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1Laboratory of Immunogenetics, VU University Medical Center, Amsterdam; 2Department of Medical Microbiology, Academic Hospital Maastricht, The Netherlands
To the EditorRecently, in the first genetic epidemiological study of the Toll-like receptor 4 (TLR4) in gram-negative infections, Read et al. [1] reported that a functional polymorphism, Asp299Gly, in the TLR4 gene is not associated with the likelihood or severity of meningococcal disease. Chlamydia trachomatis, which, like meningococcal disease, is a natural gram-negative infection, is the most prevalent sexually transmitted infection and is associated with severe complications in women with tubal infertility. Different C. trachomatis strains, called "serovars," are not clearly associated with upper-genital-tract progression [2, 3]. It is likely that other potential bacterial and host genetic factors play an important role in the susceptibility of C. trachomatis infection and, subsequently, in the development of tubal infertility. To further assess the role that the Asp299Gly polymorphism in the TLR4 gene plays in human gram-negative infections, we investigated its relation with C. trachomatis infection and tubal infertility.
In 1992, a prospective study was initiated among 240 white Dutch subfertile women (ages 1940 years). All underwent laparoscopy to assess the presence of tubal pathology [4]. C. trachomatis IgG antibody titers were determined by microimmunofluorescence, as described elsewhere [4]. All 48 women with positive IgG antibodies were included in the study. Of the 240 women studied, 35 had tubal pathology (and therefore were considered to be case patients) and 49 had no tubal pathology (and therefore were considered to be control subjects).
The functional AG missense mutation at 896 bp, Asp299Gly, in the human TLR4 gene was identified, as described elsewhere [5]. The TLR4 gene is a potentially interesting candidate for study in C. trachomatis infections, because signaling through TLR4 is activated by both lipopolysaccharide and heat-shock protein 60, of both mammalian and microbial origin [6]. This, in turn, may contribute to the development of autoimmune reactions to C. trachomatis infections in the tubae. Surprisingly, not only the study presented by Read et al. [1], concerning the likelihood and severity of meningococcal disease, but also our study, of C. trachomatis and tubal infertility (), did not result in an over- or underrepresentation, among case patients and control subjects, of the functional polymorphism of the TLR4 gene (P > .5). No statistical differences were observed between our allele frequencies and those reported by Read et al. [1]. Furthermore, the allelic frequency of the Asp299Gly polymorphism in the TLR4 gene did not differ from that in a control population in The Netherlands (authors' unpublished data). Our results support the hypothesis that the functional polymorphism in the gene encoding TLR4 function may not be a rate-limiting component for containment, by the human innate immune system, of natural gram-negative infection (due to extra- and/or intracellular pathogens). Additional information is available at the Web site of the Laboratory of Immunogenetics ().
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Table 1. Genotype and allele frequencies of the Asp299Gly polymorphism in the TLR4 gene, in Chlamydia trachomatis IgG-positive white Dutch women with (case patients) or without (control subjects) tubal pathology.
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