What’s New? Brief Reports on Clinical Research
T. Harahwa (London, UK), K. Hasegawa (Kyoto, Japan)
Familial hypercholestrolaemia (FH) is an autosomal codominant genetic disorder that results from defects of the low density lipoprotein (LDL)-receptor pathway which lead to excessive serum LDL cholesterol (LDL-C) which can be deposited in tissues and predispose to premature atherosclerotic cardiovascular disease (CVD); the main causative mutations are in the genes encoding the LDL-receptor, apolipoprotein B and proprotein convertase subtilisin/kexin type 9 (PCSK9)1-3. Past studies have estimated the prevalence of these aforementioned genetic mutations amongst individuals with FH as ranging from 33.1% to 66.5%5-8. FH has an estimated overall prevalence of 1 in 250 (0.4%) in the UK but it is estimated that up to 85% of people go undiagnosed5, 9. It is unclear exactly what proportion of patients with FH are receiving genetic screening for them and their family members but it is likely low as only an estimated one third of the population have access to an FH service in spite of the National Institute for Health and Care Excellence introducing national recommendations for index case genetic testing and cascade testing for relatives of FH patients in 2008.
Trinder et al.10 undertook a case-control cohort study in which they looked to see if there was a difference in the risk of CVD with monogenic FH when compared to polygenic FH, and if there was a difference between the risk of CVD associated with these genetic variants of FH compared with nongenetic hypercholesterolaemia to determine if genetic variant for FH alters the risk of CVD. They did so using genotyping array and exome sequencing data by the UK Biobank for 48,741 adults aged 40 to 69 to identify individuals with monogenic FH which was defined within this study as those with pathogenic or likely pathogenic LDLR, APOB and PCSK9 genetic variants, those with polygenic FH which was defined as individuals with a 223 single-nucleotide variants LDL-C polygenic score higher than the 95th percentile, and those with non-genetic hypercholesterolaemia who were identified by 1:1 matching of individuals with polygenic FH to those from the exome sequencing cohort who did not have monogenic FH. The prevalence of CVD events (defined as coronary and carotid revascularisation, myocardial infarction, ischaemic stroke and all-cause mortality) that occurred during the observation period from the point of enrolment between March 2006 and October 2010, until the end of follow-up in March 2017 was used to assess CVD risk.
Of the study cohort, 277 participants (0.57%) were found to have a monogenic FH, with 92.9% of these individuals having identified defects in the gene encoding LDLR, 4.7% for PCSK9 and 2.5% for APOB. This is in comparison to 2379 participants (4.9%) who were found to have polygenic FH and 2232 participants (4.6%) with a non-genetic cause of hypercholesterolaemia. Overall, the results showed that both monogenic (hazard ratio, 1.93; 95% CI 1.34-2.77; P<0.001) and polygenic FH (Hazard ratio (HR), 1.26; 95% Confidence Interval (CI) 1.03-1.55; P=0.03) were associated with a higher risk of CVD when compared to individuals with non-genetic hypercholesterolaemia among individuals with comparable levels of LDL-C. Additionally, individuals with monogenic FH were found to be significantly more likely to experience CVD events at 55 years or younger when compared to individuals without a monogenic FH variant (HR, 3.17; 95% CI 1.96-5.12; P<0.001).
The study demonstrated that monogenic and polygenic FH are associated with a greater risk of CVD when compared to hypercholesterolaemia due to non-genetic causes, which has been demonstrated in similar studies11-13. This study is however the first to demonstrate that monogenic FH is associated with the greatest risk of CVD when compared to other genetic variants and non-genetic hypercholesterolaemia, though it remains unclear why this is. This bears clinical significance as this supports the need for routine genetic testing of patients with clinically suspected FH to determine if they have a genetic variant of FH that is associated with an increased risk of CVD and thus require early intervention.
The main limitations of the study were firstly that some participants were on cholesterol-lowering medication prior to enrolment so there was no data on their pre-treatment lipid profiles, thus their baseline LDL-C levels had to be estimated meaning they may not be wholly accurate which is an important consideration as the study hinged on patients having comparable baseline LDL-C levels to demonstrate that the genetic variants of FH had an association with CVD risk amongst patients with similar LDL-C levels. Secondly, the study did not compare the risk of CVD of patients with monogenic FH when compared to the general population only to those with FH, meaning the findings are only applicable amongst individuals with known FH. Finally, the participants of the study were predominantly of White European ancestry thus meaning results cannot be generalised for populations of non-European ancestry.
