Abstract

The aim of this review is to present a concise overview of all data available on the immunogenetics of Chlamydia trachomatis infections, both sexually transmitted urogenital and ocular infections. Currently, candidate gene approaches are used to identify genes related to the susceptibility to and severity of C. trachomatis infections. The main focus in the review will be on data obtained by the study of human cohorts.

Introduction

Chlamydia trachomatis infection is the leading cause of blindness (trachoma) and the most prevalent sexually transmitted disease, strongly associated with pelvic inflammatory disease, ectopic pregnancy and tubal infertility. The prevalence of infection is increasing worldwide, with almost 100 million new infections each year (Starnbach & Roan, 2008).

Some striking differences between individuals are observed in the clinical course of infection with C. trachomatis. In the case of sexually transmitted infection with C. trachomatis the following differences are observed.

Transmission vs. no transmission

Not all partners of a C. trachomatis positive index patient are themselves C. trachomatis positive. Transmission of the infection from the index patient to the partner is observed in between 45% and 75%, with lower rates of transmission from asymptomatic individuals (screening population) compared with those attending an STD clinic for symptoms (Lin et al., 1998; van Valkengoed et al., 2002a, b).

Symptomatic vs. asymptomatic course of infection

The registered infections are mainly symptomatic, with people consulting a physician due to clinical symptoms and complaints. However, it is known that C. trachomatis can also run an asymptomatic course of infection in c. 80% of women and 50% of men (Stamm, 1988; Zimmermann et al., 1990).

Persistence vs. clearance of infection

In some people the infection clears spontaneously, whereas in others there is persistent infection for years. Some of the treated infections seem to reappear despite cotreatment of the partners (Weström et al., 1992; Golden et al., 2000, 2005; Morré, 2000, 2002).

Development of late complications (such as tubal infertility) vs. no development of late complications

Chlamydia trachomatis infection can ascend to the upper genital tract, resulting in pelvic inflammatory disease, ectopic pregnancy and tubal infertility. Uncontrolled immune reactions in the tubae are believed to contribute to the disease pathogenesis. Repeated infections are associated with the development of these late complications. However, only some women develop secondary complications after infection (Weström et al., 1992; Morré, 2002; Golden et al., 2005).

Ocular C. trachomatis infection causes inflammatory changes in the conjunctiva, and repeated infections sometimes lead to fibrosis and scarring of the subtarsal conjunctiva. This may cause the upper eyelid margin to turn inwards, causing the lashes to rub against the eyeball (trichiasis), which damages the cornea and leads ultimately to blindness. However, a subgroup of individuals develop more severe and persistent clinical disease in response to infection and are more likely to develop conjunctival scarring and trichiasis in later life. The reasons for this heterogeneity in susceptibility to chlamydial infection and disease progression, following a rather uniform bacterial exposure, remain incompletely understood.

In general these differences in the clinical course of infection can be explained by the interaction between the host (host factors) and the pathogen (virulence factors). This interaction is influenced by environmental factors such as coinfections. Although some studies have shown relationships between C. trachomatis serovars (Morré, 1998, 2000; Molano et al., 2004) and the clinical course of infection (Morré, 2000) and differences in infection variables between serovars have been described (Lyons et al., 2005), at present no clear single bacterial virulence factor has been identified that is related to the aforementioned differences in the clinical course of infection.

If the cellular immune response to C. trachomatis is subject to genetic influences, then the degree and mechanisms of such genetic control may have important implications for understanding the immunopathogenesis of C. trachomatis infection, therapeutic strategies and vaccine development, all of which are necessary to effectively treat and prevent C. trachomatis infection.

Chlamydia twin studies

It is clear that there are major interindividual differences in the susceptibility to and severity of infectious diseases. The best known example is malaria, which is caused by Plasmodium spp. People who are heterozygous for haemoglobin S (HbS) are protected against infection with Plasmodium falciparum, whereas those homozygous mutant for HbS have sickle cell anaemia.

Twin studies have advanced the efforts to identify susceptibility genes to infectious diseases. Comparison of concordance rates in monozygotic and dizygotic twins provides an estimate of the size of the genetic component of susceptibility, and for many infectious diseases this is substantial.

Recently, Bailey (2009) published the most relevant study in the field of Chlamydia Immunogenetics, which was presented at the Ninth International Symposium on Human Chlamydia Infections in Napa, CA, in 1998. They estimated the relative contribution of host genetics to the total variation in lymphoproliferative responses to C. trachomatis antigen by analysing these responses in 64 Gambian pairs of twins from trachoma-endemic areas. Proliferative responses to serovar A EB antigens were estimated in monozygotic and dizygotic twin pairs. They found a stronger correlation and lower within-pair variability in these responses in monozygotic compared with dizygotic twin pairs. The heritability estimate was 0.39, suggesting that host genetic factors contributed almost 40% of the variation.

Candidate gene approaches: single-nucleotide polymorphisms (SNPs)

Candidate gene analyses are conceptually the simplest approach to a complex disease trait like infectious diseases. The selection of genes can be based on mRNA expression studies, protein profiling, animal studies including knock-out models, and data obtained in similar infections (in the case of C. trachomatis, for instance, tuberculosis). In addition, often a logical selection of potential candidate genes is made on the basis of biological knowledge of the infection. For instance, C. trachomatis has lipopolysaccharide in its membrane, and the Toll-like receptor 4 (TLR4) is an lipopolysaccharide-sensing receptor on the outside of antigen-presenting cells and on epithelial cells, making this a potentially relevant candidate gene. As C. trachomatis is also present inside cells, selection of intracellular receptors involved in the recognition of molecular patterns present in C. trachomatis makes sense: for instance, TLR9, which recognizes CpG island in bacteria. Once genes have been selected, SNPs have to be identified, making use of published studies of those genes in other (infectious) diseases and using online databases, including dbSNP, the SNPper site and HapMap. Preferentially, functional SNPs have to be selected: SNPs that have a proven effect on the transcription and/or translation, resulting in higher or lower expressions of mRNAs and protein. The most widely used analysis is whether the frequency of a specific genetic variant is significantly different between diseased individuals and healthy controls (susceptibility analyses). An example is comparing C. trachomatis DNA positive individuals with C. trachomatis-negative individuals, correcting for potential confounding factors. Another possibility is to compare C. trachomatis positive patients with a different course of infection (severity analysis), for example comparing C. trachomatis positive women who develop tubal pathology with those who do not, or patients with an ocular C. trachomatis infection who develop conjunctival scarring and trichiasis in later life, with those who do not. Statistical analyses are often simple, making use of χ2 testing or similar statistical approaches. The most important variables to generate reliable data in these kinds of candidate gene approaches are:

  1. clear ethnic background definition of the population studied, as the incidence of SNP differs between different ethnic populations: for instance, the TLR4+896 A>G SNP occurs in c. 9% of Caucasians, whereas it is nonexistent in people from the orient;

  2. clinical definition of disease: how is C. trachomatis positivity defined, and how are tuba pathology and ocular severity defined? Major differences in C. trachomatis diagnostics are present, as is the case for tubal pathology definition.

Data obtained by candidate gene approaches for C. trachomatis

Pathogen recognition receptors (PRRs)

PRRs are the first line of defence against invading pathogens. These receptors are an integral part of the innate immune system and alterations of their function or expression may affect the immune response.

Several members of the TLR family, CD14, NOD2, CCR5, and MBL, have been studied in relation to C. trachomatis pathogenesis (see Fig. 1 and Tables 1 and 2). TLR4, TLR9, CD14, and NOD2 were not associated with Chlamydia infection or with tubal pathology in single gene analyses; however, women carrying two or more mutations in these genes were at increased risk of developing tubal pathology following Chlamydia infection. Chlamydial lipopolysaccharide is a relatively weak TLR4 stimulus; we have shown, however, that with other TLR SNPs it modifies the risk of developing tubal pathology. This can partly be due to the fact that chlamydial heat-shock protein 60 (HSP60) can also respond to TLR4 and human HSP60, potentially resulting in autoimmune-based tubal pathology, a mechanism described frequently in the literature. This process of TLR stimulation by nonpathogen-derived patterns is called sterile inflammation.

Figure 1

Overview of pathogen recognition receptors associated with Chlamydia trachomatis pathogenesis.

Figure 1

Overview of pathogen recognition receptors associated with Chlamydia trachomatis pathogenesis.

Table 1

Genes used in immunogenetic studies of Chlamydia infections, their biological functions and location in the genome

