Penetrance of the ε2/ε2 genotype and pathogenic APOE variants associated with familial dysbetalipoproteinemia

Aim . To evaluate the penetrance of the ε2/ε2 genotype and pathogenic APOE variants associated with familial dysbetalipoproteinemia (FD). Material and methods . The study included 51 patients with a genetic cause of FD — carriers of the ε2/ε2 genotype or pathogenic APOE variants, whose genotyped blood samples were stored in the Biobank laboratory of the National Medical Research Center for Therapy and Preventive Medicine. A triglyceride level ≥1,5 mmol/L was considered as the phenotypic manifestation of the genetic cause associated with FD. The penetrance of the ε2/ε2 genotype and the most frequent APOE variants (p.Arg154Cys and p.Gly145Asp) was estimated using the Bayesian method. Differences in the age of phenotypic manifestation onset by sex and genetic cause of FD were assessed using the Mann-Whitney U test. Results . The ε2/ε2 genotype was identified in 35 (68,6%) patients, and pathogenic APOE variants in 16. Triglyceride levels were higher in carriers of APOE variants than in carriers of the ε2/ε2 genotype (median 7,38 vs 4,03 mmol/L; p=0,046). The penetrance of ε2/ε2, p.Arg154Cys, and p.Gly145Asp was 16,3%,21,9%, and 50,0%, respectively. Phenotypic manifestation was detected earlier in men than in women (median age 48 and 55 years, respectively; p=0,017). There was no significant difference in the age of phenotypic manifestation onset between carriers of the ε2/ ε2 genotype and those with pathogenic APOE variants (p=0,932). Conclusion . For the first time in a Russian patient cohort, we showed that genetic causes of FD are characterized by incomplete penetrance. The penetrance of APOE variants associated with autosomal dominant FD was estimated to be higher than that of the ε2/ε2 genotype. The age of phenotypic manifestation onset was lower in men but did not differ between carriers of the ε2/ε2 genotype and pathogenic APOE variants.