Testing Method Clinically Ascertains Genetic Basis for Hypercholesterolemia

Next-generation sequencing technology is transforming our understanding of heterozygous familial hypercholesterolemia, including revision of prevalence estimates and attribution of polygenic effects.

The use of next-generation sequencing (NGS) technology has pinpointed specific areas of a person's DNA to more effectively diagnose genetic forms of high-cholesterol, which markedly increase risk for heart attack and stroke.

Scientists at University of Western Ontario (London, ON, Canada) and their colleagues examined the contributions of monogenic and polygenic causes in patients with severe hypercholesterolemia referred to a specialty clinic. They applied targeted next-generation sequencing with custom annotation, coupled with evaluation of large-scale copy number variation and polygenic scores for raised low-density lipoprotein cholesterol in a cohort of 313 individuals with severe hypercholesterolemia, defined as low-density lipoprotein cholesterol greater than 5.0 mmol/L (>194 mg/dL).

DNA samples were assessed by visualization on a 1% agarose gel and using a NanoDrop 1000 spectrophotometer, and the DNA was then and measured using a Qubit 2.0 fluorometer. The new genetic testing method called LipidSeq was able to identify a genetic mutation in 67% of the patients. They found that 54% were single gene mutations, and the other 13% were polygenic DNA variants, meaning they were a combination of multiple bad genes inherited together. The study also showed that the percentage of individuals with an identified genetic component increased as cholesterol levels in the patient increased. The percentage of individuals with an identified genetic component increased from 57.0% to 92.0% as low-density lipoprotein cholesterol level increased from 5.0 to >8.0 mmol/L (194 to >310 mg/dL).

Robert A. Hegele, MD, FRCPC, a professor of Endocrinology and the senior author of the study, said, “This new method provides a more cost-effective way to find these genetic links rather than sequencing the entire genome. By pre-identifying patients who have a personal and familial history of high-cholesterol, LipidSeq was able to find a genetic mutation in 67 % of those tested. This new method shows there is a benefit, especially when you can add the extra step of medically selecting those with a familial history of the disease.” LipidSeq has already been licensed for use in the USA to help clinicians identify patients with genetically-based high-cholesterol in order to guide drug prescriptions. The study was published on October 20, 2016, in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.

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