It is well established that certain dyslipidemias such as familial hypercholesterolemia (FH) are monogenic hereditary conditions. Nevertheless, until recently the clinical utility of genetic testing for these conditions has been unclear, and the majority of clinicians have relied upon phenotypic screening to diagnose probands and to identify affected family members.

However, in 2016, two publications revealed the utility of genetic testing for probands with FH. Compared to individuals with low-density lipoprotein cholesterol (LDL-C) <130 mg/dL, Khera et al.¹ found that individuals with LDL-C ≥190 mg/dL with an identifiable FH mutation have up to 22-fold greater risk of coronary artery disease (CAD), much higher than the 6-fold greater risk in those with LDL-C ≥190 mg/dL and no mutation. Later that same year, additional research revealed specific genotypes were associated with a greater risk of CAD compared to others. Loss of function mutations in LDLR were associated with more than 6-fold greater risk for premature CAD than mutations in APOB.² Therefore, genetic testing can provide useful clinical information even in patients with clinically confirmed FH.

In addition to providing information for risk stratification of patients, genetic testing can improve the diagnosis rate. Relying solely on LDL-C levels for identification is often inadequate; Abul-Husn et al.² illustrated there is significant overlap between genotype-positive and genotype-negative individuals. Furthermore, if patients have been treated with statin therapy or other lipid lowering medications for a significant amount of time, physical manifestations may no longer be present.³ Consequently, patients may not meet clinical criteria, and as a result, without genetic testing a firm diagnosis cannot be made.

Genetic testing is also an effective method for cascade screening of at-risk family members. While cascade screening can be conducted using lipid panels, genetic testing has been shown to improve sensitivity by as much as 50%.⁴ One of the reasons for this is that serum screening relies on markedly elevated cholesterol levels. However, family members do not always manifest severe forms of the condition even if the proband has significantly elevated levels.⁵ For example, by only relying on lipid levels, a family member with an LDL-C level measuring 160 mg/dL may be mistakenly thought not to have FH. This can lead to an inaccurate risk estimate, inadequate treatment and inadequate screening of future generations unless genetic testing is pursued to establish genotype.

While the utility of genetic testing in FH has been clarified in the past few years, less information is available for other hereditary dyslipidemias such as hyperchylomicronemia and dysbetalipoproteinemia. Nevertheless, genotyping can provide important information for these patients and families. Novel treatments such as anti-sense oligonucleotide therapy and RNAi inhibitors are in development for conditions such as lipodystrophy and familial chylomicronemia syndrome, both conditions with currently limited treatment options.⁷ Genetic testing will be critical in determining eligibility for these novel medications.

Additionally, there is preliminary evidence illustrating the utility of genetic testing in patients with hypertriglyceridemia for risk stratification. In the Journal of the American Medical Association in 2017, Khera et al.⁸ showed that patients with elevated triglyceride levels and a single mutation in the LPL gene had a higher risk for early-onset CAD compared to noncarriers. While further research into this topic is necessary, genetic testing clearly has the potential to improve patient care in the near future.

Concerns About Genetic Testing

It is important to discuss not only the merits of genetic testing but also common concerns. Often families and clinicians are concerned about the cost of genetic testing. The cost and testing turnaround time has decreased dramatically since the first human genome was sequenced in 2001.⁹ Currently, clinical genetic testing for FH and other dyslipidemias often costs patients less than $100 out-of-pocket, and the majority of labs offer financial assistance programs making this test affordable for many patients and families.

The other main concern patients and clinicians often express relates to insurance discrimination. While this is a valid concern, measures are in place to protect against this. In 2008, the federal law Genetic Information Nondiscrimination Act (GINA) was passed. This law protects against employers and health insurance companies discriminating against individuals based on their genetic information; however, the law does not apply to life, disability or long-term-care insurance.¹⁰ As a result, some patients opt to obtain or modify their insurance policies prior to undergoing genetic testing.

Due to the complex nature of genetic testing and its implications for the patient and family members, it is recommended that patients meet with a genetic counselor or another genetics professional prior to and after undergoing testing.¹¹ Genetic counselors are graduate level healthcare professionals who are trained in both genetics and counseling.

During this meeting, patients will have a chance to discuss the benefits and concerns mentioned above, as well as inheritance patterns, penetrance, test sensitivity and specificity and psychological concerns such as survivor guilt and grief. The majority of tertiary care centers will have genetic counselors on staff, but to locate a genetic counselor near you, please visit www.nsgc.org.

Overall, genetic testing should no longer be relegated to research space but should often be integrated into clinical care for dyslipidemias. It can provide important information regarding risk stratification and familial risks, especially in familial hypercholesterolemia. As our knowledge of hereditary dyslipidemias continues to expand, the utility of genetic testing in this space will as well.

