Lipid-related genes and their associations with coronary heart disease

Coronary heart disease (CHD) is a complex disease caused by the long-term progression of atherosclerosis. Lipids, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are well established biomarkers for CHD, and are used to predict individual 10-year risk for CHD both in the Framingham risk score and in the System for Cardiac Operative Risk Evaluation (SCORE) project. Exploring the role and relationship of lipid-related genes and lipids in CHD progression can enhance our understanding of CHD etiology. This PhD thesis was based on the following studies:

Study I explored the associations between lipid-related genes and myocardial infarction incidence. We found that a missense variant in the ABCA1 gene was consistently associated with myocardial infarction in two Swedish cohorts, as well as being weakly associated with CHD in a large meta-analysis that included 173,975 individuals of European descent.

Study II investigated large-scale genetic associations between lipid fractions, including data from 188,577 individuals. In this study, there were 157 independent loci associated with at least one lipid trait at the genome-wide significant level (P-value < 5 × 10-8), of which 62 loci were not previously reported to be associated with lipids in humans.

Study III examined the modifying effect of lifestyles on the genetic variance of CHD using twin modeling. We found that a decrease in genetic variance of CHD was dependent on increasing body mass index (BMI). This finding indicates that more genetic variants or larger effect sizes of genetic variants influence CHD in the lean group compared to the obese group.

Study IV investigated the causal relations between lipids and chronic low-degree inflammation, measured as high sensitivity C reaction protein (CRP) using a Mendelian randomization study design.We found strong observational associations between dyslipidemia (decreased HDL-C and/or increased TG) and elevated CRP, but no evidence supporting causal relations between dyslipidemia and CRP. The observational associations are likely driven by other common causes such as adiposity.

In conclusion, the findings in the current thesis highlight genetic determinants of blood lipid levels and their associations with CHD. Our results suggest a BMI-gene interaction effect on CHD. Further, our results suggest that the observational associations between dyslipidemia and chronic low-degree inflammation are more likely to be driven by other common causes such as adiposity. All these findings shed light on the complex mechanisms underlying CHD, particularly those that act through lipid metabolism pathways.

List of scientific papers

I. Song C, Pedersen NL, Reynolds CA, Sabater-Lleal M, Kanoni S, Willenborg C; CARDIoGRAMplusC4D Consortium, Syvänen AC, Watkins H, Hamsten A, Prince JA, Ingelsson E. Genetic variants from lipid-related pathways and risk for incident myocardial infarction. PLoS One. 2013;8(3):e60454.
https://doi.org/10.1371/journal.pone.0060454

II. Global Lipids Genetics Consortium. Discovery and Refinement of Loci Associated with Lipid Levels. Nat Genet. 2013 Nov;45(11):1274-83.
https://doi.org/10.1038/ng.2797

III. Song C, Chang Z, Magnusson PK, Ingelsson E, Pedersen NL. The role of lifestyle in moderating heritable factors in coronary heart disease. J Intern Med. 2013 Dec 12.
https://doi.org/10.1111/joim.12177

IV. Song C, Fall T, Ploner A, Lind L, Lannfelt L, Pedersen NL, Hägg S, Ingelsson E. The interplay between fasting blood lipids and inflammation: a Mendelian randomization study. [Manuscript]