Gene Biological effect Chromosome 
Pathogen recognition receptors 
TLR4 TLR4, in complex with CD14, has been implicated in signal transduction events induced by lipopolysaccharide found in most Gram-negative bacteria. Mutations in this gene have been associated with differences in lipopolysaccharide responsiveness 9q32–q33 
TLR9 TLR9 mediates cellular response to unmethylated CpG dinucleotides in bacterial DNA to mount an innate immune response. It is localized and acts in an intracellular compartment. CpG DNA induces a strong T-helper-1-like inflammatory response 3p21.3 
CD14 CD14 acts as a coreceptor for TLR4 and TLR2, and confers responsiveness to lipopolysaccharide, a component of the cell wall of most Gram-negative bacteria. CD14 forms a complex with lipopolysaccharide and the lipopolysaccharide-binding protein. Combined with TLR4 this complex induces NFκB associated immune responses including the release of a broad spectrum of cytokines that include TNF-α, IL-1, IL-6, and IL-8 to initiate immune response 5q31.1 
NOD2 NOD2 is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats. The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharide by recognizing the muramyl dipeptide derived from them and activating the NFκB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome 16q12 
CCR5 Potential role for the chemokine receptor in granulocyte lineage proliferation and differentiation. Chemokine receptor CCR5, a principal HIV-1 coreceptor, is post-translationally modified by O-linked glycosylation and by sulfation of its N-terminal tyrosines. Sulfated tyrosines contributed to the binding of CCR5 to MIP-1-α, MIP-1-β, and HIV-1 gp120/CD4 complexes, and to the ability of HIV-1 to enter cells expressing CCR5 and CD4. Mycobacterial HSP70, in addition to enhancing antigen delivery to human dendritic cells, signals through the CCR5 chemokine receptor, promoting dendritic cell aggregation, immune synapse formation between dendritic cells and T cells, and the generation of effector immune responses 3p21 
MBL/MBP This gene encodes the soluble mannose-binding lectin or mannose-binding protein found in serum. The protein encoded belongs to the collectin family and is an important element in the innate immune system. The protein recognizes mannose and N-acetylglucosamine on many microorganisms, and is capable of activating the classical complement pathway. Deficiencies of this gene have been associated with susceptibility to autoimmune and infectious diseases 10q11.2–q21 
Cytokines 
IL-1B IL-1 is involved in a wide variety of physiological processes, including the regulation of inflammatory, metabolic, haematopoietic and immunological mechanisms. It is produced by macrophages, neutrophils and endothelial cells. IL-1B initiates the expression of several genes coding for lymphokines. It induces natural killer (NK) cells and activates T and B cells 2q14 
IL-1RN IL-1RN specifically inhibits IL-1 bioactivity on T cells and endothelial cells in vitro and is a potent inhibitor of IL-1-induced corticosterone production in vivo. IL-1 receptor antagonist levels are elevated in the blood of patients with a variety of infectious, immune and traumatic conditions. IL-1RN is expressed in the human β cell and provides localized protection against leptin- and glucose-induced islet IL-1β 2q14.2 
IL-2 IL-2 is a powerfully immunoregulatory lymphokine that is produced by lectin- or antigen-activated T cells. It is produced not only by mature T lymphocytes on stimulation but also constitutively by certain T cell lymphoma cell lines. It augments NK cell activity. It functions as growth factor for both B and T lymphocytes 4q26–q27 
IL-4 IL-4 is a pleiotropic Th2-derived immune cytokine which is predominantly produced by activated T lymphocytes, mast cells and basophils. IL-4 has been shown to have various activities in many different cell types, such as T cells, B cells, monocytes, endothelial cells and fibroblasts 5q31.1 
IL-4R IL-4 is a cytokine produced by T cells that plays a major role in immunoglobulin E production, and regulates proliferation and differentiation of a variety of cells. It modulates the activity of these cells following binding to its cell surface receptor, IL-4R 16p12.1–p11.2 
IL-6 IL-6 is an immunoregulatory cytokine that activates a cell surface signaling assembly composed of IL-6, IL-6RA (IL-6R), and the shared signaling receptor gp130 (IL-6ST) 7p21 
IL-10 IL-10 is an anti-inflammatory cytokine. It arrests and reverses the (chronic) inflammatory response 1q31–q32 
IL-12B IL-12 is a proinflammatory cytokine. It has a broad range of biological functions, which include sustaining long-term protection against intracellular pathogens 5q31.1–q33.1 
TNF-α TNF-α is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance and cancer. Knock-out studies in mice also suggested the neuroprotective function of this cytokine 6p21.3 
LTA Lymphotoxin-α, a member of the TNF family, is a cytokine produced by lymphocytes. LTA is highly inducible, secreted, and exists as homotrimeric molecule. LTA forms heterotrimers with lymphotoxin-β, which anchors LTA to the cell surface. LTA mediates a large variety of inflammatory, immunostimulatory, and antiviral responses. LTA is also involved in the formation of secondary lymphoid organs during development and plays a role in apoptosis 6p21.3 
IFN-γ IFN-γ is secreted by Th1 cells, Tc cells, dendritic cells and NK cells. IFN-γ has antiviral, immunoregulatory, and antitumour properties. It increases antigen presentation of macrophages. IFN-γ activates and increases lysosome activity in macrophages and suppresses Th2-cell activity. It causes normal cells to express class II major histocompatibility complex (MHC) molecules, and promotes adhesion and binding required for leukocyte migration. IFN-γ promotes NK cell activity 12q14 
TGF-β Transforming growth factor-β (TGF-β) converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of IL-6, TGF-β also promotes the differentiation of naive T lymphocytes into proinflammatory IL-17 cytokine-producing T helper-17 (Th17) cells, which promote autoimmunity and inflammation. Vitamin A metabolite retinoic acid is a key regulator of TGF-β-dependent immune responses, capable of inhibiting the IL-6-driven induction of proinflammatory Th17 cells and promoting anti-inflammatory regulatory T-cell differentiation 19q13.1 
HLA 
HLA-A/-B/-C/-DQA/-DQB/-DR HLA/MHC genes are by far the most polymorphic of the human genome. The HLA proteins present antigens generated from proteins to T cells. This presentation restricts the range of cellular and antibody responses to antigens 6p21.3 
Other 
MMP9 Involved in degradation of extracellular matrix molecules. MMP9 release might induce stem cell mobilization by cleaving matrix molecules to which stem cells are attached. MMP9 expression is related to aggressive tumour behaviour by induction/promotion of angiogenesis 20q11.2–q13.1 
IκB-α IκB-α (NFκBIA) inactivates NFκB by trapping it in the cytoplasm, thus inhibiting proinflammatory signals 14q13 
IκBL This gene encodes a divergent member of the IκB family of proteins. Its function has not been determined. The gene lies within the MHC class I region on chromosome 6 6p21.3 
Gene Biological effect Chromosome 
Pathogen recognition receptors 
TLR4 TLR4, in complex with CD14, has been implicated in signal transduction events induced by lipopolysaccharide found in most Gram-negative bacteria. Mutations in this gene have been associated with differences in lipopolysaccharide responsiveness 9q32–q33 
TLR9 TLR9 mediates cellular response to unmethylated CpG dinucleotides in bacterial DNA to mount an innate immune response. It is localized and acts in an intracellular compartment. CpG DNA induces a strong T-helper-1-like inflammatory response 3p21.3 
CD14 CD14 acts as a coreceptor for TLR4 and TLR2, and confers responsiveness to lipopolysaccharide, a component of the cell wall of most Gram-negative bacteria. CD14 forms a complex with lipopolysaccharide and the lipopolysaccharide-binding protein. Combined with TLR4 this complex induces NFκB associated immune responses including the release of a broad spectrum of cytokines that include TNF-α, IL-1, IL-6, and IL-8 to initiate immune response 5q31.1 
NOD2 NOD2 is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats. The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharide by recognizing the muramyl dipeptide derived from them and activating the NFκB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome 16q12 
CCR5 Potential role for the chemokine receptor in granulocyte lineage proliferation and differentiation. Chemokine receptor CCR5, a principal HIV-1 coreceptor, is post-translationally modified by O-linked glycosylation and by sulfation of its N-terminal tyrosines. Sulfated tyrosines contributed to the binding of CCR5 to MIP-1-α, MIP-1-β, and HIV-1 gp120/CD4 complexes, and to the ability of HIV-1 to enter cells expressing CCR5 and CD4. Mycobacterial HSP70, in addition to enhancing antigen delivery to human dendritic cells, signals through the CCR5 chemokine receptor, promoting dendritic cell aggregation, immune synapse formation between dendritic cells and T cells, and the generation of effector immune responses 3p21 
MBL/MBP This gene encodes the soluble mannose-binding lectin or mannose-binding protein found in serum. The protein encoded belongs to the collectin family and is an important element in the innate immune system. The protein recognizes mannose and N-acetylglucosamine on many microorganisms, and is capable of activating the classical complement pathway. Deficiencies of this gene have been associated with susceptibility to autoimmune and infectious diseases 10q11.2–q21 
Cytokines 
IL-1B IL-1 is involved in a wide variety of physiological processes, including the regulation of inflammatory, metabolic, haematopoietic and immunological mechanisms. It is produced by macrophages, neutrophils and endothelial cells. IL-1B initiates the expression of several genes coding for lymphokines. It induces natural killer (NK) cells and activates T and B cells 2q14 
IL-1RN IL-1RN specifically inhibits IL-1 bioactivity on T cells and endothelial cells in vitro and is a potent inhibitor of IL-1-induced corticosterone production in vivo. IL-1 receptor antagonist levels are elevated in the blood of patients with a variety of infectious, immune and traumatic conditions. IL-1RN is expressed in the human β cell and provides localized protection against leptin- and glucose-induced islet IL-1β 2q14.2 
IL-2 IL-2 is a powerfully immunoregulatory lymphokine that is produced by lectin- or antigen-activated T cells. It is produced not only by mature T lymphocytes on stimulation but also constitutively by certain T cell lymphoma cell lines. It augments NK cell activity. It functions as growth factor for both B and T lymphocytes 4q26–q27 
IL-4 IL-4 is a pleiotropic Th2-derived immune cytokine which is predominantly produced by activated T lymphocytes, mast cells and basophils. IL-4 has been shown to have various activities in many different cell types, such as T cells, B cells, monocytes, endothelial cells and fibroblasts 5q31.1 
IL-4R IL-4 is a cytokine produced by T cells that plays a major role in immunoglobulin E production, and regulates proliferation and differentiation of a variety of cells. It modulates the activity of these cells following binding to its cell surface receptor, IL-4R 16p12.1–p11.2 
IL-6 IL-6 is an immunoregulatory cytokine that activates a cell surface signaling assembly composed of IL-6, IL-6RA (IL-6R), and the shared signaling receptor gp130 (IL-6ST) 7p21 
IL-10 IL-10 is an anti-inflammatory cytokine. It arrests and reverses the (chronic) inflammatory response 1q31–q32 
IL-12B IL-12 is a proinflammatory cytokine. It has a broad range of biological functions, which include sustaining long-term protection against intracellular pathogens 5q31.1–q33.1 
TNF-α TNF-α is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance and cancer. Knock-out studies in mice also suggested the neuroprotective function of this cytokine 6p21.3 
LTA Lymphotoxin-α, a member of the TNF family, is a cytokine produced by lymphocytes. LTA is highly inducible, secreted, and exists as homotrimeric molecule. LTA forms heterotrimers with lymphotoxin-β, which anchors LTA to the cell surface. LTA mediates a large variety of inflammatory, immunostimulatory, and antiviral responses. LTA is also involved in the formation of secondary lymphoid organs during development and plays a role in apoptosis 6p21.3 
IFN-γ IFN-γ is secreted by Th1 cells, Tc cells, dendritic cells and NK cells. IFN-γ has antiviral, immunoregulatory, and antitumour properties. It increases antigen presentation of macrophages. IFN-γ activates and increases lysosome activity in macrophages and suppresses Th2-cell activity. It causes normal cells to express class II major histocompatibility complex (MHC) molecules, and promotes adhesion and binding required for leukocyte migration. IFN-γ promotes NK cell activity 12q14 
TGF-β Transforming growth factor-β (TGF-β) converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of IL-6, TGF-β also promotes the differentiation of naive T lymphocytes into proinflammatory IL-17 cytokine-producing T helper-17 (Th17) cells, which promote autoimmunity and inflammation. Vitamin A metabolite retinoic acid is a key regulator of TGF-β-dependent immune responses, capable of inhibiting the IL-6-driven induction of proinflammatory Th17 cells and promoting anti-inflammatory regulatory T-cell differentiation 19q13.1 
HLA 
HLA-A/-B/-C/-DQA/-DQB/-DR HLA/MHC genes are by far the most polymorphic of the human genome. The HLA proteins present antigens generated from proteins to T cells. This presentation restricts the range of cellular and antibody responses to antigens 6p21.3 
Other 
MMP9 Involved in degradation of extracellular matrix molecules. MMP9 release might induce stem cell mobilization by cleaving matrix molecules to which stem cells are attached. MMP9 expression is related to aggressive tumour behaviour by induction/promotion of angiogenesis 20q11.2–q13.1 
IκB-α IκB-α (NFκBIA) inactivates NFκB by trapping it in the cytoplasm, thus inhibiting proinflammatory signals 14q13 
IκBL This gene encodes a divergent member of the IκB family of proteins. Its function has not been determined. The gene lies within the MHC class I region on chromosome 6 6p21.3 
Table 2

