Breast cancer and cytomegalovirus.

PURPOSE: To determine whether cytomegalovirus is causally associated with breast cancer and whether cytomegalovirus should be categorised as an oncogenic virus. METHODS: We undertook a review of published epidemiological and laboratory studies, using established causal criteria: Bradford Hill criteria to determine whether cytomegalovirus is associated with breast cancer; and Evans/Mueller criteria to determine whether cytomegalovirus should be categorised as an oncogenic virus. RESULTS: Although there are inconsistencies in the findings of published epidemiological and laboratory studies, these may be explained by factors such as: differences in timing of blood samples, differences in selection of cases and controls, or high cytomegalovirus seroprevalence among participants in the epidemiological studies; and, in the laboratory studies, differences in sample preparations, age of sample, whether or not paired breast cancer and normal breast tissue samples were used, differences in the tests, primers and/or antibodies used, differences in histological types of breast cancer studied, and/or features of the virus. CONCLUSIONS: Overall, the results of published studies of cytomegalovirus and breast cancer suggest cytomegalovirus is a causal factor for at least some types of breast cancer. If the evidence for a link between cytomegalovirus and breast cancer continues to strengthen, further research could lead to: targeted screening; therapy using antiviral drugs; and, perhaps, primary prevention of a significant proportion of breast cancer. Vaccination against viruses has already been shown to be effective in preventing cervix and liver cancer; cytomegalovirus vaccines are already under development.

The Finnish psychiatric birth cohort consortium (PSYCOHORTS) - content, plans and perspectives.

Background: Psychiatric disorders tend to be developmental, and longitudinal settings are required to examine predictors of psychiatric phenomena. Replicating and combining data and results from different birth cohorts, which are a source of reliable data, can make research even more valuable. The Finnish Psychiatric Birth Cohort Consortium (PSYCOHORTS) project combines birth cohorts in Finland. Aim: The aim of this paper is to introduce content, plans and perspectives of the PSYCOHORTS project that brings together researchers from Finland. In addition, we illustrate an example of data harmonization using available data on causes of death. Content: PSYCOHORTS includes eight Finnish birth cohorts. The project has several plans: to harmonize different data from birth cohorts, to incorporate biobanks into psychiatric birth cohort research, to apply multigenerational perspectives, to integrate longitudinal patterns of marginalization and inequality in mental health, and to utilize data in health economics research. Data on causes of death, originally obtained from Finnish Cause of Death register, were harmonized across the six birth cohorts using SAS macro facility. Results: Harmonization of the cause of death data resulted in a total of 21,993 observations from 1965 to 2015. For example, the percentage of deaths due to suicide and the sequelae of intentional self-harm was 14% and alcohol-related diseases, including accidental poisoning by alcohol, was 13%. Conclusions: PSYCOHORTS lays the foundation for complex examinations of psychiatric disorders that is based on compatible datasets, use of biobanks and multigenerational approach to risk factors, and extensive data on marginalization and inequality.

Comprehensive nationwide analysis of mother-to-child HIV transmission in Finland from 1983 to 2013.

HIV-positive children are still born in Europe despite low mother-to-child transmission (MTCT) rates. We aimed to clarify the remaining barriers to the prevention of MTCT. By combining the national registers, we identified all women living with HIV delivering at least one child during 1983-2013. Of the 212 women delivering after HIV diagnosis, 46% were diagnosed during the pregnancy. In multivariate analysis, age >30 years (P = 0.001), sexual transmission (P = 0.012), living outside of the metropolitan area (P = 0.001) and Eastern European origin (P = 0.043) were risk factors for missed diagnosis before pregnancy. The proportion of immigrants increased from 18% before 1999 to 75% during 2011-2013 (P < 0.001). They were diagnosed during the pregnancy equally to natives and achieved similar, good treatment results. No MTCT occurred when the mother was diagnosed before the delivery. In addition, 12 women had delivered in 2 years prior their HIV diagnosis, most before implementation of the national screening of pregnant women. Three of these children were infected, the last one in 2000. Our data demonstrate that complete elimination of MTCT is feasible in a high-income, low-prevalence country. This requires ongoing universal screening in early pregnancy and easy access to antiretroviral therapy to all HIV-positive people.

Serum antibody response to Chlamydia trachomatis TroA and HtrA in women with tubal factor infertility.

