Metabolomic Profiling of Carotid Intima-Media Thickness in Middle-Aged Males: A Twin Study Público

Abstract

Background: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death worldwide. Carotid intima-media thickness (IMT) is a reliable measurement of subclinical atherosclerosis and predictor of future cardiovascular events. High throughput metabolomic studies possess increased ability to detect changes of metabolic levels and exploring novel associations. This study aims to investigate the association between metabolites in plasma and carotid IMT among middle-aged male twins.

Methods: We performed an untargeted metabolome-wide association study (MWAS) including 12,527 negative ionized features and 7,508 positive ionized features using data from 92 twin pairs and 3 singletons in the Emory Twin Study. Metabolomics data were generated using fasting blood samples, and the relative abundance of metabolites was evaluated using high-performance liquid chromatography–mass spectrometry (HPLC-MS). Carotid IMT was measured using high-resolution B-mode ultrasonography. Other cardiovascular factors were measured at the same time. Mixed effect linear regression models were used to examine within-pair and between-pair effects to explain the unshared environment effects and general association. Metabolic pathway analysis was performed using Mummichog, and metabolic features were annotated via the HMDB database.

Results: According to the MWAS analyze results, among 92 twin pairs and 3 singletons, we did not identify any metabolic feature statistically significantly associated with carotid IMT. Pathway analysis further suggests 17 significant metabolism pathways, where glutathione metabolism is associated with carotid IMT regardless of the twin effects. 2 lipid metabolism pathways, including saturated fatty acids metabolism and arachidonic acid metabolism, were significantly associated between co-twins. The unshared environment effect may contribute to the difference in lipid metabolism level, which further associated with carotid IMT and related cardiovascular events.

Conclusion: No metabolite alone was statistically associated with the changes of carotid IMT in this twin study. Pathway analysis suggests the glutathione metabolism pathway is associated with carotid IMT and potential ASCVD events. The differences in unshared environmental factors between the co-twins may explain the association between lipid metabolism pathways and carotid IMT.

Table of Contents

Background ....................................................................................................................... 1

Methods .............................................................................................................................. 6

Study Population ........................................................................................................... 6

Measurements ................................................................................................................ 6

Metabolomics Measurements ....................................................................................... 7

Metabolome-wide Association Study (MWAS) and Statistical Methods ................. 8

Pathway Analysis and Annotation ............................................................................... 9

Results .............................................................................................................................. 11

Discussion......................................................................................................................... 14

Conclusion ....................................................................................................................... 17

References ........................................................................................................................ 18

Tables and Figures .......................................................................................................... 22

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Subfield / Discipline	Epidemiology - MPH & MSPH
Degree	M.S.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Epidemiology
Palavra-chave	Metabolomics Atherosclerosis Cardiovascular diseases Carotid intima-media thickness Twin study
Committee Chair / Thesis Advisor	Sun, Yan V., Emory University

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