Immunogenetic association studies on Chlamydia infections focussed on pathogen recognition receptors

Gene Polymorphism Cohort n Ethnicity Genotype frequency (%) Results Author 
Pathogen recognition receptors 
TLR4 +896A>G (Asp299Gly) Tubal infertility 35 Dutch Caucasian AA: 85.7 AG: 14.3 GG: 0.0 NS Morré et al. (2003) 
TLR4 +896A>G (Asp299Gly) Tubal pathology 227 Dutch Caucasian AA: 88.0 *G: 12.0 NS, although increasing risk for tubal pathology was observed in trend analyses Den Hartog et al. (2006) 
      Carriage of two or more SNPs in TLR9, TLR4, CD14, and CARD15/NOD2 increased the risk of developing tubal pathology following Chlamydia infection (NS)  
TLR9 −1237 T>C Tubal pathology 227 Dutch Caucasian TT: 68.0 *C: 32.0 Idem Den Hartog et al. (2006) 
TLR9 +2848 G>A Tubal pathology 227 Dutch Caucasian GG: 20.0 *A: 80.0 Idem Den Hartog et al. (2006) 
CD14 −260 C>T Chlamydia infection/tubal pathology 576/253 Dutch Caucasian CC: 28.1/27.7 CT: 50.7/49.0 TT: 21.2/23.3 NS Ouburg et al. (2005) 
CD14 −260 C>T Tubal pathology 227 Dutch Caucasian CC: 26.0 *T: 74.0 NS, although increasing risk for tubal pathology was observed in trend analyses Den Hartog et al. (2006) 
      Carriage of two or more SNPs in TLR9, TLR4, CD14, and CARD15/NOD2 increased the risk of developing tubal pathology following Chlamydia infection (NS)  
CARD15/NOD2 SNP13 (Leu1007FsInsC) Tubal pathology 227 Dutch Caucasian WT/WT: 93.0 *InsC: 7.0 Idem Den Hartog et al. (2006) 
CCR5 Δ32 Subfertility/tubal pathology 256 Dutch Caucasian WT/WT: 80.0 WT/Δ32: 19.5 Δ32/Δ32: 0.5 Decreased carriage of the CCR5 deletion in women with tubal pathology and a positive Chlamydia serology, suggesting a protective effect of the deletion against Chlamydia-induced tubal pathology Barr et al. (2005) 
MBL Codon 54 (A>B) Tubal Pathology 107 Hungarian Caucasian AA: 54.6 AB: 31.9 BB: 13.5 Carriage of the mutant allele was significantly associated with tubal occlusions (P<0.001; OR: 4.6; 95% CI: 2.3–8.9) Sziller et al. (2007) 
      Women with positive Chlamydia serology and tubal occlusions had the highest rates of B allele carriage (P=0.001; OR: 3.9; 95% CI: 1.9–8.2)  
      Allele B carriage was more frequent in Chlamydia serology negative women with blocked fallopian tubes compared with those with patent tubes (P=0.01; OR: 3.5; 95% CI: 1.3–9.0)  
MBP Codon 57 (Gly/Glu) Scarring trachoma 179 Gambian Gly/Gly: 54.2 Gly/Glu: 39.7 Glu/Glu: 6.1 NS Mozzato-Chamay et al. (2000) 
Gene Polymorphism Cohort n Ethnicity Genotype frequency (%) Results Author 
Pathogen recognition receptors 
TLR4 +896A>G (Asp299Gly) Tubal infertility 35 Dutch Caucasian AA: 85.7 AG: 14.3 GG: 0.0 NS Morré et al. (2003) 
TLR4 +896A>G (Asp299Gly) Tubal pathology 227 Dutch Caucasian AA: 88.0 *G: 12.0 NS, although increasing risk for tubal pathology was observed in trend analyses Den Hartog et al. (2006) 
      Carriage of two or more SNPs in TLR9, TLR4, CD14, and CARD15/NOD2 increased the risk of developing tubal pathology following Chlamydia infection (NS)  
TLR9 −1237 T>C Tubal pathology 227 Dutch Caucasian TT: 68.0 *C: 32.0 Idem Den Hartog et al. (2006) 
TLR9 +2848 G>A Tubal pathology 227 Dutch Caucasian GG: 20.0 *A: 80.0 Idem Den Hartog et al. (2006) 
CD14 −260 C>T Chlamydia infection/tubal pathology 576/253 Dutch Caucasian CC: 28.1/27.7 CT: 50.7/49.0 TT: 21.2/23.3 NS Ouburg et al. (2005) 
CD14 −260 C>T Tubal pathology 227 Dutch Caucasian CC: 26.0 *T: 74.0 NS, although increasing risk for tubal pathology was observed in trend analyses Den Hartog et al. (2006) 
      Carriage of two or more SNPs in TLR9, TLR4, CD14, and CARD15/NOD2 increased the risk of developing tubal pathology following Chlamydia infection (NS)  
CARD15/NOD2 SNP13 (Leu1007FsInsC) Tubal pathology 227 Dutch Caucasian WT/WT: 93.0 *InsC: 7.0 Idem Den Hartog et al. (2006) 
CCR5 Δ32 Subfertility/tubal pathology 256 Dutch Caucasian WT/WT: 80.0 WT/Δ32: 19.5 Δ32/Δ32: 0.5 Decreased carriage of the CCR5 deletion in women with tubal pathology and a positive Chlamydia serology, suggesting a protective effect of the deletion against Chlamydia-induced tubal pathology Barr et al. (2005) 
MBL Codon 54 (A>B) Tubal Pathology 107 Hungarian Caucasian AA: 54.6 AB: 31.9 BB: 13.5 Carriage of the mutant allele was significantly associated with tubal occlusions (P<0.001; OR: 4.6; 95% CI: 2.3–8.9) Sziller et al. (2007) 
      Women with positive Chlamydia serology and tubal occlusions had the highest rates of B allele carriage (P=0.001; OR: 3.9; 95% CI: 1.9–8.2)  
      Allele B carriage was more frequent in Chlamydia serology negative women with blocked fallopian tubes compared with those with patent tubes (P=0.01; OR: 3.5; 95% CI: 1.3–9.0)  
MBP Codon 57 (Gly/Glu) Scarring trachoma 179 Gambian Gly/Gly: 54.2 Gly/Glu: 39.7 Glu/Glu: 6.1 NS Mozzato-Chamay et al. (2000) 

CT, Chlamydia trachomatis; OR, odds ratio; CI, confidence interval; NS, not significant; N/A, not available; WT, wild type.

Both CCR5 and MBL were associated with late complications of Chlamydia infections (Table 2). The two most interesting findings were the MBL mutant allele in tubal pathology (P<0.001) (Sziller et al., 2007) and the role of CCR5 in tubal pathology, which was also underlined by corresponding KO murine studies (Barr et al., 2005).

Cytokines

Cytokines are involved in a wide range of biological processes (Table 1) and have an important immunoregulatory function. Changes in expression or functionality of these cytokines may result in a dysregulated immune response.

The SNPs studies in interleukin-1B (IL-1B) and its receptor antagonist tumour necrosis factor-α (TNF-α), transforming growth factor β, interferon-γ (IFN-γ) and IL-6 are not associated with tubal infertility. In addition, no associations were observed between IL-2, IL-4, IL-4R, IL-6 and IL-12B and Chlamydia infections (Table 3). IL-10 was associated with tubal pathology, but only when in combination with specific HLA-DQB alleles.

