Conditional GWAS revealing genetic impacts of lifestyle behaviors on low-density lipoprotein (LDL)

Abstract

Background: Accumulation of LDL cholesterol (LDL-c) within artery walls is strongly associated with the initiation and progression of atherosclerosis development. This complex trait is affected by multifactor involving polygenes, environments, and their interactions. Uncovering genetic architecture of LDL may help to increase the understanding of the genetic mechanism of cardiovascular diseases.

Methods: We used a genetic model to analyze genetic effects including additive, dominance, epistasis, and ethnic interactions for data from the Multi-Ethnic Study of Atherosclerosis (MESA). Three lifestyle behaviors (reading, intentional exercising, smoking) were used as cofactor in conditional models.

Results: We identified 156 genetic effects of 10 quantitative trait SNPs (QTSs) in base model and three conditional models. The total estimated heritability of these genetic effects was approximately 72.88% in the base model. Five genes (CELSR2, MARK2, ADAMTS12, PFDN4, and MAGI2) have biological functions related to LDL.

Conclusions: Compared with the based model LDL, the results in three conditional models revealed that intentional exercising and smoking could have impacts for causing and suppressing some of genetic effects and influence the levels of LDL. Furthermore, these two lifestyles could have different genetic effects for each ethnic group on a specific QTS. As most of the heritability in based model LDL and conditional model LDL|Smk was contributed from epistasis effects, our result indicated that epistasis effects played important roles in determining LDL levels. Our study provided useful insight into the biological mechanisms underlying regulation of LDL and might help in the discovery of novel therapeutic targets for cardiovascular disease.

Keywords: Atherosclerosis; Cardiovascular diseases; Ethnicity population; Genetic effects; Lifestyle behaviors; Low-density lipoprotein.