INTERACTIONS BETWEEN BIOLOGICAL SEX AND THE X-LINKED VARIANT IRAK1 HAPLOTYPE IN MODULATING CLINICAL OUTCOME AND CELLULAR PHENOTYPES AFTER TRAUMA.

Sex-related outcome differences in trauma remain controversial. The mechanisms causing sex-biased outcomes are likely to have hormonal and genetic components, in which X-linked genetic polymorphisms may play distinct roles because of X-linked inheritance, hemizygosity in males, and X chromosome mosaicism in females. The study aimed to elucidate the contribution of biological sex and the common X-linked IRAK1 haplotype to posttrauma clinical complications, inflammatory cytokine and chemokine production, and polymorphonuclear cell and monocyte activation. Postinjury clinical outcome was tested in 1507 trauma patients (1,110 males, 397 females) after stratification by sex or the variant IRAK1 haplotype. Males showed a three- to fivefold greater frequency of posttrauma sepsis, but similar mortality compared to females. Stratification by the variant IRAK1 haplotype revealed increased pneumonia and urinary tract infection in Wild type (WT) versus variant IRAK1 males, whereas increased respiratory failures in variant versus WT females. Cytokine/chemokine profiles were tested in whole blood from a subset of patients (n = 81) and healthy controls (n = 51), which indicated sex-related differences in ex vivo lipopolysaccharide responsiveness manifesting in a 1.5- to 2-fold increased production rate of tumor necrosis factor α, interleukin-1β (IL-1β), IL-10, Macrophage Inflammatory Protein-1 Alpha, and MIP1β in WT male compared to WT female trauma patients. Variant IRAK1 decreased IL-6, IL-8, and interferon gamma-induced protein 10 production in male trauma subjects compared to WT, whereas cytokine/chemokine responses were similar in variant IRAK1 and WT female trauma subjects. Trauma-induced and lipopolysaccharide-stimulated polymorphonuclear cell and monocyte activation determined by using a set of cluster of differentiation markers and flow cytometry were not influenced by sex or variant IRAK1. These findings suggest that variant IRAK1 is a potential contributor to sex-based outcome differences, but its immunomodulatory impacts are modulated by biological sex.