Table 3

Immunogenetic association studies on Chlamydia infections focussed on cytokines

Gene Polymorphism Cohort n Ethnicity Genotype frequency (%) Results Author 
Cytokines 
IL-1B −511 C>T Tubal factor subfertility 40 Dutch Caucasian CC: 40.0 CT: 52.5 TT: 7.5 NS Murillo et al. (2003) 
IL-1B +3954 C>T Tubal factor subfertility 40 Dutch Caucasian CC: 62.5 CT: 30.0 TT: 7.5 NS Murillo et al. (2003) 
IL-1RN 86 bp VNTR Tubal factor subfertility 40 Dutch Caucasian x.x: 60.0 x.2: 32.5 2.2: 7.5 NS Murillo et al. (2003) 
IL-2 −330 T>G, 160 G>T (haplotypes: G-G, T-G, T-T) Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
IL-4 −590 T>C Scarring trachoma 238 Gambian TT: 50.0 TC: 38.7 CC: 11.3 NS Mozzato-Chamay et al. (2000) 
IL-4 −1098 T>G, −590 C>T, −33 C>T (haplotypes: T-T-T, T-G-C, T-C-C, G-C-C) Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
IL-4R 1902 A>G Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
IL-6 −174 G>C Tubal infertility 70 (35 MIF+/35 MIF−) Kenyan GG: 94.0/94.0 GC: 3.0/6.0 CC: 0.0/0.0 NS Cohen et al. (2003) 
IL-6 −174 G>C 565 G>A Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
IL-10 −3575 T>A Scarring trachoma/trachiasis 651 Gambian TT: 63.0 TA: 32.0 AA: 5.0 Associated with trachomatous scarring (P=0.001; OR: 1.4; 95% CI: 1.1–1.7) Natividad et al. (2005) 
IL-10 −1082 A>G Tubal factor infertility 52 Finnish AA: 22.0 AG: 41.0 GG: 37.0 NS, however, combined carriage with DQA1*0102 or DQB1*0602 with IL1-1082AA more frequent in cases than controls (P=0.005) Kinnunen et al. (2002) 
IL-10 −1082 A>G Scarring trachoma 238 Gambian AA: 44.1 AG: 42.4 GG: 13.5 G allele more frequent in cases than in controls in an ethnic subgroup (Mandinkas) (P=0.009; OR: 5.1; 95% CI: 1.2–24.2) Mozzato-Chamay et al. (2000) 
IL-10 −1082 A>G Scarring trachoma/trachiasis 651 Gambian AA: 46.0 AG: 41.0 GG: 0.13 G allele associated with scarring trachoma in the Mandinka ethnic group (P=0.038, OR: 1.6; 95% CI: 1.1–2.4) Natividad et al. (2005) 
IL-10 −819 C>T Scarring trachoma 238 Gambian CC: 29.8 CT: 46.2 TT: 24.0 NS Mozzato-Chamay et al. (2000) 
IL-10 −592 A>C Scarring trachoma 238 Gambian AA: 24.0 AC: 47.9 CC: 28.1 NS Mozzato-Chamay et al. (2000) 
IL-10 −592 A>C Scarring trachoma/trachiasis 651 Gambian AA: 30.0 AC: 46.0 CC: 24.0 NS Natividad et al. (2005) 
IL-10 +5009 A>G Scarring trachoma/trachiasis 651 Gambian AA: 40.0 AG: 46.0 GG: 14.0 Associated with trachomatous scarring (P=0.04; OR: 1.2; 95% CI: 1.0–1.5) Natividad et al. (2005) 
IL-10 RS3024496 (3′UTR) Scarring trachoma/trachiasis 651 Gambian WT/WT: 39.6 WT/MT: 45.0 MT/MT: 13.7 Long-term complications of trachomatous scarring and the severe phenotype of trachiasis increased with the number of mutant alleles (P trend: <0.001; OR trend: 1.5; 95% CI: 1.3 –1.7; and P trend: <0.001; OR trend: 1.7; 95% CI: 1.3–2.2) Natividad et al. (2008) 
IL-10 −3575 T>A, −2763 C>A (haplotypes: T-C, T-A, A-C, A-A) Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
IL-10 −1082 A>G/−819 C>T/−592 A>C haplotypes Tubal infertility 70 (35 MIF+/35 MIF−) Kenyan GCC/GCC: 9.0/9.0 GCC/ACC: 20.0/6.0 GCC/ATA: 31.0/42.0 ACC/ACC: 9.0/0.0 ACC/ATA: 14.0/28.0 ATA/ATA: 14.0/14.0 NS Cohen et al. (2003) 
IL-10 −1082 A>G/−819 C>T/−592 A>C haplotypes Chlamydia infection (REACH study) 485 North American (71% African American) N/A GCC haplotype negatively associated with recurrent Chlamydia infection (P=0.04; OR: 0.6; 95% CI: 0.4–1.0) Wang et al. (2005) 
IL-10 −3575 T>A/−1082 T>C/−592 G>T/+5009 A>G haplotypes Scarring trachoma/trachiasis 651 Gambian TTTA: 48.1 TCGA: 7.3 TTGA: 7.8 ATTA: 0.1 ACGG: 19.2 TCGG: 6.7 ATGG: 2.3 TTGG: 8.5 TTTG: 0.0 ACGA: 0.1 ACGG and ATGG haplotypes associated with scarring trachoma (P=0.045; OR: 1.3; 95% CI: 1.0–1.6; and P=0.03; OR: 2.0; 95% CI: 1.1–3.7, respectively) Natividad et al. (2005) 
      The TCGA haplotype was associated with protection against scarring trachoma (P=0.048; OR: 0.7; 95% CI: 0.6–1.0)  
IL-12B (p40) 1188 A>C (3′ UTR) Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
TNF-α −308 G>A Scarring trachoma 153 Gambian GG: 71.6 GA: 24.1 AA: 4.2 Increased carriage of the AA genotype in patients compared to controls (P=0.03; OR: 3.4; 95% CI: 0.7–17.1). Increased number of −308 or −238 mutants in patients than controls (χ2 for trend: 8.6; P=0.003). Conway et al. (1997) 
      TNF-α-308*A significantly associated with HLA A28, B70, Cw2, DRB1*11, and DRB1*1303 alleles in study subjects (P<0.006)  
TNF-α −308 G>A Tubal infertility 70 (35 MIF+/35 MIF−) Kenyan GG 86.0/83.0 GA: 6.0/17.0 AA: 6.0/0.0 NS Cohen et al. (2003) 
TNF-α −308 G>A Scarring trachoma/trachiasis 651 Gambian GG: 60.0 GA: 36.0 AA: 0.04 TNF-α-308*A associated with trachiasis (P=0.016; OR: 1.5; 95% CI: 1.1–2.2) Natividad et al. (2007) 
TNF-α −376 G>A Scarring trachoma 238 Gambian GG: 94.5 GA: 5.5 AA: 0.0 NS Mozzato-Chamay et al. (2000) 
TNF-α −238 G>A Scarring trachoma 153 Gambian GG: 83.9 GA: 14.1 AA: 2.1 Increased number of −308 or −238 mutants in patients than controls (χ2 for trend: 8.6; P=0.003) Conway et al. (1997) 
      TNF-α-238*A significantly associated with HLA B53, Cw5, Cw6, and DRB1*09 alleles in study subjects (P<0.0004)  
TNF-α −238 G>A Scarring trachoma/trachiasis 651 Gambian GG: 87.0 GA: 13.0 AA: 0.07 NS Natividad et al. (2007) 
TNF-α −308 G>A, −238 G>A (haplotypes: G-G, A-G, G-A) Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
LTA +72 G>T Scarring trachoma/trachiasis 651 Gambian GG: 45.0 GT: 40.0 TT: 15.0 NS Natividad et al. (2007) 
LTA +252 A>G Scarring trachoma/trachiasis 651 Gambian AA: 31.0 AG: 46.0 GG: 23.0 LTA+252*G associated with trachiasis (P trend=0.018; OR: 1.4; 95% CI: 1.1–1.8) Natividad et al. (2007) 
IFN-γ +874 T>A Tubal infertility 70 (35 MIF+/35 MIF−) Kenyan TT: 0.0/8.0 TA: 31.0/36.0 AA: 69.0/56.0 NS Cohen et al. (2003) 
IFN-γ −1616 C>T Scarring trachoma/trachiasis 651 Gambian CC: 26.0 CT: 47.0 TT: 27.0 NS Natividad et al. (2005) 
IFN-γ +2200 T>C Scarring trachoma/trachiasis 651 Gambian TT: 88.0 TC: 11.0 CC: 1.0 NS Natividad et al. (2005) 
IFN-γ +3234 T>C Scarring trachoma/trachiasis 651 Gambian TT: 54.0 TC: 37.0 CC: 10.0 Associated with trachomatous scarring (P=0.04; OR: 1.2; 95% CI: 1.0–1.5) Natividad et al. (2005) 
IFN-γ +5612 C>T Scarring trachoma/trachiasis 651 Gambian CC: 49.0 CT: 41.0 TT: 10.0 NS Natividad et al. (2005) 
IFN-γ Haplotypes −1616/+2200/+3234/+5612 Scarring trachoma/trachiasis 651 Gambian CTTC: 33.7/CCTC: 6.4 CTTT: 8.9/TTCC: 28.3 TTCT: 0.2/TTTC: 0.5 TTTT: 21.9 TTCC associated with scarring trachoma (P=0.02; OR: 1.3; 95% CI: 1.0–1.6) Natividad et al. (2005) 
TGF1 Codon 10 T>C Codon 25 G>C Tubal infertility 70 (35 MIF+/35 MIF−) Kenyan TT-GG: 32.0/35.0 TC-GG: 27.0/29.0 TC-GC: 6.0/9.0 CC-GG: 29.0/18.0 TT-GC: 0.0/0.0 CC-GC: 3.0/9.0 CC-CC: 0.0/0.0 TT-CC: 0.0/0.0 TC-CC: 0.0/0.0 NS Cohen et al. (2003) 
