AGBL4, PRL8 and PCSK9 genetic variants and their interactions on dyslipidemia

This study was designed to comprehensively illuminate the genetic susceptibility to dyslipidemia on the ATP/GTP binding protein-like 4 (AGBL4), low-density lipoprotein (LDL) receptor related protein 8 (LRP8) and proprotein convertase subtilisin-like kexin type 9 (PCSK9) gene cluster regions. Genotypes of 12 single nucleotide polymorphisms (SNPs) were identified in a total of 2552 individuals (1020, hypercholesterolemia (HTC); 740, hypertriglyceridemia (HTG); 673, hyper-LDL cholesterol (HLDL-C); and 1177, hyper-apolipoproteinB100 (HApoB100), some participants overlapped more than one kind of dyslipidemia). Consequently, we confirmed previously observed significant associations between cardiometabolic risk, dyslipidemia, and SNPs in the AGBL4 (rs320018 for HTG, rs320017 for HLDL-C, rs320017 and rs320018 for HApoB100), LRP8 (rs1288521 for HApoB100) and PCSK9 (rs584626 and rs585131 for HTC, rs533375 for HTG, rs540796 for HLDL-C, and rs533375 for HApoB100). Furthermore, we elucidated distinct effects of the AGBL4, LRP8 and PCSK9 interactions towards dyslipidemia (G-GA- A-C-G-T-T-C-A-A-G for HTC; A-A-G-G-A-G-C-C-C-A-A-G and G-G-A-A-C-G-T-T-T-A-A-G for HTG; A-A-G-A-C-G-T-T-C-A-A-G, A-A-G-G-A-G-C-C-C-A-A-G and G-G-A-A-C-G-T-T-T-G-G-A for HLDL-C; and A-A-G-A-C-G-T-C-C-A-A-G for HApoB100). These findings suggest that integrative AGBL4, LRP8 and PCSK9 genetic variants and their interactions may significantly modify the risk of dyslipidemia, depending on effects of serum lipid levels.