Abstract
BackgroundSex is an important factor in the prevalence, incidence, progression, and response to treatment of many medical conditions, including autoimmune and cardiovascular diseases and psychiatric conditions. Identification of molecular differences between typical males and females can provide a valuable basis for exploring conditions differentially affected by sex.Methodology/Principal FindingsUsing multiplexed immunoassays, we analyzed 174 serum molecules in 9 independent cohorts of typical individuals, comprising 196 males and 196 females. Sex differences in analyte levels were quantified using a meta-analysis approach and put into biological context using k-means to generate clusters of analytes with distinct biological functions. Natural sex differences were established in these analyte groups and these were applied to illustrate sexually dimorphic analyte expression in a cohort of 22 males and 22 females with Asperger syndrome. Reproducible sex differences were found in the levels of 77 analytes in serum of typical controls, and these comprised clusters of molecules enriched with distinct biological functions. Analytes involved in fatty acid oxidation/hormone regulation, immune cell growth and activation, and cell death were found at higher levels in females, and analytes involved in immune cell chemotaxis and other indistinct functions were higher in males. Comparison of these naturally occurring sex differences against a cohort of people with Asperger syndrome indicated that a cluster of analytes that had functions related to fatty acid oxidation/hormone regulation was associated with sex and the occurrence of this condition.Conclusions/SignificanceSex-specific molecular differences were detected in serum of typical controls and these were reproducible across independent cohorts. This study extends current knowledge of sex differences in biological functions involved in metabolism and immune function. Deviations from typical sex differences were found in a cluster of molecules in Asperger syndrome. These findings illustrate the importance of investigating the influence of sex on medical conditions.
Highlights
Sexual dimorphism in underlying processes in medical conditions are numerous and diverse, occurring in diseases ranging from autoimmune and cardiovascular conditions to neurological conditions [1,2,3]
Though females generally show higher production of cytokines upon infection, we found that analytes related to immune cell chemotaxis and cell signalling were present at higher levels in males
To evaluate sex dimorphisms deviating from the variation seen in normal controls, we investigated a cohort of participants with Asperger syndrome, which is characterised by a pronounced sex difference in incidence
Summary
Sexual dimorphism in underlying processes in medical conditions are numerous and diverse, occurring in diseases ranging from autoimmune and cardiovascular conditions to neurological conditions [1,2,3]. Parameters such as disease prevalence, incidence, age at onset, progression, mortality, and treatment response can show sex differences [4]. The key to some of these differences may be in sex-dependent regulation of biological pathways Such differences have been investigated in the context of immune response, and elevated immune activation in females has been linked to the significantly increased susceptibility of women to multiple sclerosis (MS) and other autoimmune diseases such as rheumatoid arthritis, Grave’s disease, and lupus erythematosus [1]. Identification of molecular differences between typical males and females can provide a valuable basis for exploring conditions differentially affected by sex
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