Despite decades of progress in primary prevention and treatment of acute coronary syndromes and strokes, cardiovascular disease (CVD) remains the leading cause of death and loss of disability-adjusted life years in Western countries. In this thesis, we sought to identify risk stratifying factors beyond the traditional measures of body mass index (BMI) and dyslipidemia. In particular, we focused on the role of hepatic steatosis in obesity, and on the family history of patients with hyperlipidemia. We quantified circulating metabolites during an oral glucose tolerance test in BMI-discordant (ΔBMI ≥ 3 kg/m2) monozygotic twin pairs based on the presence of concomitant liver fat discordance. Liver fat -discordant cotwins exhibited greater putatively atherogenic differences in metabolomic parameters across a wide range of molecular classes, including lipoproteins, fatty acids, amino acids and glycoproteins. We also observed several putatively atherogenic differences between liver fat -concordant twin pairs, suggesting that increased BMI without concomitant liver fat accumulation may not be entirely neutral with respect to CVD risk. We performed the first comprehensive genotyping analysis of familial combined hyperlipidemia (FCH), a common familial hyperlipidemia typically characterized by elevations in total cholesterol or triglycerides. We observed rare high-impact variants in the APOE or APOA5 genes in only a few (3%) of hyperlipidemic family members. Almost a third of hyperlipidemic family members had elevated polygenic burden for LDL-C or triglycerides, similar to population samples with comparable lipid levels. Next, we estimated incident CVD risk in an overlapping cohort of hyperlipidemic families. We focused on common familial hyperlipidemias characterized by high LDL cholesterol or triglyceride levels after excluding individuals with monogenic FH. In our study, such familial hyperlipidemias conferred increased coronary artery disease and CVD risk, but the elevation in risk was similar to that observed in population-ascertained hyperlipidemias. Additionally, we observed highly similar lipidomic profiles consisting of 151 circulating lipid species between individuals with familial and population-ascertained hyperlipidemias. Our results add to existing support for hepatic steatosis as a more discerning stratifying CVD risk factor among individuals with increased BMI. Our findings on FCH and familial aggregation of high LDL cholesterol or triglyceride levels suggest that they share similar and overlapping pathophysiology with common population-ascertained hyperlipidemias, and may not confer differential CVD risk.
Original languageEnglish
  • Palotie, Aarno, Supervisor
  • Ripatti, Samuli, Supervisor
  • Pietiläinen, Kirsi, Supervisor
Place of PublicationHelsinki
Print ISBNs978-951-51-5564-1
Electronic ISBNs978-951-51-5565-8
Publication statusPublished - 2019
MoE publication typeG5 Doctoral dissertation (article)

Bibliographical note

M1 - 140 s. + liitteet

Fields of Science

  • Dyslipidemias
  • +genetics
  • +metabolism
  • Liver
  • Adiposity
  • Hyperlipidemia, Familial Combined
  • Hyperlipidemias
  • Atherosclerosis
  • Biomarkers
  • Body Mass Index
  • Cardiovascular Diseases
  • Cholesterol
  • Coronary Artery Disease
  • Lipids
  • Obesity
  • Risk Assessment
  • Risk Factors
  • Triglycerides
  • Twins, Monozygotic
  • 3121 General medicine, internal medicine and other clinical medicine
  • 3111 Biomedicine
  • 1184 Genetics, developmental biology, physiology

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