TY - JOUR

T1 - Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia

AU - Blokhina, Anastasia V.

AU - Ershova, Alexandra I.

AU - Kiseleva, Anna V.

AU - Sotnikova, Evgeniia A.

AU - Zharikova, Anastasia A.

AU - Zaicenoka, Marija

AU - Vyatkin, Yuri V.

AU - Ramensky, Vasily E.

AU - Kutsenko, Vladimir A.

AU - Garbuzova, Elizaveta V.

AU - Divashuk, Mikhail G.

AU - Litinskaya, Olga A.

AU - Pokrovskaya, Maria S.

AU - Shalnova, Svetlana A.

AU - Meshkov, Alexey N.

AU - Drapkina, Oxana M.

PY - 2024/12

Y1 - 2024/12

N2 - Familial dysbetalipoproteinemia (FD) is a highly atherogenic, prevalent genetically based lipid disorder. About 10% of FD patients have rare APOE variants associated with autosomal dominant FD. However, there are insufficient data on the relationship between rare APOE variants and FD. Genetic data from 4720 subjects were used to identify rare APOE variants and investigate their pathogenicity for autosomal dominant FD. We observed 24 variants in 86 unrelated probands. Most variants were unique (66.7%). Five identified APOE variants (p.Glu63ArgfsTer15, p.Gly145AlafsTer97, p.Lys164SerfsTer87, p.Arg154Cys, and p.Glu230Lys) are causal for autosomal dominant FD. One of them (p.Lys164SerfsTer87) was described for the first time. When we compared clinical data, it was found that carriers of pathogenic or likely pathogenic APOE variants had significantly higher triglyceride levels (median 5.01 mmol/L) than carriers of benign or likely benign variants (median 1.70 mmol/L, p = 0.034) and variants of uncertain significance (median 1.38 mmol/L, p = 0.036). For the first time, we estimated the expected prevalence of causal variants for autosomal dominant FD in the population sample: 0.27% (one in 619). Investigating the spectrum of APOE variants may advance our understanding of the genetic basis of FD and underscore the importance of APOE gene sequencing in patients with lipid metabolism disorders.

AB - Familial dysbetalipoproteinemia (FD) is a highly atherogenic, prevalent genetically based lipid disorder. About 10% of FD patients have rare APOE variants associated with autosomal dominant FD. However, there are insufficient data on the relationship between rare APOE variants and FD. Genetic data from 4720 subjects were used to identify rare APOE variants and investigate their pathogenicity for autosomal dominant FD. We observed 24 variants in 86 unrelated probands. Most variants were unique (66.7%). Five identified APOE variants (p.Glu63ArgfsTer15, p.Gly145AlafsTer97, p.Lys164SerfsTer87, p.Arg154Cys, and p.Glu230Lys) are causal for autosomal dominant FD. One of them (p.Lys164SerfsTer87) was described for the first time. When we compared clinical data, it was found that carriers of pathogenic or likely pathogenic APOE variants had significantly higher triglyceride levels (median 5.01 mmol/L) than carriers of benign or likely benign variants (median 1.70 mmol/L, p = 0.034) and variants of uncertain significance (median 1.38 mmol/L, p = 0.036). For the first time, we estimated the expected prevalence of causal variants for autosomal dominant FD in the population sample: 0.27% (one in 619). Investigating the spectrum of APOE variants may advance our understanding of the genetic basis of FD and underscore the importance of APOE gene sequencing in patients with lipid metabolism disorders.

KW - APOE

KW - apolipoprotein E

KW - autosomal dominant

KW - dyslipidemia

KW - familial dysbetalipoproteinemia

KW - hyperlipoproteinemia type III

KW - pathogenicity

KW - phenotype/genotype correlation

KW - remnant lipoproteins

KW - triglycerides

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85212237038&origin=inward&txGid=89442ee1c30cba30eb953d21590e9c8f

UR - https://www.mendeley.com/catalogue/f0bf4614-e76c-34a0-82e3-632c883b94d7/

U2 - 10.3390/ijms252312651

DO - 10.3390/ijms252312651

M3 - Article

VL - 25

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 23

M1 - 12651

ER -