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Chlamydia trachomatis: identification of susceptibility markers for ocular and sexually transmitted infection by immunogenetics

Servaas A. Morré, Ouafae Karimi, Sander Ouburg
DOI: http://dx.doi.org/10.1111/j.1574-695X.2009.00536.x 140-153 First published online: 1 March 2009


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.

  • Chlamydia trachomatis infections
  • immunogenetics
  • single-nucleotide polymorphisms
  • pathogen recognition receptors
  • Toll-like receptors
  • cytokines


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.

View this table:
Table 1

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

GeneBiological effectChromosome
Pathogen recognition receptors
TLR4TLR4, 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 responsiveness9q32–q33
TLR9TLR9 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 response3p21.3
CD14CD14 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 response5q31.1
NOD2NOD2 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 syndrome16q12
CCR5Potential 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 responses3p21
MBL/MBPThis 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 diseases10q11.2–q21
IL-1BIL-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 cells2q14
IL-1RNIL-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-1β2q14.2
IL-2IL-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 lymphocytes4q26–q27
IL-4IL-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 fibroblasts5q31.1
IL-4RIL-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-4R16p12.1–p11.2
IL-6IL-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-10IL-10 is an anti-inflammatory cytokine. It arrests and reverses the (chronic) inflammatory response1q31–q32
IL-12BIL-12 is a proinflammatory cytokine. It has a broad range of biological functions, which include sustaining long-term protection against intracellular pathogens5q31.1–q33.1
TNF-αTNF-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 cytokine6p21.3
LTALymphotoxin-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 apoptosis6p21.3
IFN-γIFN-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 activity12q14
TGF-βTransforming 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 differentiation19q13.1
HLA-A/-B/-C/-DQA/-DQB/-DRHLA/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 antigens6p21.3
MMP9Involved 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 angiogenesis20q11.2–q13.1
IκB-αIκB-α (NFκBIA) inactivates NFκB by trapping it in the cytoplasm, thus inhibiting proinflammatory signals14q13
IκBLThis 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 66p21.3
View this table:
Table 2

Immunogenetic association studies on Chlamydia infections focussed on pathogen recognition receptors

GenePolymorphismCohortnEthnicityGenotype frequency (%)ResultsAuthor
Pathogen recognition receptors
TLR4+896A>G (Asp299Gly)Tubal infertility35Dutch CaucasianAA: 85.7 AG: 14.3 GG: 0.0NSMorré et al. (2003)
TLR4+896A>G (Asp299Gly)Tubal pathology227Dutch CaucasianAA: 88.0 *G: 12.0NS, although increasing risk for tubal pathology was observed in trend analysesDen 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>CTubal pathology227Dutch CaucasianTT: 68.0 *C: 32.0IdemDen Hartog et al. (2006)
TLR9+2848 G>ATubal pathology227Dutch CaucasianGG: 20.0 *A: 80.0IdemDen Hartog et al. (2006)
CD14−260 C>TChlamydia infection/tubal pathology576/253Dutch CaucasianCC: 28.1/27.7 CT: 50.7/49.0 TT: 21.2/23.3NSOuburg et al. (2005)
CD14−260 C>TTubal pathology227Dutch CaucasianCC: 26.0 *T: 74.0NS, although increasing risk for tubal pathology was observed in trend analysesDen 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/NOD2SNP13 (Leu1007FsInsC)Tubal pathology227Dutch CaucasianWT/WT: 93.0 *InsC: 7.0IdemDen Hartog et al. (2006)
CCR5Δ32Subfertility/tubal pathology256Dutch CaucasianWT/WT: 80.0 WT/Δ32: 19.5 Δ32/Δ32: 0.5Decreased 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 pathologyBarr et al. (2005)
MBLCodon 54 (A>B)Tubal Pathology107Hungarian CaucasianAA: 54.6 AB: 31.9 BB: 13.5Carriage 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)
MBPCodon 57 (Gly/Glu)Scarring trachoma179GambianGly/Gly: 54.2 Gly/Glu: 39.7 Glu/Glu: 6.1NSMozzato-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 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.

