Chapter 4 TLR2, TLR4, and TLR9 haplotypes in the susceptibility to and severity of Chlamydia trachomatis infections in Dutch women

Chlamydia trachomatis (Ct) infections have remarkable interindividual differences in the clinical course which are for 40% based on host genetic variation including genes encoding immunoregulatory and bacteria sensing proteins. As patient-related immunomodulating factors, toll-like receptors (TLRs) are closely involved in pathogen recognition and host defence in Ct infections. Here we study the single nucleotide polymorphisms (SNPs) and their haplotypes in TLR2, in relation to the susceptibility to, and severity of Ct infections. We hypothesise that infection is a complex entity of multifactorial traits in which multiple genes are involved. Therefore, we performed multigen analyses. We analyzed the 5 SNPs in a cohort of 770 Dutch Caucasian women with sexually transmitted diseases (n: 731) or tubal pathology (n: 39). We identified a trend showing a protective effect for TLR9-1237 CC in Ct-positive patients (p: 0.056, OR: 0.14, 95%CI: 0.02 – 1.12). Haplotype analyses show a trend for TLR2 haplotype I (-16934 T/ +2477 G) in the protection against the development of symptoms and tubal pathology (P trend : 0.03) after Chlamydia infection. In the susceptibility cohort, TLR9 haplotype III (-1237 C / +2848 A) shows a decreasing significant trend in the development of symptoms after CT infection (p: 0.02, OR: 0.55, 95%CI: 0.33-0.91). Logistic regression of the TLR2 haplotypes, TLR4 +896 A>G, and TLR9 haplotypes shows that the TLR2 haplotype combinations AG-TA and AG-TG confer risk (OR 3.4 (p: 0,01) and OR 1.6 (p: 0,03), while the TLR9 haplotype combination TG-TA protects against CT infections (OR: 0.4, p: 0.004)). Our study shows that both TLR2 and TLR9 genes and combinations do influence the clinical course of Chlamydia infections. TLR2, TLR4, and TLR9 haplotypes in Chlamydia trachomatis infections 111 Author summary Chlamydia trachomatis (Ct) infections are the most prevalent bacterial STD know remarkable interindividual differences in the clinical course, which are for 40% based on host genetic variation including in genes encoding immune regulatory and bacteria sensing proteins. As patient-related immunomodulating factors, toll like receptors (TLRs) are closely involved in pathogen recognition and host defence in Ct infections. Here we study genetic variations of the TLR2, TLR4, and TLR9 genes in relation to the susceptibility to, and severity of Ct infections. We also hypothesise that infection is a complex entity of multifactorial traits in which multiple genes are involved. We analyzed women with or without Chlamydia infection, and women with or without tubal pathology. Our results show that genetic variation in TLR9 …