Genetic risk score in patients with the APOE2/E2 genotype as a predictor of familial dysbetalipoproteinemia

Background: Familial dysbetalipoproteinemia (FD) is an autosomal recessive (rarely dominant) inherited disorder that is almost exclusively associated with the apolipoprotein E gene (APOE) variability. Nonetheless, only a small proportion of APOE2/E2 subjects develop the phenotype for mixed dyslipidemia; the context of other trigger metabolic or genetic factors remains unknown. Methods: One hundred and one patients with FD and eighty controls (all APOE2/E2 homozygotes; rs429358) were screened for 18 single -nucleotide polymorphisms (SNPs) within the genes involved in triglyceride metabolism. Results: Two SNPs were significantly associated with the FD phenotype (rs439401 within APOE; P < 0.0005 and rs964184 within ZPR1/APOA5/A4/C3/A1 gene cluster; P < 0.0001). Unweighted genetic risk scores - from these two SNPs (GRS2), and, also, additional 13 SNPs with P -value below 0.9 (GRS15) - were created as an additional tool to improve the risk estimation of FD development in subjects with the APOE2/E2 genotype. Both GRS2 and GRS15 were significantly ( P < 0.0001) increased in patients and both GRSs discriminated almost identically between the groups ( P = 0.86). Subjects with an unweighted GRS2 of three or more had an almost four -fold higher risk of FD development than other individuals (odds ratio (OR) 3.58, 95% confidence interva (CI): 1.78-7.18, P < 0.0005). Conclusions: We identified several SNPs that are individual additive factors influencing FD development. The use of unweighted GRS2 is a simple and clinically relevant tool that further improves the prediction of FD in APOE2/E2 homozygotes with corresponding biochemical characteristics. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of National Lipid Association. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )