Integrative mutation, haplotype and GG interaction evidence connects ABGL4, LRP8 and PCSK9 genes to cardiometabolic risk

abstract: ...This study is expected to investigate the association of ATP/GTP binding protein-like 4 (AGBL4), LDL receptor related protein 8 (LRP8) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gene single nucleotide variants (SNVs) with lipid metabolism in 2,552 individuals (Jing, 1,272 and Han, 1,280). We identified 12 mutations in this motif. The genotype and allele frequencies of these variants were different between the two populations. Multiple-locus linkage disequilibrium (LD) elucidated the detected sites are not statistically independent. Possible integrative haplotypes and gene-by-gene (GG) interactions, comprising mutations of the AGBL4 , LRP8 and PCSK9 associated with total cholesterol (TC, AGBL4 G-G-A, PCSK9 C-G-A-A and G-G-A-A-C-A-T-T-T-G-G-A), triglyceride (TG, AGBL4 G-G-A, LRP8 G-A-G-C-C, PCSK9 C-A-A-G, A-A-G-G-A-G-C-C-C-A-A-G and A-A-G-G-A-G-C-C-C-G-A-A), HDL cholesterol (HDL-C, AGBL4 A-A-G and A-A-G-A-A-G-T-C-C-A-A-G) and the apolipoprotein(Apo)A1/ApoB ratio (A1/B, PCSK9 C-A-A-G) in Jing minority. However, in the Hans, with TG ( AGBL4 G-G-A, LRP8 G-A-G-C-C, PCSK9 C-A-A-G, A-A-G-G-A-G-C-C-C-A-A-G and A-A-G-G-A-G-C-C-C-G-A-A), HDL-C ( LRP8 A-A-G-T-C), LDL-C ( LRP8 A-A-G-T-C and A-A-G-A-A-G-T-C-C-A-A-G) and A1/B ( LRP8 A-C-A-T-T and PCSK9 C-A-A-G). Association analysis based on haplotype clusters and GG interactions probably increased power over single-locus tests especially for TG.

... protein-like 4 (AGBL4), LDL receptor related protein 8 (LRP8) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gene single nucleotide variants (SNVs) with lipid metabolism in 2,552 individuals (Jing, 1,272 and Han, 1,280). We identified 12 mutations in this motif. The genotype and allele frequencies of these variants were different between the two populations. Multiple-locus linkage disequilibrium (LD) elucidated the detected sites are not statistically independent. Possible integrative haplotypes and gene-by-gene (GG) interactions, comprising mutations of the AGBL4 , LRP8 and PCSK9 associated with total cholesterol (TC, AGBL4 G-G-A, PCSK9 C-G-A-A and G-G-A-A-C-A-T-T-T-G-G-A), triglyceride (TG, AGBL4 G-G-A, LRP8 G-A-G-C-C, PCSK9 C-A-A-G, A-A-G-G-A-G-C-C-C-A-A-G and A-A-G-G-A-G-C-C-C-G-A-A), HDL cholesterol (HDL-C, AGBL4 A-A-G and A-A-G-A-A-G-T-C-C-A-A-G) and the apolipoprotein(Apo)A1/ApoB ratio (A1/B, PCSK9 C-A-A-G) in Jing minority. However, in the Hans, with TG ( AGBL4 G-G-A, LRP8 G-A

... (SNVs) and regions of linkage disequilibrium (LD) independent of annotation or relationship to nearby genes 10 . Recently, the compelling genes for modifying lipid metabolism emerged from very large replicated GWAS: the ATP/GTP binding protein-like 4 gene ( AGBL4 [MIM 616476]), the LDL receptor related protein 8 gene ( LRP8 [MIM 602600]) and the proprotein convertase subtilisin/kexin type 9 gene ( PCSK9 [MIM 607786]) 11 12 13 14 15 16 . The objective of this study was to perform association analysis to identify integrative mutations, haplotypes and gene-by-gene (GG) interactions of the AGBL4 (rs320017 A>G, rs320018 A>G and rs320019 G>A), LRP8 (rs6694764 G>A, rs1288519 A>C, rs872315 G>A, rs1288520 C>T and rs1288521 C>T) and PCSK9 (rs533375 C>T, rs584626 A>G, rs585131 A>G and rs540796 G>A) associated with lipid phenotypic variations in the Jing and Han populations. Furthermore, we wanted to test if the association analysis of these loci based on haplotype clusters and GG interactions increase

... equilibrium (HWE, P >0.05 for all). We tested each mutation individually for association with plasma lipid levels separately in each population. We discovered the association of the AGBL4 , LRP8 and PCSK9 mutations with TC (rs320017, rs320018, rs320019 and rs533375), TG (rs320017, rs320018, rs320019, rs6694764, rs872315, rs1288520, rs1288521, rs533375, rs584626, rs585131 and rs540796) and HDL-C (rs6694764, rs1288519, rs872315, rs1288520, rs1288521 and rs585131) in Jing minority. However, in the Hans, with

... separately in each population. Figures 3 and 4 show the LD blocks and the haplotypes for blocks separately in the Jing and Han ethnic groups. As shown in Table 4 , the commonest haplotypes were AGBL4 A-A-G, LRP8 G-A-G-C-C and PCSK9 C-A-A-G (>50% of the samples). The frequencies of the AGBL4 A-A-G, AGBL4 G-G-A, LRP8 A-A-G-T-C, LRP8 A-C-A-T-T, LRP8 G-A-G-C-C, PCSK9 C-A-A-G, PCSK9 C-G-A-A and PCSK9 T-G-G-A haplotypes were quantitative significantly different between the Jing and Han populations ( P <0.050.001). We confirmed that the AGBL4 , LRP8 and PCSK9 haplotypes were associated with TC ( AGBL4 G-G-A and PCSK9 C-G-A-A), TG ( AGBL4 G-G-A, LRP8 G-A-G-C-C and PCSK9 C-A-A-G), HDL-C ( AGBL4 A-A-G), ApoA1 ( PCSK9 C-A-A-G), and A1/B ( PCSK9 C-A-A-G) in Jing minority. However, they were associated with TG ( AGBL4 G-G-A, LRP8 G-A-G-C-C and PCSK9 C-A-A-G), HDL-C ( LRP8 A-A-G-T-C), LDL-C ( LRP8 A-A-G-T-C), ApoA1 ( PCSK9 C-G-A-A), ApoB ( AGBL4 G-G-A) and A1/B ( LRP8 A-C-A-T-T and PCSK9 C-A-A-G) in Han

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Gene: AGBL4 - ATP/GTP binding protein-like 4 - (NCBI)

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