Whole-Exome Sequencing to Identify Novel Biological Pathways Associated With Infertility After Pelvic Inflammatory Disease

Abstract

Background Ideal management of sexually transmitted infections (STI) may require risk markers for pathology or vaccine development. Previously, we identified common genetic variants associated with chlamydial pelvic inflammatory disease (PID) and reduced fecundity. As this explains only a proportion of the long-term morbidity risk, we utilized whole-exome sequencing to identify biological pathways that may be associated with STI-related infertility. Methods We obtained stored DNA from 43 non-Hispanic black women with PID from the PID Evaluation and Clinical Health Study. Infertility was assessed at a mean of 84 months. Principal component analysis revealed no population stratification. Potential covariates did not significantly differ between groups. Sequencing kernel association test (SKAT) was used to examine associations between aggregates of variants on a single gene and infertility. The results from the SKAT test were used to choose “focus genes” (p-value <0.01; n=150) for subsequent Ingenuity Pathway Analysis (IPA) to identify “gene sets” that are enriched in biologically relevant pathways. Results Pathway analysis revealed that focus genes were enriched in canonical pathways including, Interleukin-1 (IL-1) signaling, P2Y Purinergic Receptor signaling, and Bone Morphogenic Protein (BMP) signaling. Conclusions Focus genes were enriched in pathways that impact innate and adaptive immunity, protein kinase A activity, cellular growth and DNA repair. These may alter host resistance or immunopathology following infection. Targeted sequencing of biological pathways identified in this study may provide insight into STI-related infertility.

Chlamydia trachomatis antigen induces TLR4‐TAB1‐mediated inflammation, but not cell death, in maternal decidua cells

“…Interestingly, an activated TAB1 pathway was recently identified among women with C. trachomatis-induced infertility using wholeexome sequencing and path analyses. 47 TLR4 is also indicated in upper genital tract ascension of C. trachomatis in women with suspected pelvic inflammatory disease. 48 There is a strong scientific premise to suggest that identifying peri-conception contributors to defective C. trachomatis screening is suboptimal in pregnancy, coupled with treatment delays and risk of recurrent/persistent infection; there is a need to improve understanding of chlamydia-induced decidual damage for the development of novel therapies that can be coupled with antibiotic treatment to reduce the burden of disease.…”

“…Interestingly, an activated TAB1 pathway was recently identified among women with C. trachomatis ‐induced infertility using whole‐exome sequencing and path analyses 47 . TLR4 is also indicated in upper genital tract ascension of C. trachomatis in women with suspected pelvic inflammatory disease 48 .…”

National Institute of Allergy and Infectious Diseases workshop report: “Chlamydia vaccines: The way forward”

“…Biomarkers that indicate upper genital tract tissue damage would be useful for trial design and other aspects of Ct vaccine development [8], and may result from insights into the human immune response. Using a Ct whole proteome array [9], humoral immune responses in women were mapped for identifying biomarkers to aid diagnosis of tubal infertility [10,11].…”

Generalized multi‐SNP mediation intersection–union test

“…Repeated infection leads to worse disease. Host genetics shapes susceptibility to chlamydia disease and/or reinfection (Bailey et al ., 2009; Taylor et al ., 2017; Zheng et al ., 2018). DNA biomarkers for susceptibility to ascension or risk of reinfection are critically needed for targeted screening for women at high risk of disease and vaccine development.…”