Gene Polymorphism Cohort n Ethnicity Genotype frequency (%) Results Author 
Cytokines 
IL-1B −511 C>T Tubal factor subfertility 40 Dutch Caucasian CC: 40.0 CT: 52.5 TT: 7.5 NS Murillo et al. (2003) 
IL-1B +3954 C>T Tubal factor subfertility 40 Dutch Caucasian CC: 62.5 CT: 30.0 TT: 7.5 NS Murillo et al. (2003) 
IL-1RN 86 bp VNTR Tubal factor subfertility 40 Dutch Caucasian x.x: 60.0 x.2: 32.5 2.2: 7.5 NS Murillo et al. (2003) 
IL-2 −330 T>G, 160 G>T (haplotypes: G-G, T-G, T-T) Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
IL-4 −590 T>C Scarring trachoma 238 Gambian TT: 50.0 TC: 38.7 CC: 11.3 NS Mozzato-Chamay et al. (2000) 
IL-4 −1098 T>G, −590 C>T, −33 C>T (haplotypes: T-T-T, T-G-C, T-C-C, G-C-C) Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
IL-4R 1902 A>G Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
IL-6 −174 G>C Tubal infertility 70 (35 MIF+/35 MIF−) Kenyan GG: 94.0/94.0 GC: 3.0/6.0 CC: 0.0/0.0 NS Cohen et al. (2003) 
IL-6 −174 G>C 565 G>A Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
IL-10 −3575 T>A Scarring trachoma/trachiasis 651 Gambian TT: 63.0 TA: 32.0 AA: 5.0 Associated with trachomatous scarring (P=0.001; OR: 1.4; 95% CI: 1.1–1.7) Natividad et al. (2005) 
IL-10 −1082 A>G Tubal factor infertility 52 Finnish AA: 22.0 AG: 41.0 GG: 37.0 NS, however, combined carriage with DQA1*0102 or DQB1*0602 with IL1-1082AA more frequent in cases than controls (P=0.005) Kinnunen et al. (2002) 
IL-10 −1082 A>G Scarring trachoma 238 Gambian AA: 44.1 AG: 42.4 GG: 13.5 G allele more frequent in cases than in controls in an ethnic subgroup (Mandinkas) (P=0.009; OR: 5.1; 95% CI: 1.2–24.2) Mozzato-Chamay et al. (2000) 
IL-10 −1082 A>G Scarring trachoma/trachiasis 651 Gambian AA: 46.0 AG: 41.0 GG: 0.13 G allele associated with scarring trachoma in the Mandinka ethnic group (P=0.038, OR: 1.6; 95% CI: 1.1–2.4) Natividad et al. (2005) 
IL-10 −819 C>T Scarring trachoma 238 Gambian CC: 29.8 CT: 46.2 TT: 24.0 NS Mozzato-Chamay et al. (2000) 
IL-10 −592 A>C Scarring trachoma 238 Gambian AA: 24.0 AC: 47.9 CC: 28.1 NS Mozzato-Chamay et al. (2000) 
IL-10 −592 A>C Scarring trachoma/trachiasis 651 Gambian AA: 30.0 AC: 46.0 CC: 24.0 NS Natividad et al. (2005) 
IL-10 +5009 A>G Scarring trachoma/trachiasis 651 Gambian AA: 40.0 AG: 46.0 GG: 14.0 Associated with trachomatous scarring (P=0.04; OR: 1.2; 95% CI: 1.0–1.5) Natividad et al. (2005) 
IL-10 RS3024496 (3′UTR) Scarring trachoma/trachiasis 651 Gambian WT/WT: 39.6 WT/MT: 45.0 MT/MT: 13.7 Long-term complications of trachomatous scarring and the severe phenotype of trachiasis increased with the number of mutant alleles (P trend: <0.001; OR trend: 1.5; 95% CI: 1.3 –1.7; and P trend: <0.001; OR trend: 1.7; 95% CI: 1.3–2.2) Natividad et al. (2008) 
IL-10 −3575 T>A, −2763 C>A (haplotypes: T-C, T-A, A-C, A-A) Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
IL-10 −1082 A>G/−819 C>T/−592 A>C haplotypes Tubal infertility 70 (35 MIF+/35 MIF−) Kenyan GCC/GCC: 9.0/9.0 GCC/ACC: 20.0/6.0 GCC/ATA: 31.0/42.0 ACC/ACC: 9.0/0.0 ACC/ATA: 14.0/28.0 ATA/ATA: 14.0/14.0 NS Cohen et al. (2003) 
IL-10 −1082 A>G/−819 C>T/−592 A>C haplotypes Chlamydia infection (REACH study) 485 North American (71% African American) N/A GCC haplotype negatively associated with recurrent Chlamydia infection (P=0.04; OR: 0.6; 95% CI: 0.4–1.0) Wang et al. (2005) 
IL-10 −3575 T>A/−1082 T>C/−592 G>T/+5009 A>G haplotypes Scarring trachoma/trachiasis 651 Gambian TTTA: 48.1 TCGA: 7.3 TTGA: 7.8 ATTA: 0.1 ACGG: 19.2 TCGG: 6.7 ATGG: 2.3 TTGG: 8.5 TTTG: 0.0 ACGA: 0.1 ACGG and ATGG haplotypes associated with scarring trachoma (P=0.045; OR: 1.3; 95% CI: 1.0–1.6; and P=0.03; OR: 2.0; 95% CI: 1.1–3.7, respectively) Natividad et al. (2005) 
      The TCGA haplotype was associated with protection against scarring trachoma (P=0.048; OR: 0.7; 95% CI: 0.6–1.0)  
IL-12B (p40) 1188 A>C (3′ UTR) Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
TNF-α −308 G>A Scarring trachoma 153 Gambian GG: 71.6 GA: 24.1 AA: 4.2 Increased carriage of the AA genotype in patients compared to controls (P=0.03; OR: 3.4; 95% CI: 0.7–17.1). Increased number of −308 or −238 mutants in patients than controls (χ2 for trend: 8.6; P=0.003). Conway et al. (1997) 
      TNF-α-308*A significantly associated with HLA A28, B70, Cw2, DRB1*11, and DRB1*1303 alleles in study subjects (P<0.006)  
TNF-α −308 G>A Tubal infertility 70 (35 MIF+/35 MIF−) Kenyan GG 86.0/83.0 GA: 6.0/17.0 AA: 6.0/0.0 NS Cohen et al. (2003) 
TNF-α −308 G>A Scarring trachoma/trachiasis 651 Gambian GG: 60.0 GA: 36.0 AA: 0.04 TNF-α-308*A associated with trachiasis (P=0.016; OR: 1.5; 95% CI: 1.1–2.2) Natividad et al. (2007) 
TNF-α −376 G>A Scarring trachoma 238 Gambian GG: 94.5 GA: 5.5 AA: 0.0 NS Mozzato-Chamay et al. (2000) 
TNF-α −238 G>A Scarring trachoma 153 Gambian GG: 83.9 GA: 14.1 AA: 2.1 Increased number of −308 or −238 mutants in patients than controls (χ2 for trend: 8.6; P=0.003) Conway et al. (1997) 
      TNF-α-238*A significantly associated with HLA B53, Cw5, Cw6, and DRB1*09 alleles in study subjects (P<0.0004)  
TNF-α −238 G>A Scarring trachoma/trachiasis 651 Gambian GG: 87.0 GA: 13.0 AA: 0.07 NS Natividad et al. (2007) 
TNF-α −308 G>A, −238 G>A (haplotypes: G-G, A-G, G-A) Chlamydia infection (REACH study) 485 North American (71% African American) N/A NS Wang et al. (2005) 
LTA +72 G>T Scarring trachoma/trachiasis 651 Gambian GG: 45.0 GT: 40.0 TT: 15.0 NS Natividad et al. (2007) 
LTA +252 A>G Scarring trachoma/trachiasis 651 Gambian AA: 31.0 AG: 46.0 GG: 23.0 LTA+252*G associated with trachiasis (P trend=0.018; OR: 1.4; 95% CI: 1.1–1.8) Natividad et al. (2007) 
IFN-γ +874 T>A Tubal infertility 70 (35 MIF+/35 MIF−) Kenyan TT: 0.0/8.0 TA: 31.0/36.0 AA: 69.0/56.0 NS Cohen et al. (2003) 
IFN-γ −1616 C>T Scarring trachoma/trachiasis 651 Gambian CC: 26.0 CT: 47.0 TT: 27.0 NS Natividad et al. (2005) 
IFN-γ +2200 T>C Scarring trachoma/trachiasis 651 Gambian TT: 88.0 TC: 11.0 CC: 1.0 NS Natividad et al. (2005) 
IFN-γ +3234 T>C Scarring trachoma/trachiasis 651 Gambian TT: 54.0 TC: 37.0 CC: 10.0 Associated with trachomatous scarring (P=0.04; OR: 1.2; 95% CI: 1.0–1.5) Natividad et al. (2005) 
IFN-γ +5612 C>T Scarring trachoma/trachiasis 651 Gambian CC: 49.0 CT: 41.0 TT: 10.0 NS Natividad et al. (2005) 
IFN-γ Haplotypes −1616/+2200/+3234/+5612 Scarring trachoma/trachiasis 651 Gambian CTTC: 33.7/CCTC: 6.4 CTTT: 8.9/TTCC: 28.3 TTCT: 0.2/TTTC: 0.5 TTTT: 21.9 TTCC associated with scarring trachoma (P=0.02; OR: 1.3; 95% CI: 1.0–1.6) Natividad et al. (2005) 
TGF1 Codon 10 T>C Codon 25 G>C Tubal infertility 70 (35 MIF+/35 MIF−) Kenyan TT-GG: 32.0/35.0 TC-GG: 27.0/29.0 TC-GC: 6.0/9.0 CC-GG: 29.0/18.0 TT-GC: 0.0/0.0 CC-GC: 3.0/9.0 CC-CC: 0.0/0.0 TT-CC: 0.0/0.0 TC-CC: 0.0/0.0 NS Cohen et al. (2003) 

