Genome-wide transcriptome analysis reveals sex-specific biological differences in the early phase of an acute...

Clinical outcomes of acute myocardial infarction (AMI) are known to vary between females and males; however, the nature of this sex dimorphism remains controversial. Most AMI transcriptomic studies have not considered differences between females and males, and combined sexes in their analysis to increase sample size and gain power (canonical approach). Our objective was to (1) use a sex-specific differentially expressed gene meta-analysis (ss-DEGma) in blood and (2) identify sex-specific pathways related to the early phase of AMI.

Gene expression data (7 sets) for sex-combined (canonical) and sex-specific analysis (ss-DEGma) were obtained from the publicly-available GEO database. Datasets from whole blood and peripheral blood cells sampled within 3 days post-AMI were analyzed using GEO2R. The massiR tool identified sex in 72% of samples. The top-ranking DEGs were used to identify significant sex-specific biological pathways in the KEGG database (FDR <0.05).

We performed this meta-analysis in 291 women and 452 men and > 20,000 genes (see Table for identified DEGs). Sex-combined DEGs yielded 100 significant KEGG pathways. Sex-specific DEGs yielded 8/61 (13%) additional new pathways not identified by the sex-combined analysis. Sex-combined pathways were predominantly immunological (35%), while male- and female-specific pathways were 43% and 18% immunological, respectively. Proliferative and metabolic pathways were the next most represented pathways in females, which were not present in males at all.

We present 8 new sex-specific AMI-related transcriptional pathways not identified in the canonical sex-combined analysis. Furthermore, we find that 53% of pathways identified in the canonical sex-combined analysis are not shared between sexes. This data underscores an urgent need for prospective sex-specific transcriptomic analysis to define the sex-specific biological difference post-AMI.