Investigations of novel subtypes of high-density lipoprotein in relation to cardiometabolic traits, lifestyle factors, and cardiovascular disease in three US-based cohorts
Nutritional Sciences
Public Health, Healthcare Research, Social and Occupational Medicine
Final Report Abstract
Ample evidence from observational studies indicates that high HDL levels strongly associate with a lower risk of cardiovascular disease (CVD). However, approaches to increase HDL cholesterol (HDL-C) alone do not reduce CVD risk. HDL is increasingly recognized as a herterogeneous group of particles varying in protein composition, structure, and functional properties. To provide further insight into the cardiometabolic propertied of HDL subspecies defined by the presence or absence of coexisting lipoproteins, we examined novel HDL subspecies in relation to cardiometabolic traits, modifiable lifestyle factors and the risk for incident coronary heart disease (CHD). As apolipoproteins are intimately involved in Alzheimer’s disease (AD), the most common form of dementia, we explored novel HDL subspecies in relation to Alzheimer’s pathology. In 3,631 participants of the Diet Cancer and Health study free of CHD, greater adiposity and less physical activity were associated with higher HDL containing apolipoprotein CIII (apoCIII) and lower HDL lacking apoCIII. Adherence to the Mediterranean dietary pattern and smoking were unrelated to the HDL subspecies. HDL with and without apoCIII was differentially associated with liver fat content in 5,009 participants of the Multi-Ethnic Study of Atherosclerosis without heavy alcohol consumption. Participants with higher levels of HDL without apoCIII had lower liver fat content. In contrast, no association was observed for HDL with apoCIII. Among 4,659 participants of the Multi-Ethnic Study of Atherosclerosis with noninvasive imaging measures of atherosclerosis, HDL with and without apoCIII were divergently associated with carotid plaque score, intima-media thickness, and coronary artery calcification. Together, these results suggest that adiposity and sedentary lifestyle are associated with a less favourable HDL subspecies profile. The findings support the existence of distinct apoCIII- defined HDL subspecies with respect to cardiometabolic disease risk. In a case-cohort study nested within the Danish Diet, Cancer and Health study including 1,750 participants selected randomly at baseline and 1,949 incident CHD cases during a mean follow up of 9 years, the concentration of apoE in unfractionated HDL was unrelated to CHD risk. In contrast, the concentration of apoE in HDL lacking apoCIII was inversely associated with CHD risk. The concentration of apoE in HDL that also contains apoCIII was not statistically significantly related to CHD risk. In summary, higher apoE in HDL showed cardioprotective associations only in the absence of apoC-III. The results point to the importance of considering heterogeneity of types of HDL rather than focusing on overall HDL-cholesterol concentration for CHD risk prediction. Our findings that CSF levels of some apolipoproteins implicated in the pathophysiology of dementia might be better approximated by specific plasma apolipoprotein subspecies than total plasma concentrations supported the significance of studying apolipoprotein subspeciation in plasma in relation to brain structure and function. In 176 participants of the Ginkgo Evaluation of Memory Study who were free of clinical dementia, higher total apoE was associated with lower ß-amyloid deposition on Pittsburgh compound B PET scans. Associations were of similar magnitude for apoE found in the HDL fraction of plasma only and for subspecies of apoE containing or lacking apoJ or apoC-III, and the subspecies of apoA-I containing apoE. Despite apoA-I being unrelated to hippocampal volume, subspecies of apoA-I containing or lacking apoJ and/or apoC-III showed opposite associations with hippocampal volume. ApoJ was also related to higher hippocampal volume. Higher concentrations of apoE lacking apoJ were associated with higher white matter lesion volume. In summary, these results demonstrate that HDL subspecies as defined by their specific protein cargo may be important minimally invasive biomarkers indicative of Alzheimer’s pathology CHD risk.
Publications
- (2018) Apolipoproteins E and CIII interact to regulate HDL metabolism and coronary heart disease risk. JCI insight 3 (4)
Morton, Allyson M.; Koch, Manja; Mendivil, Carlos O.; Furtado, Jeremy D.; Tjønneland, Anne; Overvad, Kim; Wang, Liyun; Jensen, Majken K.; Sacks, Frank M.
(See online at https://doi.org/10.1172/jci.insight.98045) - HDL-cholesterol and apolipoproteins in relation to dementia. Curr Opin Lipidol. 2016;27(1):76-87
Koch M, Jensen MK
(See online at https://doi.org/10.1097/MOL.0000000000000257) - Apolipoproteins and their subspecies in human cerebrospinal fluid and plasma. Alzheimers Dement (Amst). 2017;6:182-187
Koch M, Furtado JD, Falk K, Leypoldt F, Mukamal KJ, Jensen MK
(See online at https://doi.org/10.1016/j.dadm.2017.01.007) - Associations of anthropometry and lifestyle factors with HDL subspecies according to apolipoprotein C-III. J Lipid Res. 2017;58(6):1196-1203
Koch M, Furtado JD, Jiang GZ, Gray BE, Cai T, Sacks F, Tjønneland A, Overvad K, Jensen MK
(See online at https://doi.org/10.1194/jlr.P073288)