Persistent genital chlamydial infection may lead to tubal factor infertility (TFI). Chlamydia trachomatis TroA and HtrA are proteins expressed during persistent chlamydial infection in vitro. We studied serum IgG antibody response against these proteins by EIA in women with TFI and in subfertile women without tubal pathology. Altogether, 22 of 258 subfertile women (8.5%) had TFI which was unilateral in 17 cases and bilateral in 5 cases. Overall, 55 (21.3%) of the 258 women had TroA and 39 (15.1%) had HtrA antibodies. Seropositivity to TroA and HtrA was more common among women with TFI than women with other causes for subfertility (45.5 vs. 19.1%, p = 0.004 for TroA; 36.4 vs. 13.1%, p = 0.004 for HtrA). Mean absorbance values and the prevalence of TroA and HtrA antibodies increased with increasing severity of TFI. On the basis of our results, TroA and HtrA serology has the potential to be further developed to a specific biomarker for C. trachomatis-related TFI.

Humoral response to John Cunningham virus during pregnancy in multiple sclerosis.

BACKGROUND: Pregnancy induces an immunosuppressive state in the mother to ensure immunological acceptance of the foetus. Impairment of cell-mediated immune responses may render the mother susceptible to intracellular pathogens. It is not presently known whether pregnancy alters the immunosurveillance for John Cunningham virus (JCV), an opportunistic pathogen associated with natalizumab treatment for multiple sclerosis (MS). OBJECTIVE: To evaluate whether the humoral immune response to JCV is altered during pregnancy among MS patients and healthy controls to get insight to potential pregnancy-induced alterations related to immune response to JCV during pregnancy. METHODS: Serum anti-JCV-antibody-indices (JCV-Ab-index) were determined by a two-step second-generation enzyme-linked immunosorbent assay in 49 MS patients during and after pregnancy and in 49 healthy controls during pregnancy. For comparison, total IgG levels and antibodies against Epstein-Barr, cytomegalo and measles viruses were similarly measured. RESULTS: The JCV-Ab-indices of MS patients were not altered during the pregnancy (1st vs. 3rd trimester, 0.62 vs. 0.77, p = 0.99). Contrary to this, in the healthy controls JCV-Ab-indices (p = 0.005), antibody levels to the other viruses, and total IgG levels (p < 0.0001) decreased significantly during pregnancy. CONCLUSIONS: JCV-Ab levels remain unaltered during MS pregnancy, while the total IgG concentration is reduced/diluted due to increasing plasma volumes during the course of pregnancy. This may imply a biologically significant alteration in the immune response to JCV during MS pregnancy.

Association of serum 25-hydroxyvitamin D concentration with HLA-B, -DRB1 and -DQB1 genetic polymorphisms.

BACKGROUND/OBJECTIVES: The human leukocyte antigen (HLA) gene region associates with the risk for several autoimmune diseases, including type 1 diabetes. An association between vitamin D deficiency and several autoimmune diseases has been suggested. We tested the association between serum 25-hydroxyvitamin D (25OHD) concentrations and HLA alleles in pregnant Finnish women. SUBJECTS/METHODS: HLA-B (n=395), HLA-DRB1 (n=501) and HLA-DQB1 (n=475) alleles were genotyped in pregnant women (mothers of children who later developed type 1 diabetes and mothers of non-diabetic children). HLA-B alleles were divided into supertypes that share similar peptide-binding specificity. Serum 25OHD concentration had been previously measured in these women from sera collected during the first trimester of pregnancy. Multiple testing was controlled for using the false discovery rate method. RESULTS: An association was found between 25OHD concentration and HLA-B44 supertype (P=0.009); women with HLA-B44 supertype (B*18, B*37, B*40 and B*44 alleles) had lower 25OHD concentrations. No association was found between HLA-DRB1 or -DQB1 alleles and 25OHD concentration. CONCLUSIONS: In this study we found for the first time an association between HLA genetic polymorphisms and 25OHD concentration. In future studies, the mechanistic background of this association and the role of vitamin D in the regulation of HLA gene expression should be investigated.

Changes in objectively measured smoking in pregnancy by time and legislative changes in Finland: a retrospective cohort study.

