Monogenic FH and clinically defined FH remain largely undertreated
This study investigated the prevalence and impact of monogenic FH and clinically defined FH in a large proportion of the Icelandic population.
Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in IcelandLiterature - Björnsson E, Thorgeirsson G, Helgadóttir A et al. - Arterioscler Thromb Vasc Biol. 2021 Oct;41(10):2616-2628. doi: 10.1161/ATVBAHA.120.315904
Introduction and methods
Background
Familial hypercholesterolemia (FH) is most often diagnosed based on clinical presentation, without conformation of a causative mutation by genetic testing [1].
Aim of the study
This study investigated the prevalence and impact of monogenic FH and clinically defined FH in a large proportion of the Icelandic population.
Study design
The prevalence of monogenic FH was examined in 166281 Icelandic participants [2], which represents a large proportion of the total Icelandic population (total inhabitants of Iceland on January 1, 2020: 364164). The prevalence of clinical FH was estimated in a subsample of 79058 living participants between 20 and 80 years old with at least one LDL-c measurement. Clinical FH was defined as probable or definite FH based on a modified version of the Dutch Lipid Clinic Network (DLCN) criteria which excluded physical examination findings and genetic information. Risk for CAD, treatment with lipid-lowering agents and achievement of LDL-c targets were compared between participants with monogenic and clinically defined FH.
Main results
- The prevalence of monogenetic FH in this Icelandic population was 1 in 836 (0.12%).
- Monogenic FH was associated with a greater risk of CAD (OR 3.43, 95%CI 2.25-5.22, P=9.8x10^-9), early-onset CAD (in men<50 years and in women <60 years, OR 5.14, 95%CI 2.84-9.28, P=5.9x10^-8), and aortic valve stenosis (OR 3.41, 95%CI 1.16-10.05, P=0.026), compared to noncarriers.
- 2.2% of individuals in the studied population fulfilled the criteria for clinically defined FH, of whom only 5.2% had monogenic FH.
- 40.0% of patients with monogenic FH and 21.9% with mutation-negative clinically defined FH received high-potency statins. 28.1% and 17.9% received neither statins nor ezetimibe, respectively.
- 11.0% of patients with monogenic FH and 24.9% with mutation-negative clinically defined FH achieved an LDL-c level<2.6 mmol/L. LDL-c levels <1.8 mmol/L were achieved by none of the patients with monogenic FH and 5.2% with mutation-negative clinically defined FH.
- The polygenic contribution in mutation-negative clinically defined FH was estimated using an LDL-c genetic score based on 345 lipid-associated variants. 78.7% of individuals with mutation-negative clinically defined FH had values >50th percentile, 58.7% >70th percentile, 26.2% > 90th percentile, and 15.0% >95th percentile. This suggests that a large proportion of individuals with mutation-negative clinically defined FH has a high polygenic burden of LDL-c raising variants.
Conclusion
The prevalence of monogenic FH in this large Icelandic population was 1 in 836 (0.12%). This is lower than the estimated prevalence in populations in other countries [3-7]. Only a small proportion of individuals with clinically defined FH had monogenic FH. Both patients with clinically defined FH and monogenic FH are undertreated and only very few achieved LDL-c targets recommended by recent ESC/EAS guidelines.
References
1. Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM, Baum SJ, Bourbon M, Carrié A, Cuchel M, et al; Convened by the Familial Hypercholesterolemia Foundation. Clinical genetic testing for familial hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72:662–680. doi: 10.1016/j.jacc.2018.05.044
2. Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, Besenbacher S, Magnusson G, Halldorsson BV, Hjartarson E, et al. Large-scale whole-genome sequencing of the Icelandic population. Nat Genet. 2015;47:435–444. doi: 10.1038/ng.3247
3. Abul-Husn NS, Manickam K, Jones LK, Wright EA, Hartzel DN, Gonzaga-Jauregui C, O’Dushlaine C, Leader JB, Lester Kirchner H, Lindbuchler DM, et al. Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science. 2016;354:aaf7000. doi: 10.1126/science.aaf7000
4. Benn M, Watts GF, Tybjærg-Hansen A, Nordestgaard 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;37:1384–1394. doi: 10.1093/eurheartj/ehw028
5. Khera AV, Won HH, Peloso GM, Lawson KS, Bartz TM, Deng X, van Leeuwen EM, Natarajan P, Emdin CA, Bick AG, et al. Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. J Am Coll Cardiol. 2016;67:2578–2589. doi: 10.1016/j.jacc.2016.03.520
6. Trinder M, Francis GA, Brunham LR. Association of Monogenic vs Polygenic Hypercholesterolemia With Risk of Atherosclerotic Cardiovascular Disease. JAMA Cardiol. 2020;5:390–399. doi: 10.1001/jamacardio.2019.5954
7. Grzymski JJ, Elhanan G, Morales Rosado JA, Smith E, Schlauch KA, Read R, Rowan C, Slotnick N, Dabe S, Metcalf WJ, et al. Population genetic screening efficiently identifies carriers of autosomal dominant diseases. Nat Med. 2020;26:1235–1239. doi: 10.1038/s41591-020-0982-5