Going forward, as medicine moves towards becoming more personalised it will useful to do routine genetic testing on individuals with the clinical phenotype of FH as it may allow for early preventative intervention to reduce the incidence of premature CVD. However, with the estimated prevalence of monogenic FH in the current study only being 0.57%, a figure much higher than that quoted in previous studies, there is the question of the cost-benefit performance of genetic screening in this case. FH remains largely undiagnosed meaning that the prevalence may be higher than we realise, which coupled with the fact that the cost for sequencing DNA has progressively decreased over the years and continues to do so, makes the case in favour of carrying out routine genetic testing or at the very least, screening a greater proportion of patients in the community than are currently being screened.
- Benn M, Watts GF, Tybjærg-Hansen A, Nordestagaard BG. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. Eur Heart J. 2016; 37(17):1384-1394. doi:10.1093/eurheartj/ehw028.
- Kerr M, Pears R, Miedzybrodzka Z, et al. Cost effectiveness of cascade testing for familial hypercholesterolaemia services in the UK. Eur Heart J. 2017; 38(23):1832-1839. doi: 1093/eurheartj/ehx111.
- Akioyamen LE, Genest J, Shan SD, et al. Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systemic review and meta-analysis. BMJ Open. 2017; 7(9):e016461. doi:10.1136/bmjopen-2017-016461.
- Qureshi N, Weng S, Tranter J, et al. Feasibility of improving identification of familial hypercholestrolaemia in general practice: intervention development study. BMJ Open. 6(5):e011734. doi:10.1136/bmjopen-2016-011734.
- Humphries SE, Whittall RA, Hubbart CS, et al. Genetic causes of familial hypercholestrolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. J Med Genet. 2006; 43(12):943-949. doi:10.1136/jmg.2006.038356.
- Damgaard D, Larsen ML, Nissen PH, et al. The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolaemia in a Danish population. Atherosclerosis. 2005; 180(1):155-160. doi:10.1016/j.atherosclerosis.2004.12.001.
- Fouchier SW, Defesche JC, Umans-Eckenhausen MA, et al. The molecular basis of familial hypercholesterolaemia in The Netherlands. Human Genetics. 2001; 109:602-615. doi:10.1007/s00439-001-0628-8.
- Civeira F, Ros E, Jarauta E, et al. Comparison of genetic versus clinical diagnosis in familial hypercholesterolaemia. Am J Cardiol. 2008; 102(9):1187-1193. doi:10.1016/j.amjcard.2008.06.056.
- Barbir M, Breen J, Neves E, et al. Diagnosis, management and prognosis of familial hypercholestrolaemia in a UK tertiary cardiac centre. Clinical Lipidology and Metabolic Disorders. 2019; 14(1):1-10. doi:10.1080/17584299.2019.1587877.
- Trinder MT., Francis GA., Brunham LR. Association of Monogenic vs Polygenic Hypercholesterolemia With Risk of Atherosclerotic Cardiovascular Disease. JAMA Cardiol. Published online 21 February 2020. doi:10.1001/jamacardio.2019.5954.
- Khera AV., Won HH., Peloso GM., et al. Diagnostic Yield of Sequencing Familial Hypercholesterolemia Genes in Severe Hypercholesterolemia. J Am Coll Cardiol. 2016; 67(22):2578-2589. doi:10.1016/j.jacc.2016.03.520.
- Tada H., Kawashiri MA., Nohara A., et al. Impact of clinical signs and genetic diagnosis of familial hypercholesterolaemia on the prevalence of coronary artery disease in patients with severe hypercholesterolaemia. Eur Heart J. 2017; 38(20):1573-1579. doi:10.1093/eurheartj/ehx004.
- Trinder M., Li X., DeCastro ML., et al. Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia. J Am Coll Cardiol. 2019; 74(4):512-522. doi:10.1016/j.jacc.2019.05.043.