OBJECTIVES: To study the changes in prevalence, characteristics and outcomes of pregnant smokers over time and legislative changes. DESIGN AND SETTING: Retrospective nationwide cohort. PARTICIPANTS: Our study consisted of 9627 randomly selected pregnancies from the Finnish Maternity Cohort (1987-2011), with demographic characteristics and pregnancy and perinatal data obtained from the Medical Birth Registry and early pregnancy serum samples analysed for cotinine levels. Women were categorised based on their self-reported smoking status and measured cotinine levels (with ≥4.73 ng/mL deemed high). Data were stratified to three time periods based on legislative changes in the Tobacco Act. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence of pregnant smokers and demographics, and perinatal and pregnancy outcomes of pregnant smokers over time. RESULTS: Overall, 71.6% of women were non-smokers, 16.2% were active cigarette smokers, 7.7% undisclosed smoking but had high cotinine levels and 4.5% were inactive cigarette smokers. The prevalence of active cigarette smokers decreased from mid-1990s onwards among women aged ≥30 years, probably due to the ban of cigarette smoking in most workplaces. We observed no changes in the prevalence of inactive smokers or women who undisclosed smoking by time or legislative changes.Women who undisclosed smoking had similar characteristics and perinatal outcomes as inactive and active smokers. Compared with non-smokers, women who undisclosed smoking were more likely to be young, unmarried, have a socioeconomic status lower than white-collar worker and have a preterm birth. CONCLUSIONS: Women who undisclosed smoking were very similar to pregnant cigarette smokers. We observed a reduction in the prevalence of active pregnant cigarette smokers after the ban of indoor smoking in workplaces and restaurants, mostly among women aged ≥30 years.

Contribution of IL-12A and IL-12B polymorphisms to Chlamydia trachomatis-specific cell-mediated immune responses.

Inherited variance in the IL-12B gene is associated with susceptibility to Chlamydia trachomatis-induced tubal factor infertility and disease severity. In this study, our aim was to discover how polymorphisms in IL-12-coding genes influence C. trachomatis-induced immune responses and IL-12 production. The study population consisted of 240 women. IL-12A and IL-12B single nucleotide polymorphisms (SNPs) were determined from isolated DNA using the Sequenom system with matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. We studied lymphocyte proliferative (LP) responses to C. trachomatis strains E and F elementary bodies (EBs) and recombinant chlamydial heat-shock protein 60 (CHSP60) antigen. IL-12p40 and IL-12p70 levels were measured using the BD Flex Set method. We found a statistically significant association between the C. trachomatis EB antigen-specific LP response and the rs2853694 SNP (P = 0.02). Our study demonstrates that the IL-12 cytokine family is involved in C. trachomatis-specific immune responses. Moreover, C. trachomatis-induced IL-12 production and the IL-12B rs2853694 SNP partially explain individual variation in the C. trachomatis LP response.

Anti-Mullerian hormone and risk of invasive serous ovarian cancer.

PURPOSE: Epithelial ovarian cancers either arise directly from Mullerian-type epithelium or acquire Mullerian characteristics in the course of neoplastic transformation. The anti-Mullerian hormone (AMH) causes regression of Mullerian structures during fetal development in males and has been shown to inhibit the growth of epithelial ovarian cancer. Therefore, we hypothesized that pre-diagnostic serum concentrations of AMH are inversely associated with risk of invasive serous ovarian cancer. METHODS: A case-control study (107 cases, 208 controls) was nested within the population-based Finnish Maternity Cohort (1986-2007). The sample donated during the first trimester of the last pregnancy preceding cancer diagnosis of the case subjects was selected for the study. For each case, two controls, matched on age and date at sampling, as well as parity at sampling and at cancer diagnosis were selected. AMH was measured by a second-generation AMH ELISA. Conditional logistic regression was used to compute odds ratios (OR) and 95 % confidence intervals (CI) for invasive serous ovarian cancer associated with AMH concentrations. RESULTS: Overall AMH concentrations were not associated with risk of invasive serous ovarian cancer (OR 0.93; 95 % CI 0.49-1.77 for top vs. bottom tertile, P trend=0.83). In women older than the median age at sampling (32.7 years), a doubling of AMH was associated with decreased risk (OR 0.69; 95 % CI 0.49-0.96), whereas an increased risk (OR 1.64; 95 % CI 1.06-2.54) was observed in younger women, P homogeneity = 0.002. CONCLUSIONS: In this first prospective investigation, risk of invasive serous ovarian cancer was not associated with pre-diagnostic AMH concentrations overall; however, the association may depend on age at AMH measurement.

Elevated maternal C-reactive protein and autism in a national birth cohort.

Autism is a complex neuropsychiatric syndrome with a largely unknown etiology. Inflammation during pregnancy may represent a common pathway by which infections and other insults increase risk for the disorder. Hence, we investigated the association between early gestational C-reactive protein (CRP), an established inflammatory biomarker, prospectively assayed in maternal sera, and childhood autism in a large national birth cohort with an extensive serum biobank. Other strengths of the cohort included nearly complete ascertainment of pregnancies in Finland (N=1.2 million) over the study period and national psychiatric registries consisting of virtually all treated autism cases in the population. Increasing maternal CRP levels, classified as a continuous variable, were significantly associated with autism in offspring. For maternal CRP levels in the highest quintile, compared with the lowest quintile, there was a significant, 43% elevated risk. This finding suggests that maternal inflammation may have a significant role in autism, with possible implications for identifying preventive strategies and pathogenic mechanisms in autism and other neurodevelopmental disorders.

