Lipidomic architecture shared by subclinical markers of osteoporosis and atherosclerosis: The Cardiovascular Risk in Young Finns Study.

Abstract

Studies have shown that osteoporosis and atherosclerosis are comorbid conditions sharing common risk factors and pathophysiological mechanisms. Understanding these is crucial in order to develop shared methods for risk stratification, prevention, diagnosis and treatment. The aim of this study was to apply a system-level bioinformatics approach to lipidome-wide data in order to pinpoint the lipidomic architecture jointly associated with surrogate markers of these complex comorbid diseases. The study was based on the Cardiovascular Risk in Young Finns Study cohort from the 2007 follow-up (n=1494, aged 30-45years, women: 57%). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyse the serum lipidome, involving 437 molecular lipid species. The subclinical osteoporotic markers included indices of bone mineral density and content, measured using peripheral quantitative computer tomography from the distal and shaft sites of both the tibia and the radius. The subclinical atherosclerotic markers included carotid and bulbus intima media thickness measured with high-resolution ultrasound. Weighted co-expression network analysis was performed to identify networks of densely interconnected lipid species (i.e. lipid modules) associated with subclinical markers of both osteoporosis and atherosclerosis. The levels of lipid species (lipid profiles) of each of the lipid modules were summarized by the first principal component termed as module eigenlipid. Then, Pearson's correlation (r) was calculated between the module eigenlipids and the markers. Lipid modules that were significantly and jointly correlated with subclinical markers of both osteoporosis and atherosclerosis were considered to be related to the comorbidities. The hypothesis that the eigenlipids and profiles of the constituent lipid species in the modules have joint effects on the markers was tested with multivariate analysis of variance (MANOVA). Among twelve studied molecular lipid modules, we identified one module with 105 lipid species significantly and jointly associated with both subclinical markers of both osteoporosis (r=0.24, p-value=2×10-20) and atherosclerosis (r=0.16, p-value=2×10-10). The majority of the lipid species in this module belonged to the glycerolipid (n=60), glycerophospholipid (n=13) and sphingolipid (n=29) classes. The module was also enriched with ceramides (n=20), confirming their significance in cardiovascular outcomes and suggesting their joint role in the comorbidities. The top three of the 37 statistically significant (adjusted p-value<0.05) lipid species jointly associated with subclinical markers of both osteoporosis and atherosclerosis within the module were all triacylglycerols (TAGs) - TAG(18:0/18:0/18:1) with an adjusted p-value of 8.6×10-8, TAG(18:0/18:1/18:1) with an adjusted p-value of 3.7×10-6, and TAG(16:0/18:0/18:1) with an adjusted p-value of 8.5×10-6. This study identified a novel lipid module associated with both surrogate markers of both subclinical osteoporosis and subclinical atherosclerosis. Alterations in the metabolism of the identified lipid module and, more specifically, the TAG related molecular lipids within the module may provide potential new biomarkers for testing the comorbidities, opening avenues for the emergence of dual-purpose prevention measures.