Abstract
Objective: Approximately 5% of women suffer from recurrent vulvovaginal candidiasis (RVVC). It has been hypothesized that genetic factors play an important role in the susceptibility to RVVC. The aim of this study was to assess the effect of genetic variants of genes encoding for pattern recognition receptors (PRRs) on susceptibility to RVVC.Study design: For the study, 119 RVVC patients and 263 healthy controls were recruited. Prevalence of polymorphisms in five PRRs involved in recognition of Candida were investigated in patients and controls. In silico and functional studies were performed to assess their functional effects.Results: Single nucleotide polymorphisms (SNPs) in TLR1, TLR4, CLEC7A, and CARD9 did not affect the susceptibility to RVVC. In contrast, a non-synonymous polymorphism in TLR2 (rs5743704, Pro631His) increased the susceptibility to RVVC almost 3-fold. Furthermore, the TLR2 rs5743704 SNP had deleterious effects on protein function as assessed by in silico analysis, and in vitro functional assays suggested that it reduces production of IL-17 and IFNγ upon stimulation of peripheral blood mononuclear cells with Candida albicans. No effects were observed on serum mannose-binding lectin concentrations.Condensation: This study demonstrates the association of susceptibility to RVVC with genetic variation in TLR2, most likely caused by decreased induction of mucosal antifungal host defense.Conclusion: Genetic variation in TLR2 may significantly enhance susceptibility to RVVC by modulating host defense mechanisms against Candida. Additional studies are warranted to assess systematically the role of host genetic variation for susceptibility to RVVC.
Highlights
Candida microorganisms, especially Candida albicans, often colonize the genital tract in women, and under certain conditions are responsible for mucosal inflammation (Hurley, 1977; Fleury, 1981; Odds, 1988; Fidel and Sobel, 1996; Giraldo et al, 2000; Sobel, 2007)
Single nucleotide polymorphisms (SNPs) in TLR1, TLR4, CLEC7A, and CARD9 did not affect the susceptibility to recurrent vulvovaginal candidiasis (RVVC)
The TLR2 rs5743704 SNP had deleterious effects on protein function as assessed by in silico analysis, and in vitro functional assays suggested that it reduces production of IL-17 and IFNγ upon stimulation of peripheral blood mononuclear cells with Candida albicans
Summary
Especially Candida albicans, often colonize the genital tract in women, and under certain conditions are responsible for mucosal inflammation (Hurley, 1977; Fleury, 1981; Odds, 1988; Fidel and Sobel, 1996; Giraldo et al, 2000; Sobel, 2007). Most women have at least one event of VVC in their lifetime, while up to 5–8% suffer from recurrent vulvovaginal candidiasis (RVVC), defined as at least three infections per year (Hurley, 1977; Sobel, 2007). The vast majority of RVVC patients are healthy women without any identifiable predisposing or episode precipitating factors (Morton, 1977; Sobel, 1985,1993; Kent, 1991; Mardh et al, 2002). No distinct C. albicans strains, the species that causes more that 90% of the VVC episodes, have been described in RVVC patients, arguing against microbiological factors as the major determinants of VVC or susceptibility to recurrent disease (Kent, 1991; Sobel, 1993).
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