CT, Chlamydia trachomatis; OR, odds ratio; CI, confidence interval; NS, not significant; N/A, not available; RO, relative odds; WT, wild type; MT, mutant.

Different SNPs in the TNF-α, IL-10, IFN-γ and IL-4 genes have been studied in relation to ocular Chlamydia infections. Several SNPs are associated with either scarring trachoma or trachiasis; however, some results, especially in the IL-10 haplotypes, seem contradictory (Table 3) in part because different IL-10 SNPs and haplotypes were studied in different ethnic populations.

IL-4 SNPs were not found to be associated with either urogenital or ocular Chlamydia infections, indicating that this gene may not be involved in Chlamydia pathogenesis.

IFN-γ was found to be associated with ocular infection but not with urogenital infections, indicating site-specific differences in the immune response to Chlamydia.

In summary, IL-10 SNPs and haplotypes have been associated with tubal infertility (P=0.005; Kinnunen et al., 2002), scarring trachoma and trachiasis, for example in scarring trachoma (P=0.009; Mozzato-Chamay et al., 2000) (Table 3).

Human leukocyte antigen (HLA)

The HLA system is a very versatile system able to recognize a variety of pathogens. Various HLA alleles have been linked to (infectious) disease pathogenesis. It is therefore not surprising that the scientific literature describes associations between HLA alleles and Chlamydia pathogenesis (see Table 4).

Table 4

Immunogenetic association studies on Chlamydia infections focussed on HLA and other proteins

Gene Polymorphism Cohort n Ethnicity Genotype frequency (%) Results Author 
HLA 
HLA DQA DQB Tubal factor infertility and tubal ligation 47 and 46 (respectively) Nairobi  DQA*0101 and DQB*0501 positively associated with CT tubal infertility (OR: 4.9; 95% CI: 1.3–18.6, and OR: 6.8; 95% CI: 1.6–29.2, respectively) Cohen et al. (2000) 
      DQA*0102 negatively associated with CT tubal infertility (OR: 0.2; 95% CI: 0.005–0.6)  
HLA DQA1 DQB1 Tubal factor infertility 52 Finnish  DQB1*0602 more frequent in cases compared to controls (P=0.04). Combined carriage with DQA1*0102 or DQB1*0602 with IL1-1082AA more frequent in cases than controls (P=0.005) Kinnunen et al. (2002) 
HLA DQA DQB DR Tubal infertility 70 (35 MIF+/35 MIF−) Kenyan  HLA-DR1*1503 was more frequent in MIF– women compared to MIF+ women (OR: 0.05; 95% CI: 0–0.7). Cohen et al. (2003) 
      DRB5*0101 was less common in MIF+women than in MIF– women (OR: 0.2; 95% CI: 0.02–1.0)  
HLA A B Cw DRB1 DQB1 Scarring trachoma 153 Gambian A28: 25.8 The A28 allele was more frequent in cases than in controls (P=0.046; OR: 1.9; 95% CI: 1.0–3.5). HLA subtyping found allele A*6802 more frequent in cases than controls (P=0.009; OR: 3.1; 95% CI: 1.3–7.4) Conway et al. (1996) 
HLA A B C DRB1 DQB1 Chlamydia infection (REACH study) 485 North American (71% African American)  DRB1*03-DQB1*04 and DQB1*06 associated with recurrent Chlamydia infections (P<0.01; RO>2.0) Wang et al. (2005) 
HLA DQA DQB PID (PEACH study) Chlamydia cervicitis 92 American (2/3 ‘Black’) N/A Carriage of the DQA*0301 allele was more common among women with Chlamydia cervicitis (OR: 4.4; 95% CI: 1.6–12.0). Similar results were found for women carrying HLADQA*0501 (OR: 1.8; 95% CI: 0.7–4.9) Ness et al. (2004) 
Other 
MMP9 rs2664538 A>G (Q279R) Scarring trachoma/trachiasis 651 Gambian AA: 55.0 AG: 35.0 GG: 10.0 G allele associated with decreased risk for scarring trachoma and trachiasis (P=0.012; OR: 0.7; 95% CI: 0.6–0.9; and P=0.021; OR: 0.7; 95% CI: 0.5−0.9) Natividad et al. (2006) 
      Heterozygotes (Q279R AG) were at lower risk of both TS and TT (P=0.004; OR: 0.7; 95% CI: 0.5–0.8; and P=0.006; OR: 0.6, 95% CI: 0.4–0.9, respectively)  
MMP9 rs2250889 C>G (R574P) Scarring trachoma/trachiasis 651 Gambian CC: 73.0 CG: 25.0 GG: 2.0 NS Natividad et al. (2006) 
MMP9 rs13969 A>C (G607G) Scarring trachoma/trachiasis 651 Gambian AA: 35.0 AC: 46.0 CC: 20.0 NS Natividad et al. (2006) 
MMP9 rs13925 G>A (V694) Scarring trachoma/trachiasis 651 Gambian GG: 75.0 GA: 23.0 AA: 2.0 NS Natividad et al. (2006) 
MMP9 Haplotype rs2664538 A>G /rs2250889 C>G /rs13969 A>C rs13925 G>A Scarring trachoma/trachiasis 651 Gambian ACCG: 36.0 ACAG: 23.0 GCAA: 14.0 GCAG: 10.0 AGAG: 10.0 AGCG: 4.0 GCCG: 2.0 The risk of both TS and TT decreased with the number of copies of the haplotype GCAG (P trend=0.07; OR: 0.8; 95% CI: 0.6–1.0; and P trend=0.03; OR: 0.7; 95% CI: 0.5–1.0, for TS and TT, respectively) Natividad et al. (2006) 
IκB-α −881 A>G Scarring trachoma 199 Gambian AA: 94.5 AG: 5.0 GG: 0.5 The −881G/−826T haplotype was significantly decreased in cases compared to controls (P=0.046) Mozzato-Chamay et al. (2001) 
IκB-α −826 C>T Scarring trachoma 199 Gambian CC: 94.5 CT: 5.0 TT: 0.5 Idem Mozzato-Chamay et al. (2001) 
IκB-α −297 C>T Scarring trachoma 199 Gambian CC: 98.0 CT: 2.0 TT: 0.0 NS Mozzato-Chamay et al. (2001) 
IκB-α Haplotype −881/−826/−297 Scarring trachoma 199 Gambian ACC: 95.0 GTC: 3.8 ACT: 0.5 GTT: 0.6 NS Mozzato-Chamay et al. (2001) 
IκBL −63 A>T Scarring trachoma/trachiasis 651 Gambian AA: 30.0 AT: 47.0 TT: 22.0 IκBL −63*T associated with trachiasis (P trend=0.004; OR: 1.5, 95% CI: 1.1–1.9) Natividad et al. (2007) 
Haplotype: IκBL-63/LTA+77/LTA+252/TNF-308/TNF-238 Scarring trachoma/trachiasis 651 Gambian ATAGG: 41.0 TGGGG: 22.0 TGGAG: 17.0 AGAGG: 11.0 AGAGA: 8.0 AGGGG:<1.0 AGGAG:<1.0 TGAGA:<1.0 TGAGG:<1.0 TTGGG:<1.0 TTAGG:<1.0 Two haplotypes (TGGGG and TGGAG) were independently associated with the risk for trachiasis (P=0.005; OR: 1.6; 95% CI: 1.2–2.2; and P=0.015; OR: 1.5; 95% CI: 1.1–2.2, respectively) Natividad et al. (2007) 
      The ATAGG haplotype was found to confer protection against trachiasis  
      Trend analyses showed that increasing number of the TGGGG haplotype increased the risk of trachiasis (P trend=0.018; OR: 1.5; 95% CI: 1.1–2.0), whereas the ATAGG haplotype lowered trachiasis risk with increasing numbers of haplotypes (P trend=0.012; OR: 0.75; 95% CI: 0.6–1.0)  
Gene Polymorphism Cohort n Ethnicity Genotype frequency (%) Results Author 
HLA 
HLA DQA DQB Tubal factor infertility and tubal ligation 47 and 46 (respectively) Nairobi  DQA*0101 and DQB*0501 positively associated with CT tubal infertility (OR: 4.9; 95% CI: 1.3–18.6, and OR: 6.8; 95% CI: 1.6–29.2, respectively) Cohen et al. (2000) 
      DQA*0102 negatively associated with CT tubal infertility (OR: 0.2; 95% CI: 0.005–0.6)  
HLA DQA1 DQB1 Tubal factor infertility 52 Finnish  DQB1*0602 more frequent in cases compared to controls (P=0.04). Combined carriage with DQA1*0102 or DQB1*0602 with IL1-1082AA more frequent in cases than controls (P=0.005) Kinnunen et al. (2002) 
HLA DQA DQB DR Tubal infertility 70 (35 MIF+/35 MIF−) Kenyan  HLA-DR1*1503 was more frequent in MIF– women compared to MIF+ women (OR: 0.05; 95% CI: 0–0.7). Cohen et al. (2003) 
      DRB5*0101 was less common in MIF+women than in MIF– women (OR: 0.2; 95% CI: 0.02–1.0)  
HLA A B Cw DRB1 DQB1 Scarring trachoma 153 Gambian A28: 25.8 The A28 allele was more frequent in cases than in controls (P=0.046; OR: 1.9; 95% CI: 1.0–3.5). HLA subtyping found allele A*6802 more frequent in cases than controls (P=0.009; OR: 3.1; 95% CI: 1.3–7.4) Conway et al. (1996) 
HLA A B C DRB1 DQB1 Chlamydia infection (REACH study) 485 North American (71% African American)  DRB1*03-DQB1*04 and DQB1*06 associated with recurrent Chlamydia infections (P<0.01; RO>2.0) Wang et al. (2005) 
HLA DQA DQB PID (PEACH study) Chlamydia cervicitis 92 American (2/3 ‘Black’) N/A Carriage of the DQA*0301 allele was more common among women with Chlamydia cervicitis (OR: 4.4; 95% CI: 1.6–12.0). Similar results were found for women carrying HLADQA*0501 (OR: 1.8; 95% CI: 0.7–4.9) Ness et al. (2004) 
Other 
MMP9 rs2664538 A>G (Q279R) Scarring trachoma/trachiasis 651 Gambian AA: 55.0 AG: 35.0 GG: 10.0 G allele associated with decreased risk for scarring trachoma and trachiasis (P=0.012; OR: 0.7; 95% CI: 0.6–0.9; and P=0.021; OR: 0.7; 95% CI: 0.5−0.9) Natividad et al. (2006) 
      Heterozygotes (Q279R AG) were at lower risk of both TS and TT (P=0.004; OR: 0.7; 95% CI: 0.5–0.8; and P=0.006; OR: 0.6, 95% CI: 0.4–0.9, respectively)  
MMP9 rs2250889 C>G (R574P) Scarring trachoma/trachiasis 651 Gambian CC: 73.0 CG: 25.0 GG: 2.0 NS Natividad et al. (2006) 
MMP9 rs13969 A>C (G607G) Scarring trachoma/trachiasis 651 Gambian AA: 35.0 AC: 46.0 CC: 20.0 NS Natividad et al. (2006) 
MMP9 rs13925 G>A (V694) Scarring trachoma/trachiasis 651 Gambian GG: 75.0 GA: 23.0 AA: 2.0 NS Natividad et al. (2006) 
MMP9 Haplotype rs2664538 A>G /rs2250889 C>G /rs13969 A>C rs13925 G>A Scarring trachoma/trachiasis 651 Gambian ACCG: 36.0 ACAG: 23.0 GCAA: 14.0 GCAG: 10.0 AGAG: 10.0 AGCG: 4.0 GCCG: 2.0 The risk of both TS and TT decreased with the number of copies of the haplotype GCAG (P trend=0.07; OR: 0.8; 95% CI: 0.6–1.0; and P trend=0.03; OR: 0.7; 95% CI: 0.5–1.0, for TS and TT, respectively) Natividad et al. (2006) 
IκB-α −881 A>G Scarring trachoma 199 Gambian AA: 94.5 AG: 5.0 GG: 0.5 The −881G/−826T haplotype was significantly decreased in cases compared to controls (P=0.046) Mozzato-Chamay et al. (2001) 
IκB-α −826 C>T Scarring trachoma 199 Gambian CC: 94.5 CT: 5.0 TT: 0.5 Idem Mozzato-Chamay et al. (2001) 
IκB-α −297 C>T Scarring trachoma 199 Gambian CC: 98.0 CT: 2.0 TT: 0.0 NS Mozzato-Chamay et al. (2001) 
IκB-α Haplotype −881/−826/−297 Scarring trachoma 199 Gambian ACC: 95.0 GTC: 3.8 ACT: 0.5 GTT: 0.6 NS Mozzato-Chamay et al. (2001) 
IκBL −63 A>T Scarring trachoma/trachiasis 651 Gambian AA: 30.0 AT: 47.0 TT: 22.0 IκBL −63*T associated with trachiasis (P trend=0.004; OR: 1.5, 95% CI: 1.1–1.9) Natividad et al. (2007) 
Haplotype: IκBL-63/LTA+77/LTA+252/TNF-308/TNF-238 Scarring trachoma/trachiasis 651 Gambian ATAGG: 41.0 TGGGG: 22.0 TGGAG: 17.0 AGAGG: 11.0 AGAGA: 8.0 AGGGG:<1.0 AGGAG:<1.0 TGAGA:<1.0 TGAGG:<1.0 TTGGG:<1.0 TTAGG:<1.0 Two haplotypes (TGGGG and TGGAG) were independently associated with the risk for trachiasis (P=0.005; OR: 1.6; 95% CI: 1.2–2.2; and P=0.015; OR: 1.5; 95% CI: 1.1–2.2, respectively) Natividad et al. (2007) 
      The ATAGG haplotype was found to confer protection against trachiasis  
      Trend analyses showed that increasing number of the TGGGG haplotype increased the risk of trachiasis (P trend=0.018; OR: 1.5; 95% CI: 1.1–2.0), whereas the ATAGG haplotype lowered trachiasis risk with increasing numbers of haplotypes (P trend=0.012; OR: 0.75; 95% CI: 0.6–1.0)  