View this table:
Table 3

Immunogenetic association studies on Chlamydia infections focussed on cytokines

GenePolymorphismCohortnEthnicityGenotype frequency (%)ResultsAuthor
IL-1B−511 C>TTubal factor subfertility40Dutch CaucasianCC: 40.0 CT: 52.5 TT: 7.5NSMurillo et al. (2003)
IL-1B+3954 C>TTubal factor subfertility40Dutch CaucasianCC: 62.5 CT: 30.0 TT: 7.5NSMurillo et al. (2003)
IL-1RN86 bp VNTRTubal factor subfertility40Dutch Caucasianx.x: 60.0 x.2: 32.5 2.2: 7.5NSMurillo et al. (2003)
IL-2−330 T>G, 160 G>T (haplotypes: G-G, T-G, T-T)Chlamydia infection (REACH study)485North American (71% African American)N/ANSWang et al. (2005)
IL-4−590 T>CScarring trachoma238GambianTT: 50.0 TC: 38.7 CC: 11.3NSMozzato-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)485North American (71% African American)N/ANSWang et al. (2005)
IL-4R1902 A>GChlamydia infection (REACH study)485North American (71% African American)N/ANSWang et al. (2005)
IL-6−174 G>CTubal infertility70 (35 MIF+/35 MIF−)KenyanGG: 94.0/94.0 GC: 3.0/6.0 CC: 0.0/0.0NSCohen et al. (2003)
IL-6−174 G>C 565 G>AChlamydia infection (REACH study)485North American (71% African American)N/ANSWang et al. (2005)
IL-10−3575 T>AScarring trachoma/trachiasis651GambianTT: 63.0 TA: 32.0 AA: 5.0Associated with trachomatous scarring (P=0.001; OR: 1.4; 95% CI: 1.1–1.7)Natividad et al. (2005)
IL-10−1082 A>GTubal factor infertility52FinnishAA: 22.0 AG: 41.0 GG: 37.0NS, 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>GScarring trachoma238GambianAA: 44.1 AG: 42.4 GG: 13.5G 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>GScarring trachoma/trachiasis651GambianAA: 46.0 AG: 41.0 GG: 0.13G 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>TScarring trachoma238GambianCC: 29.8 CT: 46.2 TT: 24.0NSMozzato-Chamay et al. (2000)
IL-10−592 A>CScarring trachoma238GambianAA: 24.0 AC: 47.9 CC: 28.1NSMozzato-Chamay et al. (2000)
IL-10−592 A>CScarring trachoma/trachiasis651GambianAA: 30.0 AC: 46.0 CC: 24.0NSNatividad et al. (2005)
IL-10+5009 A>GScarring trachoma/trachiasis651GambianAA: 40.0 AG: 46.0 GG: 14.0Associated with trachomatous scarring (P=0.04; OR: 1.2; 95% CI: 1.0–1.5)Natividad et al. (2005)
IL-10RS3024496 (3′UTR)Scarring trachoma/trachiasis651GambianWT/WT: 39.6 WT/MT: 45.0 MT/MT: 13.7Long-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)485North American (71% African American)N/ANSWang et al. (2005)
IL-10−1082 A>G/−819 C>T/−592 A>C haplotypesTubal infertility70 (35 MIF+/35 MIF−)KenyanGCC/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: 14.0/14.0NSCohen et al. (2003)
IL-10−1082 A>G/−819 C>T/−592 A>C haplotypesChlamydia infection (REACH study)485North American (71% African American)N/AGCC 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 haplotypesScarring trachoma/trachiasis651GambianTTTA: 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: 0.1ACGG 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)485North American (71% African American)N/ANSWang et al. (2005)
TNF−308 G>AScarring trachoma153GambianGG: 71.6 GA: 24.1 AA: 4.2Increased 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−308 G>ATubal infertility70 (35 MIF+/35 MIF−)KenyanGG 86.0/83.0 GA: 6.0/17.0 AA: 6.0/0.0NSCohen et al. (2003)
TNF−308 G>AScarring trachoma/trachiasis651GambianGG: 60.0 GA: 36.0 AA: 0.04TNF-α-308*A associated with trachiasis (P=0.016; OR: 1.5; 95% CI: 1.1–2.2)Natividad et al. (2007)
TNF−376 G>AScarring trachoma238GambianGG: 94.5 GA: 5.5 AA: 0.0NSMozzato-Chamay et al. (2000)
TNF−238 G>AScarring trachoma153GambianGG: 83.9 GA: 14.1 AA: 2.1Increased 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−238 G>AScarring trachoma/trachiasis651GambianGG: 87.0 GA: 13.0 AA: 0.07NSNatividad et al. (2007)
TNF−308 G>A, −238 G>A (haplotypes: G-G, A-G, G-A)Chlamydia infection (REACH study)485North American (71% African American)N/ANSWang et al. (2005)
LTA+72 G>TScarring trachoma/trachiasis651GambianGG: 45.0 GT: 40.0 TT: 15.0NSNatividad et al. (2007)
LTA+252 A>GScarring trachoma/trachiasis651GambianAA: 31.0 AG: 46.0 GG: 23.0LTA+252*G associated with trachiasis (P trend=0.018; OR: 1.4; 95% CI: 1.1–1.8)Natividad et al. (2007)
IFN+874 T>ATubal infertility70 (35 MIF+/35 MIF−)KenyanTT: 0.0/8.0 TA: 31.0/36.0 AA: 69.0/56.0NSCohen et al. (2003)
IFN−1616 C>TScarring trachoma/trachiasis651GambianCC: 26.0 CT: 47.0 TT: 27.0NSNatividad et al. (2005)
IFN+2200 T>CScarring trachoma/trachiasis651GambianTT: 88.0 TC: 11.0 CC: 1.0NSNatividad et al. (2005)
IFN+3234 T>CScarring trachoma/trachiasis651GambianTT: 54.0 TC: 37.0 CC: 10.0Associated with trachomatous scarring (P=0.04; OR: 1.2; 95% CI: 1.0–1.5)Natividad et al. (2005)
IFN+5612 C>TScarring trachoma/trachiasis651GambianCC: 49.0 CT: 41.0 TT: 10.0NSNatividad et al. (2005)
IFNHaplotypes −1616/+2200/+3234/+5612Scarring trachoma/trachiasis651GambianCTTC: 33.7/CCTC: 6.4 CTTT: 8.9/TTCC: 28.3 TTCT: 0.2/TTTC: 0.5 TTTT: 21.9TTCC associated with scarring trachoma (P=0.02; OR: 1.3; 95% CI: 1.0–1.6)Natividad et al. (2005)
TGF1Codon 10 T>C Codon 25 G>CTubal infertility70 (35 MIF+/35 MIF−)KenyanTT-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: 0.0/0.0NSCohen 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).

