Racial Variation in Toll-like Receptor Variants Among Women With Pelvic Inflammatory Disease

Pelvic inflammatory disease (PID), the infection and inflammation of the female upper genital tract, is a condition that can lead to infertility, chronic pelvic pain, and ectopic pregnancy [1]. Microbes such as Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, and aerobes and anaerobes commonly associated with bacterial vaginosis (BV) have been implicated in the etiology of PID [2]. Race is a risk factor for PID, as well as chlamydia, gonorrhea, and BV [3–6]. Racial disparities exist in other inflammatory diseases including preterm birth, systemic lupus erythematosus, and cardiovascular disease [7–9]. The reasons for these racial differences are not completely understood. Socioeconomic, behavioral, and psychosocial factors only explain some of the racial disparities [10, 11]. Studies have found that African Americans are more likely to carry alleles that upregulate proinflammatory cytokines including interleukin 6, interleukin 1, and tumor necrosis factor (TNF) [12–14]. This may result in an imbalanced immune response, leading to excessive and harmful inflammation. As African Americans are at increased risk for inflammatory diseases, genetic variations that lead to increased inflammatory responses in the presence of infectious agents may also be more frequent in this group. The innate immune system relies on pattern recognition receptors (PRRs) for microbial recognition. Toll-like receptors (TLRs) are a family of PRRs that are essential for microbial elimination through the induction of inflammatory cytokine and chemokine genes [15]. The adaptor molecules Toll/interleukin-1 receptor domain–containing adaptor protein (TIRAP) and myeloid differentiation primary response protein 88 (MyD88) help to mediate TLR signaling. Examination of human tissues for expression of TLRs has revealed messenger RNA for TLRs 1–9 in uterine epithelium [16]. TLR2 is highly expressed in fallopian tubes and the cervix [17], whereas TLR4 is weakly expressed in fallopian tubes [17], and transcripts of TLR4 and its adaptor MD-2 are not detected in human cervical epithelial cells [18]. TLR2 forms homodimers with itself or heterodimers with TLR1 or TLR6 to bind pathogen ligands, whereas TLR4 requires the adaptor protein MD-2. TLR2 and TLR4 can recognize several bacteria associated with PID, including C. trachomatis, N. gonorrhoeae, and M. genitalium [18–20]. Although TLRs play a critical role in cytokine expression, few studies have examined racial differences in functional TLR polymorphisms. Barreiro et al suggests that variants in TLR genes may result in differential contributions to disease outcomes following infection in different populations [21]. For example, after examining the evolution of TLRs and their contribution to host defense, the authors found that Europeans had a diminished TLR2:TLR1-mediated immune response reducing inflammation. Thus, the authors concluded that those who carry certain alleles may avoid excessive inflammation, possibly inferring a selective advantage [21]. We have previously found that TLR1 variants are associated with C. trachomatis, upper genital tract infection, and reduced pregnancy rates among African American women with PID [22]. As racial disparities in reproductive and infectious diseases exist and TLR genes are involved in immunopathology, our objective was to determine the racial differences in the genotypic distribution of functional TLR variants among women with clinically suspected PID. We hypothesized that African American women would be more likely to carry TLR variants that are reported to increase inflammatory responses compared to white women. In addition, we examined the associations between race, TLR single-nucleotide polymorphisms (SNPs), and upper genital tract infection and inflammation.