Monogenic FH and clinically defined FH remain largely undertreated
Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland
Introduction and methods
Familial hypercholesterolemia (FH) is most often diagnosed based on clinical presentation, without conformation of a causative mutation by genetic testing .
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.
The prevalence of monogenic FH was examined in 166281 Icelandic participants , 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.
- 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.
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.