TY - THES
T1 - Genetic Determinants of Dyslipidemia
AU - V Varga, Tibor
N1 - Defence details
Date: [2016-04-22]
Time: [09:00]
Place: [Aulan, CRC, Jan Waldenströms gata 35, Skånes universitetssjukhus i Malmö.]
External reviewer(s)
Name: [Karpe, Fredrik]
Title: [professor]
Affiliation: [University of Oxford, UK]
ISSN: 1652-8220
Lund University, Faculty of Medicine Doctoral Dissertation Series 2016:32
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Genetic epidemiology
KW - Genetic polymorphism
KW - dyslipidaemia
KW - Cholesterol
KW - Triglyceride
KW - Genetic risk
KW - genetic risk score
KW - Single nucleotide polymorphism
KW - Prediction
KW - Gene-environment interactions
KW - Randomized controlled trial
KW - prospective cohort studies
KW - Observational study
KW - GLACIER Study
KW - Diabetes Prevention Program
M3 - Doctoral Thesis (compilation)
SN - 978-91-7619-258-0
PB - Lund University: Faculty of Medicine
CY - Lund
ER -