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

Date Published: May 31, 2019

Publisher: Public Library of Science

Author(s): Eleonora Khlebus, Vladimir Kutsenko, Alexey Meshkov, Alexandra Ershova, Anna Kiseleva, Anton Shevtsov, Natalia Shcherbakova, Anastasiia Zharikova, Vadim Lankin, Alla Tikhaze, Irina Chazova, Elena Yarovaya, Oksana Drapkina, Sergey Boytsov, Farook Thameem.


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.

Partial Text

Atherosclerosis is a complex multifactorial disease that is a major cause of cardiovascular disorders and a leading cause of mortality in developed countries. Over the last few decades, it was also suggested that the low density lipoprotein (LDL) oxidation plays an important role in the development and progression of atherosclerosis and its complications [1–4].

For more information, see S1 Appendix.

The major finding of this study is association of the oxLDL levels with both common and rare variants of the APOB gene. For the first time, we showed the association of the rare variants with the circulating oxLDL levels. Additionally, we performed the joint analysis of rare, low-frequency and common APOB variants. Whereas the group of variants associated with oxLDL levels was revealed, the rare or novel variants still should be interpreted cautiously. It is necessary to evaluate the variant and the gene in the context of the patient’s and family’s history, physical examinations, and previous laboratory tests to distinguish between variants that cause the patient’s disorder and those that are benign. Functional evaluation can also provide a more definitive assessment of the variant pathogenicity.