Dyslipidemia is a chronic deviation from normal blood lipid levels that can lead to atherosclerosis and other cardiovascular diseases; dyslipidemia and its sequelae are caused by the complex interplay of genetic and environmental factors. Although circulating concentrations of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (LDL-C) have a strong genetic underpinning, not much is known about the genetic factors that affect long-term deteriorations in lipid concentrations. Through the work described in this thesis I sought to identify novel genetic loci associated with long-term lipid level changes and identify gene × environment interactions influencing blood lipid and lipoprotein concentrations.
In Papers I and II, large European prospective cohort studies with long-term follow-up were analyzed. The Gene–Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk (GLACIER) Study (N=3,495) was analyzed in the discovery phase of these studies. The MDC, PIVUS, ULSAM and MRC Ely studies (Nmax=8,263) were utilized as replication cohorts. In Paper III, Scandinavian adults from the GLACIER, MDC, Inter99 and Health 2006 Studies were meta-analyzed (Nmax=18,190). In Paper IV, analyses were conducted in the Diabetes Prevention Program (DPP) (N=2,993) multi-ethnic randomized clinical trial. Participants from the GLACIER Study and DPP, the two discovery studies intensively used in this thesis, were genotyped with the Illumina CardioMetaboChip array.
In Paper I, TC- and TG-specific genetic risk scores (GRSs) were robustly associated with TC- and TG level changes, respectively. Three genomic loci, APOE, TRIB1 and APOA1 were associated with either TC- or TG changes and were replicated in subsequent analyses. In Paper II, in addition to the findings of Paper I, seven further loci were associated with TC- or TG changes. Of these, variants at CAPN3, HPR and SIX5 showed suggestive evidence for association with coronary artery disease. In Paper III, a robust sex-heterogeneous interaction between the TG-related GRS and body mass index was observed for circulating blood TG levels. In Paper IV, an interaction between the large HDL particle-associated GRS and the lifestyle intervention for large HDL particle concentrations was observed.
In conclusion, this thesis work shows genetic associations for long-term lipid changes and demonstrates examples of gene × environment interactions that influence blood lipid concentrations.
- Franks, Paul, handledare
- Rosengren, Anders, handledare
- Renström, Frida, handledare
|Tilldelningsdatum||2016 apr. 22|
|Status||Published - 2016|
Place: [Aulan, CRC, Jan Waldenströms gata 35, Skånes universitetssjukhus i Malmö.]
Name: [Karpe, Fredrik]
Affiliation: [University of Oxford, UK]
Lund University, Faculty of Medicine Doctoral Dissertation Series 2016:32