorts — the British Heart Foundation study, the Oxford familial hypercholesterolemia study and the Department of Health familial hypercholesterolemia audit project — and healthy controls from the UK Whitehall II (WHII) study for 12 common LDL-raising alleles. They compared the gene score distribution among patients with the disease with an identified mutation, no confirmed mutation and healthy controls. The researchers also included patients with familial hypercholesterolemia from Hôpital de Jolimont in Haine-Saint-Paul, Belgium, for validation analyses.
“The current study was designed to investigate whether individuals who inherit many small-effect, LDL cholesterol-raising sequence differences in a wide range of genes might have received a clinical diagnosis of familial hypercholesterolemia, which would influence the efficacy of any cascade screening program since the odds of finding relatives with grossly elevated LDL in such cases would be less than the expected 50%,” Humphries said in a press release.
The researchers identified 321 U.K. and 451 Belgian patients without mutations and 319 U.K. and 273 Belgian patients with mutations. They included 3,020 controls from the WHII study.
Results indicated a strong link between the mean weighted LDL gene score of the controls (0.9; standard deviation [SD]=0.23) and LDL concentration (P=1.4 × 10–77). The researchers observed a significantly higher mean weighted LDL score in U.K. patients without mutations (1; SD=0.21) compared with controls (P=4.5 × 10–16) and Belgian patients without mutations (0.99; SD=0.19; P=5.2 × 10–20). Similarly, they found that U.K. (0.95; SD=0.2; P=1.6 × 10–5) and Belgian (0.92; SD=0.2; P=.04) patients with mutations also had significantly higher mean weighted LDL scores than controls.
Additionally, data demonstrated that 52% of the U.K. patients without mutations had a score within the top three deciles of the WHII weighted LDL gene score distribution, whereas only 11% were within the lowest three deciles.
Value of cascade testing
In light of their findings, Humphries suggested that the cause of hypercholesterolemia be taken into account when considering cascade testing.
“We propose that the clinical diagnosis of familial hypercholesterolemia should be restricted to those in whom a mutation can be identified, whereas those with no detected mutation should be given the clinical diagnosis of polygenic hypercholesterolemia,” Humphries said. “Both groups of patients will need statin therapy, but the cost effectiveness of familial hypercholesterolemia cascade testing will differ depending on whether or not there is a polygenic or a single mutation cause.”
Nevertheless, Evan A. Stein, MD, of the Metabolic and Atherosclerosis Research Center in Cincinnati, and Frederick J. Raal, MD, of the University of Witwatersrand in Johannesburg, wrote in an accompanying commentary that they recommend caution.
“All people, irrespective of age, with raised LDL-C concentrations in whom no secondary cause can be identified, especially if they have a family history of premature coronary artery disease, should be treated for presumptive familial hypercholesterolemia according to clinical criteria,” they wrote. “To add the complexity of [single nucleotide polymorphism] analysis for minor genes and eliminate cascade LDL-C and clinical testing of relatives of patients with polygenic familial hypercholesterolemia does not seem to be warranted, and could even be diversionary.”
For more information:
Stein EA. Lancet. 2013;doi:10.1016/S0140-6736(13)60187-7.
Talmud PJ. Lancet. 2013;doi:10.1016/S0140-6736(12)62127-8.
Disclosure: See the study for a full list of relevant financial disclosures. Stein and Raal report no relevant financial disclosures.