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. 2012;7(12):e51504.
doi: 10.1371/journal.pone.0051504. Epub 2012 Dec 12.

Molecular sex differences in human serum

Jordan M Ramsey  1 , Emanuel Schwarz, Paul C Guest, Nico J M van Beveren, F Markus Leweke, Matthias Rothermundt, Bernhard Bogerts, Johann Steiner, Liliana Ruta, Simon Baron-Cohen, Sabine Bahn
Affiliations

Molecular sex differences in human serum

Jordan M Ramsey et al. PLoS One. 2012.

Abstract

Background: Sex 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 findings: Using 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/significance: Sex-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.

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Conflict of interest statement

Competing Interests: ES, PCG and SB are consultants for Myriad Genetics Inc. The other authors have no potential conflict of interest.

Figures

Figure 1
Figure 1. PCA plots showing individual molecules.
A) Assignment of analyte clusters to biological functions; B) Sex differences as determined by meta-analysis. Colouring indicates significance (q<0.05). The grey area indicates analytes that show no significant sex differences. Plots were generated using data from cohort 7, in which 167 analytes were measured in 162 typical controls (81 females, 81 males).
Figure 2
Figure 2. Sex differences of composite variables summarizing analyte clusters.
Values for typical individuals were pooled across nine cohorts; values for Asperger syndrome participants were calculated from cohort 10. The x-axis shows the difference between composite values that reflect the average molecular levels in males and females. Horizontal bars indicate 95% confidence intervals of the difference between sexes.
Figure 3
Figure 3. Sex-specific effects in networks for Asperger syndrome.
Top networks of the cluster of molecules associated with energy production, fatty acid metabolism, and hormone levels from Ingenuity Pathway Knowledgebase software. Individual molecules are coloured according to significant sex difference in controls. Molecules with significant sex-disease interactions from are circled. A2M (alpha 2 macroglobulin), ADIPOQ (adiponectin), RAGE (receptor for advanced glycosylation end products), ANGPT2 (angiopoietin 2), ARNT (aryl hydrocarbon receptor nuclear translocator), CRP (C-reactive protein), ENA-78 (epithelial derived neutrophil activating protein 78), EDNRB (endothelin receptor type B), EPO (erythropoietin), ERK (extracellular-signal-regulated kinase), FCER1A (Fc fragment of IgE, high affinity I, receptor for alpha polypeptide), GAB1 (GRB2-associated binding protein 1), GCLC (glutamate-cysteine ligase, catalytic subunit), IL17F (interleukin-17F), Jnk (c-Jun N-terminal kinase), SCF (stem cell factor), LEP (leptin), LHB (luteinizing hormone beta polypeptide), Mapk (mitogen-activated protein kinase), NFkB (complex) (nuclear factor of kappa light polypeptide gene enhancer in B-cells), NOX3 (NADPH oxidase 3), P38 MAPK (P38 mitogen-activated protein kinase), PRKAA1 (protein kinase, AMP-activated, alpha 1 catalytic subunit), PRKAA2 (protein kinase, AMP-activated, alpha 2 catalytic subunit), PSMD4 (proteasome (prosome, macropain) 26S subunit, non-ATPase, 4), SMPD2 (sphingomyelin phosphodiesterase 2, neutral membrane (neutral sphingomyelinase)), TFF3 (trefoil factor 3), AGT (angiotensinogen), APOA1 (apolipoprotein AI), COL18A1 (collagen, type XVIII, alpha 1), CXCL11 (chemokine (C-X-C motif) ligand 11), BLC (B lymphocyte chemoattractant), MIG (monokine induced by gamma interferon), Fcgr2 (Fc gamma R2), FDX1 (ferredoxin 1), FDXR (ferredoxin reductase), FSH (follicle stimulation hormone), GCLC (glutamate-cysteine ligase, catalytic subunit), GH (growth hormone), GHR (growth hormone receptor), SGOT (serum glutamic oxaloacetic transaminase), KIM-1 (kidney injury molecule 1), HSD3B2 (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2), IL6 (interleukin-6), ITK (IL2-inducible T-cell kinase), LDLR (low density lipoprotein receptor), LPL (lipoprotein lipase), LSS (lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase)), MSMO1 (methylsterol monooxygenase 1), NLRP12 (NLR family, pyrin domain containing 12), NPPB (brain natriuretic peptide), NR1H4 (nuclear receptor subfamily 1, group H, member 4), OSMR (oncostatin M receptor), PI3K (complex) (phosphoinositide-3-kinase), SCARB1 (scavenger receptor class B, member 1), TBG (thyroxine binding globulin), SST (somatostatin), Stat5a/b (signal transducer and activator of transcription a/b), TCR (T-cell receptor), TNF-alpha (tumor necrosis factor-alpha), TNFRSF11B (tumor necrosis factor receptor superfamily, member 11b), VWF (von Willebrand factor).
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