Multiple rare and common variants in APOB gene locus associated with oxidatively modified low-density lipoprotein levels

PLoS One. 2019 May 31;14(5):e0217620. doi: 10.1371/journal.pone.0217620. eCollection 2019.

Abstract

Oxidatively modified low-density lipoproteins (oxLDL) play an important role in the occurrence and progression of atherosclerosis. To identify the genetic factors influencing the oxLDL levels, we have genotyped 776 DNA samples of Russian individuals for 196,725 single-nucleotide polymorphisms (SNPs) using the Cardio-MetaboChip (Illumina, USA) and conducted genome-wide association study (GWAS). Fourteen common variants in the locus including APOB gene were significantly associated with the oxLDL levels (P < 2.18 × 10-7). These variants explained only 6% of the variation in the oxLDL levels. Then, we assessed the contribution of rare coding variants of APOB gene to the oxLDL levels. Individuals with the extreme oxLDL levels (48 with the lowest and 48 with the highest values) were selected for targeted sequencing of the region including APOB gene. To evaluate the contribution of the SNPs to the oxLDL levels we used various statistical methods for the association analysis of rare variants: WST, SKAT, and SKAT-O. We revealed that both synonymous and nonsynonymous SNPs affected the oxLDL levels. For the joint analysis of the rare and common variants, we conducted the SKAT-C testing and found a group of 15 SNPs significantly associated with the oxLDL levels (P = 2.14 × 10-9). Our results indicate that the oxLDL levels depend on both common and rare variants of the APOB gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atherosclerosis / epidemiology
  • Atherosclerosis / genetics*
  • Atherosclerosis / pathology
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Lipoproteins / genetics
  • Lipoproteins, LDL / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Sequence Alignment
  • Sequence Analysis, Protein

Substances

  • Lipoproteins
  • Lipoproteins, LDL
  • oxidized low density lipoprotein

Grants and funding

This research was supported by grant of Russian Scientific Foundation 14-15-00245.