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

Sci Rep. 2016 Nov 17;6:37375. doi: 10.1038/srep37375.

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 (G × G) 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 G × G interactions probably increased power over single-locus tests especially for TG.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Apolipoprotein A-I / genetics
  • Apolipoprotein A-I / metabolism
  • Apolipoproteins B / genetics
  • Apolipoproteins B / metabolism
  • Carboxypeptidases / genetics*
  • Carboxypeptidases / metabolism
  • Cardiovascular Diseases / ethnology
  • Cardiovascular Diseases / genetics*
  • Cardiovascular Diseases / metabolism
  • Cardiovascular Diseases / pathology
  • China
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Cohort Studies
  • Epistasis, Genetic*
  • Ethnic Groups
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Haplotypes
  • Humans
  • LDL-Receptor Related Proteins / genetics*
  • LDL-Receptor Related Proteins / metabolism
  • Linkage Disequilibrium
  • Lipid Metabolism
  • Male
  • Metabolic Syndrome / ethnology
  • Metabolic Syndrome / genetics*
  • Metabolic Syndrome / metabolism
  • Metabolic Syndrome / pathology
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Proprotein Convertase 9 / genetics*
  • Proprotein Convertase 9 / metabolism
  • Risk
  • Triglycerides / blood

Substances

  • Apolipoprotein A-I
  • Apolipoproteins B
  • Cholesterol, HDL
  • Cholesterol, LDL
  • LDL-Receptor Related Proteins
  • Triglycerides
  • low density lipoprotein receptor-related protein 8
  • Carboxypeptidases
  • AGBL4 protein, human
  • PCSK9 protein, human
  • Proprotein Convertase 9