CT, Chlamydia trachomatis; OR, odds ratio; CI, confidence interval; NS, not significant; N/A, not available; RO, relative odds.

Several HLA alleles have been associated with increased risk for urogenital Chlamydia infections and its late complications. Similarly, associations have been found between HLA alleles and ocular Chlamydia infections. The strongest association was found by Conway (1996) with HLA subtyping for allele A*6802, which was more frequent in cases of C. trachomatis infections as compared with controls (P=0.009).

Besides the HLA associations for urogenital tract and ocular C. trachomatis infections, HLA association has also been described for C. trachomatis-based reactive arthritis (ReA). The mechanisms that lead to the development of ReA are complex and basically involve an interaction between an arthritogenic agent and a predisposed host. The involvement of C. trachomatis in HLA-B27-associated ReA is well described (Colmegna et al., 2004). In addition, recently a Chlamydia positive Japanese man with Reiter's syndrome, negative for HLA-B27 or any other HLA-B27 cross-reactive major histocompatibility complex class I antigens, was positive for HLA-B51. It was therefore suggested that the combination of Chlamydia infection and HLA-B51 might play a role in the pathogenesis of Reiter's syndrome (Shimamoto et al., 2000).

These results indicate that the HLA system has a profound impact on Chlamydia pathogenesis, which is not limited to specific ethnic populations.

Other approaches

Matrix metalloproteinases are involved in the turnover of the extracellular matrix, and through that process have been associated with disease processes. It has been shown that a specific SNP and a haplotype of MMP9 decrease the risk of trachomatous scarring and trachiasis with P-values of up to 0.006 (see Table 4).

The IκBα and IκBL proteins are part of the inhibitory mechanism that reduces nuclear factor κB (NFκB) activation, thus limiting proinflammatory immune responses. IκBα SNPs reduce the risk of scarring trachoma, whereas IκBL SNPs confer a risk for trachiasis.

A haplotype spanning IκBL, lymphotoxin-α and TNF-α confers both protection and risk for trachiasis, depending on the specific haplotype (Table 4).

In summary, current immunogenetic studies on C. trachomatis are slowly revealing in more detail that host genetic factors contribute almost 40% to the variation in responses to C. trachomatis between individuals. The clearest and most reproduced finding in ocular and sexually transmitted infection by C. trachomatis for susceptibility and severity factors is the role of HLA, IL-10 and traits of genetic variation in multiple genes including TLRs. Future studies will further pinpoint relevant genetic bio-markers. These studies are being substantiated by different types of data: (1) KO murine work (the relevance for TLR2, TLR4 and TLR9 has been presented at the Sixth Meeting of the European Society for Chlamydia Research) and forward genetics; (2) in vitro studies to assess the role of susceptibility genes in C. trachomatis–host interactions; (3) mRNA profiling in C. trachomatis and the human host to identify genes of interest; and (4) genomic-wide approaches in C. trachomatis and the human host to identify genes and regions of interest, relevant though costly approaches and the reason why candidate gene approaches are still very relevant.

Concluding remarks

There are several potential gains on a human health level to be achieved by immunogenetic studies of C. trachomatis infections: (1) further insight into the immunopathogenesis of C. trachomatis infections; (2) important implications for the understanding of C. trachomatis–host interactions; (3) identification of genetic markers of the susceptibility to and severity of C. trachomatis infections; (4) identification of these genetic markers can be used to develop diagnostic tools that can determine an individual's predisposition to infection and the risk to develop late complications; finally (5) these studies will allow the development of novel tools for the detection and treatment of, and vaccine development for, C. trachomatis infections.

Two major issues have to be addressed to maximize the output of the immunogenetic approaches for C. trachomatis:

  1. the cohorts in which the current studies have been done are still (relatively) small and have to be extended both for ocular infections and sexually transmitted infections. One of the goals of the European Framework 6 funded EpiGenChlamydia Consortium (http://www.EpiGenChlamydia.EU) is to generate large cohorts in Europe and Africa. For this collection, biomedical ethical issues relating to the generation of multiethnical biobanks will need to be addressed properly.

  2. Besides the candidate gene approaches, SNP chip approaches also have to be used to assess more genes and pathways, including those not addressed in the current candidate gene approaches. At the Sixth Meeting of the European Society of Chlamydia Research in Aarhus, Denmark, this July, three groups already showed preliminary work and the use of small dedicated SNP chips: the UK (London and Oxford) group of David Mabey, Robin Bailey and Dominic Kwiatkowski, the group of Deborah Dean (California) and our group (Amsterdam, the Netherlands).

These studies will provide new insights and new pathways to be studied, further advancing the exciting field of Immunogenetics of C. trachomatis infections.

Statement

This is an invited MiniReview based on the Sixth Meeting of the European Society for Chlamydia Research.

Acknowledgements

The work of this manuscript is part of the goals described in the European Framework Programme 6 (FP6) funded EpiGenChlamydia Consortium (EU FP6 LSHG-CT-2007-037637) a Co-ordination Actions, in functional genomics research entitled: Contribution of molecular epidemiology and host–pathogen genomics to understand Chlamydia trachomatis disease (see additional information at http://www.EpiGenChlamydia.EU).

References

Bailey
R.L.
Natividad-Sancho
A.
Fowler
A.
Peeling
RWW
Mabey
DCW
Whittle
H.C.
Jepson
A.P.
(
2009
)
Host genetic contribution to the cellular immune response to Chlamydia trachomatis: heritability estimate from a Gambian twin study
.
Drugs Today
 
45
:
in press
.
Barr
E.L.
Ouburg
S.
Igietseme
J.U.
et al
. (
2005
)
Host inflammatory response and development of complications of Chlamydia trachomatis genital infection in CCR5-deficient mice and subfertile women with the CCR5delta32 gene deletion
.
J Microbiol Immunol Infect
 
38
:
244
254
.
Cohen
C.R.
Sinei
S.S.
Bukusi
E.A.
Bwayo
J.J.
Holmes
K.K.
Brunham
R.C.
(
2000
)
Human leukocyte antigen class II DQ alleles associated with Chlamydia trachomatis tubal infertility
.
Obstet Gynecol
 
95
:
72
77
.
Cohen
C.R.
Gichui
J.
Rukaria
R.
Sinei
S.S.
Gaur
L.K.
Brunham
R.C.
(
2003
)
Immunogenetic correlates for Chlamydia trachomatis-associated tubal infertility
.
Obstet Gynecol
 
101
:
438
444
.
Colmegna
I.
Cuchacovich
R.
Espinoza
L.R.
(
2004
)
HLA-B27-associated reactive arthritis: pathogenetic and clinical considerations
.
Clin Microbiol Rev
 
