The circulating lipidome is largely defined by sex descriptors in the GOLDN, GeneBank and the ADNI studies

Abstract

Biological sex is one of the major anthropometric factors which influences 21 physiology, metabolism and health status. We have investigated the effect of sexual 22 dimorphism on the blood lipidome profile in three large population level studies -the 23 Alzheimer's disease neuroimaging initiative -ADNI (n =806), the GeneBank 24 Functional Cardio-Metabolomics cohort (n= 1015) and the Genetics of Lipid lowering 25Drugs and Diet Network -GOLDN (n=422). In total, 355 unique lipids from 15 lipid 26 classes were detected across all three studies using LC-MS. Sixty percent of these 27 lipids differed between men and women in all three cohorts, and up to 87% of all 28 lipids demonstrated sex differences in at least one cohort. ChemRICH enrichment 29 statistics on lipid classes showed that phosphatidylcholines, 30 phosphatidylethanolamines, phosphatidylinositols, ceramides, sphingomyelins and 31 cholesterol esters were found at higher levels in female subjects while 32 triacylglycerols and lysophosphatidylcholines were found at higher levels in male 33 participants across the three cohorts. This strong sex effect on the blood lipidome 34suggests that specific regulatory mechanisms may exist that regulate lipid 35 metabolism in a different manner between men and women. Cohort studies involving 36 blood lipidomics should consider separate analyses for male and female participants 37 instead of combined analyses treating sex as a confounding factor. 38 39 phospholipids, triacylglycerol 40 41 Introduction 42Differences between the sexes are one of the fundamental variations in biology [1]. 43Sex disparities in research can ignore discoveries of the biological mechanisms that 44 are specific to particular sex, leading to missing opportunities in developing new sex-45 specific therapeutic strategies[2]. Sex differences have been observed for gut 46 microbiota[3] and transcriptome [4], suggesting that sex-specific strategies for health 47 improvement are needed. 48Metabolomics has been validated for molecular epidemiology to discover risk factors 49 and biological mechanisms for diseases. Several epidemiological studies have 50 investigated biological sex as a main factor to define a person's metabolome. 51Differential network analysis of metabolomics data for 844 healthy subjects 52 suggested a sex-related variability in branched chain amino acids, ketone bodies, All lipid classes were found to be significantly different between men and women in 131 at least one cohort. The most drastic effects were observed for sphingomyelins, 132 triacylglycerol and phosphatidylcholines in the GOLDN and the GeneBank cohorts. 133Triacylglycerols and lysophosphatidylcholines were consistently higher in men 134 across the three cohorts. Ceramides were higher in men in the GOLDN study but 135 not in the ADNI cohort.

Exploration of Blood Lipoprotein and Lipid Fraction Profiles in Healthy Subjects through Integrated Univariate, Multivariate, and Network Analysis Reveals Association of Lipase Activity and Cholesterol Esterification with Sex and Age

“…Variations in the blood lipid profiles are associated not only with particular pathophysiological statuses but also with sex and age: women tend to have higher levels of triglyceride VLDL than men [ 12 ], whereas men have higher total triglycerides and cholesterol levels [ 13 ], and the overall concentration of VLDL in men increases with age, while it decreases in women [ 5 ].…”

Sexual Dimorphism of the Mouse Plasma Metabolome Is Associated with Phenotypes of 30 Gene Knockout Lines

“…On the other hand, though sexual dimorphism was also observed in many human healthy cohort studies, the sex effect on metabolism can differ greatly between humans and mice as well as between different human cohorts [ 49 , 50 , 91 , 92 , 93 ]. Sexual dimorphism is expected to be different between species.…”

Changes in lipidomic profile by anti-retroviral treatment regimen

“…Lipidomic assays were conducted at the West Coast Metabolomics Center (WCMC). The methods of lipid extraction have been described elsewhere [37,38] . In brief, a minimum of 400 μL aliquots of plasma were sent to WCMC.…”

“…For the current evaluation, pre and post first ART (i.e., treatment-naive) plasma samples for The methods of lipid extraction have been described elsewhere. [37,38] In brief, a minimum of 400 mL aliquots of plasma were sent to WCMC. Samples were thawed on ice and added to 225 mL of cold methanol, mixed, and shaken for 10 s. Subsequently, 750 mL of methyl tert-butyl ether (MTBE) was added with 10 minutes of continuous shaking.…”