Genetic testing for familial hypercholesterolemia: Impact on diagnosis, treatment and cardiovascular risk. (August 2019)

• Record Type: Journal Article
• Authors: Lee, Seohyuk; Akioyamen, Leo E; Aljenedil, Sumayah; Rivière, Jean-Baptiste; Ruel, Isabelle; Genest, Jacques
• Is Part Of: European journal of preventive cardiology. Volume 26:Number 12(2019)
• Page Start: 1262
• Page End: 1270
• Publication Date: 2019-08
• Subjects: Familial hypercholesterolemia -- low-density lipoprotein -- genetic testing -- atherosclerotic cardiovascular disease; Cardiovascular system -- Diseases -- Prevention -- Periodicals; Cardiac patients -- Rehabilitation -- Periodicals; 616.12
• DOI: 10.1177/2047487319829746
• Languages: English
• ISSNs: 2047-4873

Abstract

Aims: Familial hypercholesterolemia (FH) is the most common genetic disorder in medicine, with a prevalence of 1/250. Affected individuals have elevated low-density lipoprotein cholesterol (LDL-C) and an increased lifetime risk of atherosclerotic cardiovascular disease (ASCVD). The diagnosis of FH is based on algorithms that include LDL-C levels, physical manifestations, family history of high LDL-C and premature ASCVD, and, more recently, genetic testing. We sought to determine the impact of genetic testing on the: 1) diagnosis of 'definite familial hypercholesterolemia', 2) initiation and adherence of lipid-lowering therapy and 3) risk of ASCVD. Methods: We performed a systematic review and meta-analysis, pooling odds ratios and 95% confidence intervals for ASCVD from studies comparing risk estimates in individuals harboring FH-causing variants and unaffected individuals. Results: After screening 3304 unique publications, 56 studies were included in the analysis. 1) Genetic testing provided confirmation of FH in 28–80%, over clinical criteria alone, depending on the diagnostic algorithm and the method of analysis. In two large population-based studies comprising 76, 751 individuals, an FH-causing variant was identified in only 1.7–2.5% of subjects with an LDL-C > 4.9 mmol/L (190 mg/dL). 2) A confirmed molecular diagnosis increased lipid-lowering therapy adherence (five studies, n = 4181 definite FH). 3) Loss-of-function variant of the LDLR were at a markedly increased risk of myocardial infarction (odds ratio 6.77, 95% confidence interval 4.75–9.66), and patients with a milder (hypomorphic) pathogenic LDLR change had a 4.4-fold increase in risk (odds ratio 4.4, 95% confidence interval 2.34–8.26), compared with controls. Conclusion: DNA sequencing confirms the diagnosis of FH but has a poor yield in unselected patients whose sole criterion is an elevated LDL-C. Initiation and adherence to treatment is improved. The risk of ASCVD is 4.4- to 6.8-fold increased in patients with an FH-causing variant compared with controls, depending on the severity of the DNA change.