17
:
348
369
.
Conway
D.J.
Holland
M.J.
Campbell
A.E.
Bailey
R.L.
Krausa
P.
Peeling
R.W.
Whittle
H.C.
Mabey
D.C.
(
1996
)
HLA class I and II polymorphisms and trachomatous scarring in a Chlamydia trachomatis-endemic population
.
J Infect Dis
 
174
:
643
646
.
Conway
D.J.
Holland
M.J.
Bailey
R.L.
Campbell
A.E.
Mahdi
O.S.
Jennings
R.
Mbena
E.
Mabey
DCW
(
1997
)
Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid
.
Infect Immun
 
65
:
1003
1006
.
Den Hartog
J.E.
Ouburg
S.
Land
J.A.
Lyons
J.M.
Ito
J.I.
Peña
A.S.
Morré
S.A.
(
2006
)
Do host genetic traits in the bacterial sensing system play a role in the development of Chlamydia trachomatis-associated tubal pathology in subfertile women?
BMC Infect Dis
 
6
:
e122
.
Golden
M.R.
Schillinger
J.A.
Markowitz
L.
St. Louis
M.E.
(
2000
)
Duration of untreated genital infections with Chlamydia trachomatis. A review of the literature
.
Sex Transm Dis
 
27
:
329
337
.
Golden
M.R.
Whittington
W.L.
Handsfield
H.H.
et al
. (
2005
)
Effect of expedited treatment of sex partners on recurrent or persistent gonorrhea or chlamydial infection
.
New Engl J Med
 
352
:
676
685
.
Kinnunen
A.H.
Surcel
H.M.
Lehtinen
M.
Karhukorpi
J.
Tiitinen
A.
Halttunen
M.
Bloigu
A.
Morrison
R.P.
Karttunen
R.
Paavonen
J.
(
2002
)
HLA DQ alleles and interleukin-10 polymorphism associated with Chlamydia trachomatis-related tubal factor infertility: a case-control study
.
Hum Reprod
 
17
:
2073
2078
.
Lin
J-SL
Donegan
S.P.
Heeren
T.C.
et al
. (
1998
)
Transmission of Chlamydia trachomatis and Neisseria gonorrhoeae among men with urethritis and their female sex partners
.
J Infect Dis
 
178
:
1707
1712
.
Lyons
J.M.
Ito
J.I.
Jr
Peña
A.S.
Morré
S.A.
(
2005
)
Differences in growth characteristics and elementary body associated cytotoxicity between Chlamydia trachomatis oculogenital serovars D and H and Chlamydia muridarum
.
J Clin Pathol
 
58
:
397
401
.
Molano
M.
Meijer
C.J.
Morré
S.A.
Pol
R.
Van Den Brule
A.J.
(
2004
)
Combination of PCR targeting the VD2 of omp1 and reverse line blot analysis for typing of urogenital Chlamydia trachomatis serovars in cervical scrape specimens
.
J Clin Microbiol
 
42
:
2935
2939
.
Morré
S.A.
Moes
R.
Van Valkengoed
I.
Boeke
J.P.
Van Eijk
J.T.
Meijer
C.J.
Van den Brule
A.J.
(
1998
)
Genotyping of Chlamydia trachomatis in urine specimens will facilitate large epidemiological studies
.
J Clin Microbiol
 
36
:
3077
3078
.
Morré
S.A.
Rozendaal
L.
Van Valkengoed
IGM
et al
. (
2000
)
Urogenital Chlamydia trachomatis serovars in men and women having either a symptomatic or an asymptomatic infection: an association with clinical manifestations?
J Clin Microbiol
 
38
:
2292
2296
.
Morré
S.A.
Van Den Brule
A.J.
Rozendaal
L.
Boeke
A.J.
Voorhorst
F.J.
De Blok
S.
Meijer
C.J.
(
2002
)
The natural course of asymptomatic Chlamydia trachomatis infections: 45% clearance and no development of clinical PID after one-year follow-up
.
Int J STD AIDS
 
13
(
suppl 2
):
12
18
.
Morré
S.A.
Murillo
L.S.
Bruggeman
C.A.
Peña
A.S.
(
2003
)
The role that the functional Asp299Gly polymorphism in the toll-like receptor-4 gene plays in susceptibility to Chlamydia trachomatis-associated tubal infertility
.
J Infect Dis
 
187
:
341
342
.
Mozzato-Chamay
N.
Mahdi
OSM
Jallow
O.
Mabey
DCW
Bailey
R.L.
Conway
D.J.
(
2000
)
Polymorphisms in candidate genes and risk of scarring trachoma in a Chlamydia trachomatis — endemic population
.
J Infect Dis
 
182
:
1545
1548
.
Mozzato-Chamay
N.
Corbett
E.L.
Bailey
R.L.
Mabey
D.C.
Raynes
J.
Conway
D.J.
(
2001
)
Polymorphisms in the IkappaB-alpha promoter region and risk of diseases involving inflammation and fibrosis
.
Genes Immun
 
2
:
153
155
.
Murillo
L.S.
Land
J.A.
Pleijster
J.
Bruggeman
C.A.
Peña
A.S.
Morré
S.A.
(
2003
)
Interleukin-1B (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) gene polymorphisms are not associated with tubal pathology and Chlamydia trachomatis-related tubal factor subfertility
.
Hum Reprod
 
18
:
2309
2314
.
Natividad
A.
Wilson
J.
Koch
O.
et al
. (
2005
)
Risk of trachomatous scarring and trichiasis in Gambians varies with SNP haplotypes at the interferon-gamma and interleukin-10 loci
.
Genes Immun
 
6
:
332
340
.
Natividad
A.
Cooke
G.
Holland
M.J.
Burton
M.J.
Joof
H.M.
Rockett
K.
Kwiatkowski
D.P.
Mabey
DCW
Bailey
R.L.
(
2006
)
A coding polymorphism in matrix metalloproteinase 9 reduces risk of scarring sequelae of ocular Chlamydia trachomatis infection
.
BMC Med Genet
 
7
:
e40
.
Natividad
A.
Hanchard
N.
Holland
M.J.
et al
. (
2007
)
Genetic variation at the TNF locus and the risk of severe sequelae of ocular Chlamydia trachomatis infection in Gambians
.
Genes Immun
 
8
:
288
295
.
Natividad
A.
Holland
M.J.
Rockett
K.A.
Forton
J.
Faal
N.
Joof
H.M.
Mabey
D.C.
Bailey
R.L.
Kwiatkowski
D.P.
(
2008
)
Susceptibility to sequelae of human ocular chlamydial infection associated with allelic variation in IL10 cis-regulation
.
Hum Mol Genet
 
17
:
323
329
.
Ness
R.B.
Brunham
R.C.
Shen
C.
Bass
D.C.
(
2004
)
Associations among human leukocyte antigen (HLA) class II DQ variants, bacterial sexually transmitted diseases, endometritis, and fertility among women with clinical pelvic inflammatory disease
.
Sex Transm Dis
 
31
:
301
304
.
Ouburg
S.
Spaargaren
J.
Den Hartog
J.E.
Land
J.A.
Fennema
HSA
Pleijster
J.
Peña
A.S.
Morré
S.A.
ICTI consortium
(
2005
)
The CD14 functional gene polymorphism −260 C>T is not involved in either the susceptibility to Chlamydia trachomatis infection or the development of tubal pathology
.
BMC Infect Dis
 
5
:
e114
.
Shimamoto
Y.
Sugiyama
H.
Hirohata
S.
(
2000
)
Reiter's syndrome associated with HLA-B51
.
Intern Med
 
39
:
182
184
.
Stamm
W.E.
(
1988
)
Diagnosis of Chlamydia trachomatis genitourinary infections
.
Ann Intern Med
 
108
:
710
717
.
Starnbach
M.N.
Roan
N.R.
(
2008
)
Conquering sexually transmitted diseases
.
Nat Rev Immunol
 
8
:
313
317
.
Sziller
I.
Babula
O.
Ujházy
A.
Nagy
B.
Hupuczi
P.
Papp
Z.
Linhares
I.M.
Ledger
W.J.
Witkin
S.S.
(
2007
)
Chlamydia trachomatis infection, Fallopian tube damage and a mannose-binding lectin codon 54 gene polymorphism
.
Hum reprod
 
22
:
1861
1865
.
Van Valkengoed
I.G.
Morré
S.A.
Van Den Brule
A.J.
Meijer
C.J.
Bouter
L.M.
Van Eijk
J.T.
Boeke
A.J.
(
2002a
)
Partner notification among asymptomatic Chlamydia trachomatis cases, by means of mailed specimens
.
Brit J Gen Pract
 
52
:
652
654
.
Van Valkengoed
I.G.
Morré
S.A.
Van Den Brule
A.J.
Meijer
CJLM
Bouter
L.M.
Van Eijk
J.T.
Boeke
A.J.
(
2002b
)
Follow-up, treatment, and reinfection rates among asymptomatic Chlamydia trachomatis cases in general practice
.
Brit J Gen Pract
 
52
:
623
627
.
Wang
C.
Tang
J.
Geisler
W.M.
Crowley-Nowick
P.A.
Wilson
C.M.
Kaslow
R.A.
(
2005
)
Human leukocyte antigen and cytokine gene variants as predictors of recurrent Chlamydia trachomatis infection in high-risk adolescents
.
J Infect Dis
 
191
:
1084
1092
.
Weström
L.
Joesoef
R.
Reynolds
G.
Hadgu
A.
Tompson
S.E.
(
1992
)
Pelvic inflammatory disease and fertility. A cohort study of 1844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results
.
Sex Trans Dis
 
19
:
185
192
.
Zimmermann
H.L.
Potterat
J.J.
Dukes
R.L.
Muth
J.B.
Zimmermann
H.O.
Fogle
J.S.
Pratts
C.I.
(
1990
)
Epidemiologic differences between Chlamydia and gonorrhea
.
Am J Public Health
 
80
:
1338
1342
.

Author notes

Servaas Morré's work on this review was on behalf of the European Framework Programme Six (FP6) EpiGenChlamydia Consortium.
Editor: Svend Birkelund