February 21st, 2013

Study Casts Doubt on Value of Genetic Testing for Familial Hypercholesterolemia

The recent introduction of two drugs specifically targeted to treat people with the rare but dangerous condition of homozygous familial hypercholesterolemia (FH) has caused increased interest in figuring out the best strategy to identify people with the disorder. Now a new study published online in the Lancet suggests that one of the main screening plans that relies on genetic tests will fail to identify a substantial portion of FH patients, both homozygous and heterozygous.

Investigators from the U.K. and Belgium analyzed DNA from several cohorts of FH and non-FH patients. Their chief finding was that a large percentage of FH patients did not have one of the single genetic mutations known to cause FH. Instead, these “polygenic” patients were found to have variants in multiple genes, each of which had a small LDL-raising effect that, when combined, resulted in LDL levels similar to those in people with known FH mutations.

A second major finding was that other genes may play an important contributing role in determining LDL levels even in monogenic FH patients. This finding may partly account for the common finding that affected relatives of monogenic FH patients often have less severe forms of FH.

The authors propose 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 distinction would not have a big impact on treatment, because both groups would require lipid-lowering therapy, according to the authors.

But the distinction would have important implications for FH screening. “Cascade” screening, in which DNA tests are recommended for all relatives of patients with a clinical diagnosis of FH, should only be performed on the monogenic patients, they maintain.

In a Lancet press release, lead researcher Steve Humphries said:

“Cascade [family] testing of the roughly 40% of patients with a clinical diagnosis of FH and an identifiable causative mutation would eliminate staff and screening costs associated with screening relatives of the remaining 60% of patients without an identifiable mutation. This is very likely to be more cost-effective, but proving this will require a more detailed analysis.”

In an accompanying comment,  Evan Stein and Frederick Raal write:

“…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 as presumptive FH according to clinical criteria. To add the complexity of SNP analysis for minor genes and eliminate cascade LDL-C and clinical testing of relatives of patients with polygenic FH does not appear warranted and could even be diversionary.”

One cholesterol expert, who did not wish to be identified, offered the following comment: 

“The take home is that genetic screening is not a panacea and that screening based on fasting lipids makes most sense. Indeed, I never understood genetic screening for this disease anyway, since the phenotype (hypercholesterolemia) is what kills people, not the genotype, the phenotype is readily available with a blood test, the disease is not immediately fatal (it takes years to develop), and treatment is based on the numbers. It is like asking for a gene test for sickle cell anemia. You can look at blood and make the diagnosis.”


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