Future Directions – Polygenic Risk Scores

It would be remiss not to mention polygenic risk scores in an article discussing genetic testing for dyslipidemias. While they are not typically incorporated into clinical practice currently, this is likely to change in the near future. A significant portion of patients with negative genetic test results for familial hypercholesterolemia or monogenic hypertriglyceridemia have high polygenic risk scores.^12,13 These scores assess an individual's risk to develop a certain dyslipidemia by assessing how many and which common, small-effect genetic variants (single nucleotide polymorphisms) they carry.

While it is clear that these scores help explain an individual's dyslipidemia in certain cases, there is still debate about how many and which variants should be included and whether the scores should be weighted or unweighted.¹⁴ As a result, clinical tests are not yet available, but it is important to keep in mind that these polygenic risk scores likely explain a large portion of the missing heritability in FH and other hereditary dyslipidemias. Consequently, genetic testing panels will likely incorporate them in the future.

A Note of Caution

In this era of precision medicine, more and more individuals are turning to direct-to-consumer genetic testing for genomic health information. Current tests on the market typically offer information on ancestry, carrier status for recessive conditions and phenotypic traits such as hair loss and eye color. These tests do not at this time, however, include analysis for the genes associated with FH or other hereditary dyslipidemias.¹⁵ Patients can request a third party company analyze their raw data, and this may reveal variants in genes associated with dyslipidemia. It is critical to confirm all variants detected in this manner using a clinical lab prior to using the information for medical management as a 40% false positive rate has been reported in these analyses.¹⁶

References

1. Khera AV, Won HH, Peloso GM, et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol 2016.7;67:2578-89.
2. Abul-Husn NS, Manickam K, Jones LK, et al. Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science 2016;354.
3. Tsouli SG, Xydis V, Argyropoulou MI, Tselepis AD, Elisaf M, Kiortsis DN. Regression of Achilles tendon thickness after statin treatment in patients with familial hypercholesterolemia: an ultrasonographic study. Atherosclerosis 2009;205:151-5.
4. Leren TP, Finborud TH, Manshaus TE, Ose L, Berge KE. Diagnosis of familial hypercholesterolemia in general practice using clinical diagnostic criteria or genetic testing as part of cascade genetic screening. Community Genet 2008;11:26-35.
5. Besseling J, Huijgen R, Martin SS, Hutten BA, Kastelein JJ, Hovingh GK. Clinical phenotype in relation to the distance-to-index-patient in familial hypercholesterolemia. Atherosclerosis 2016;246:1-6.
6. Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015;36:2425-37.
7. Wierzbicki AS, Viljoen A. Anti-sense oligonucleotide therapies for the treatment of hyperlipidaemia. Expert Opin Biol Ther 2016;16:1125-34.
8. Khera AV, Won HH, Peloso GM, et al. Association of rare and common variation in the lipoprotein lipase gene with coronary artery disease. JAMA 2017;317:937-46.
9. Wetterstrand KA. DNA Sequencing Costs: Data from the NHGRI Genome Sequencing Program (GSP). Available at www.genome.gov/sequencingcostsdata. Accessed 24 Apr 2018.
10. Coalition for Genetic Fairness. GINA: An Overview. 2008. Available at http://www.geneticfairness.org/ginaresource_overview.html. Accessed 30 Apr 2018.
11. Gidding SS, Champagne MA, de Ferranti SD, et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation 2015;132:2167-92.
12. Futema M, Shah S, Cooper JA, et al. Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries. Clin Chem 2015;61:231-8.
13. Stahel P, Xiao C, Hegele RA, Lewis GF. Polygenic risk for hypertriglyceridemia can mimic a major monogenic mutation. Ann Intern Med 2017;167:360-1.
14. Dron JS, Hegele RA. Polygenic influences on dyslipidemias. Curr Opin Lipidol 2018;29:133-43.
15. 23andMe. Explore 23andMe genetic reports. 2018. https://medical.23andme.org/reports. Accessed 24 Apr 2018.
16. Tandy-Connor S, Guiltinian J, Krempely K, et al. False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genet Med 2018.

Keywords: Dyslipidemias, Genetic Testing, Hyperlipoproteinemia Type II, Cholesterol, LDL, Hyperlipoproteinemia Type I, Hyperlipoproteinemia Type III, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Genome, Human, Genotype, Penetrance, Insurance, Long-Term Care, Coronary Artery Disease, Polymorphism, Single Nucleotide, RNA Interference, Tertiary Care Centers, Hypertriglyceridemia, Base Sequence, Lipodystrophy, Genomics, Patient Care, Apolipoproteins B, Oligonucleotides, Antisense, Triglycerides

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