View this table:
Table 4

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

GenePolymorphismCohortnEthnicityGenotype frequency (%)ResultsAuthor
HLADQA DQBTubal factor infertility and tubal ligation47 and 46 (respectively)NairobiDQA*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)
HLADQA1 DQB1Tubal factor infertility52FinnishDQB1*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)
HLADQA DQB DRTubal infertility70 (35 MIF+/35 MIF−)KenyanHLA-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)
HLAA B Cw DRB1 DQB1Scarring trachoma153GambianA28: 25.8The 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)
HLAA B C DRB1 DQB1Chlamydia infection (REACH study)485North 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)
HLADQA DQBPID (PEACH study) Chlamydia cervicitis92American (2/3 ‘Black’)N/ACarriage 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)
MMP9rs2664538 A>G (Q279R)Scarring trachoma/trachiasis651GambianAA: 55.0 AG: 35.0 GG: 10.0G 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)
MMP9rs2250889 C>G (R574P)Scarring trachoma/trachiasis651GambianCC: 73.0 CG: 25.0 GG: 2.0NSNatividad et al. (2006)
MMP9rs13969 A>C (G607G)Scarring trachoma/trachiasis651GambianAA: 35.0 AC: 46.0 CC: 20.0NSNatividad et al. (2006)
MMP9rs13925 G>A (V694)Scarring trachoma/trachiasis651GambianGG: 75.0 GA: 23.0 AA: 2.0NSNatividad et al. (2006)
MMP9Haplotype rs2664538 A>G /rs2250889 C>G /rs13969 A>C rs13925 G>AScarring trachoma/trachiasis651GambianACCG: 36.0 ACAG: 23.0 GCAA: 14.0 GCAG: 10.0 AGAG: 10.0 AGCG: 4.0 GCCG: 2.0The 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>GScarring trachoma199GambianAA: 94.5 AG: 5.0 GG: 0.5The −881G/−826T haplotype was significantly decreased in cases compared to controls (P=0.046)Mozzato-Chamay et al. (2001)
IκB-α−826 C>TScarring trachoma199GambianCC: 94.5 CT: 5.0 TT: 0.5IdemMozzato-Chamay et al. (2001)
IκB-α−297 C>TScarring trachoma199GambianCC: 98.0 CT: 2.0 TT: 0.0NSMozzato-Chamay et al. (2001)
IκB-αHaplotype −881/−826/−297Scarring trachoma199GambianACC: 95.0 GTC: 3.8 ACT: 0.5 GTT: 0.6NSMozzato-Chamay et al. (2001)
IκBL−63 A>TScarring trachoma/trachiasis651GambianAA: 30.0 AT: 47.0 TT: 22.0IκBL −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-238Scarring trachoma/trachiasis651GambianATAGG: 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:<1.0Two 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.


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


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).


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

  • Editor: Svend Birkelund


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