Increased thyroid autoimmunity among women with multiple sclerosis in the postpartum setting.

BACKGROUND: Multiple sclerosis (MS) patients are predisposed to thyroid abnormalities, but the risk for pregnancy-related thyroid pathology among MS patients has not been evaluated. OBJECTIVES: The objectives of this research are to prospectively evaluate the prevalence of thyroid autoimmunity among MS patients in relation to pregnancy, and to investigate its impact on pregnancy outcome, postpartum depression and fatigue. METHODS: Forty-six pregnant MS patients underwent repeat testing for serum thyroid antibodies (Abs), clinical evaluation and thyroid hormone measurement. Results were compared to 35 age-matched healthy mothers. RESULTS: At six months postpartum 35.3% of MS patients presented elevated levels of thyroid Abs compared to 5.7% of controls, p = 0.01. Mean thyroid Ab concentrations among MS patients were significantly reduced during pregnancy and returned to maximal levels at six months postpartum. The proportion of individuals with postpartum thyroid dysfunction did not differ significantly between MS patients and healthy controls (3.4% vs 2.9%, p = 1.00). Elevated thyroid Ab levels did not increase the risk for adverse pregnancy outcome, fatigue or postpartum depression. CONCLUSIONS: Considering the tendency of MS mothers to develop thyroid autoimmunity postpartum and in association to treatments, we recommend screening MS patients for thyroid dysfunction (TSH) during early pregnancy and after delivery.

Effect of IL12A and IL12B polymorphisms on the risk of Chlamydia trachomatis-induced tubal factor infertility and disease severity.

BACKGROUND: Interleukin-12 (IL-12) and related cytokines induce activation and differentiation of T cells. Our aim was to investigate the associations between genetic differences in IL-12-family cytokines and the pathogenesis of chlamydial disease. METHODS: The final study population consisted of 100 women with Chlamydia trachomatis-induced tubal factor infertility (TFI) and 125 pregnant women as controls. Three single nucleotide polymorphisms (SNPs) of IL12A and seven SNPs of IL12B genes were determined from isolated DNA using the Sequenom system with matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. RESULTS: We found that the IL12B SNP rs3212227 was associated with both susceptibility and severity of TFI. The minor allele C was rare and only one CC homozygote was found among the controls. AC heterozygotes were more common among TFI cases than among controls (P = 0.009) and were associated with increased risk of TFI [odds ratios (OR) = 2.44, 95% confidence intervals (CI) = 1.23-4.87]. Carrying the minor allele C was also associated with disease severity (P for trend = 0.008) and moderate (OR = 2.51, 95% CI = 1.06-5.95) and severe tubal damage (OR = 2.73, 95% CI = 1.15-6.52). CONCLUSIONS: The results suggest that variation in the IL12B gene partly explains inter-individual differences in disease susceptibility and severity.

Serum 25-hydroxyvitamin D level during early pregnancy and type 1 diabetes risk in the offspring.

AIMS/HYPOTHESIS: Vitamin D deficiency during the fetal period or infancy is one of the suggested environmental factors for type 1 diabetes and for its increasing incidence. To test this hypothesis we compared serum 25-hydroxyvitamin D (25(OH)D) levels during early pregnancy in mothers of children who subsequently developed type 1 diabetes (case mothers) with mothers of non-diabetic healthy children (control mothers) of the same age. METHODS: Children with type 1 diabetes were identified from the nationwide prescription register. 25(OH)D concentration was measured from serum samples collected during the first trimester of pregnancy from all Finnish women (Finnish Maternity Cohort). A total of 343 case mothers and 343 control mothers were included in the study. Samples were collected throughout the year. Samples from case and control mothers were matched on the day of collection. RESULTS: Mean 25(OH)D levels in case mothers (43.9 nmol/l) and control mothers (43.7 nmol/l) were not different. Of all mothers, 481 (70.1%) were vitamin D-deficient or -insufficient. CONCLUSIONS/INTERPRETATION: No difference was found in serum 25(OH)D concentrations during first trimester of pregnancy between mothers whose children later on developed type 1 diabetes, and mothers of non-diabetic ' healthy' children of the same age. It is difficult to detect possible effects of mothers' vitamin D deficiency during early pregnancy on the development of type 1 diabetes in the offspring in this population, as such a large proportion of mothers were vitamin D-deficient or -insufficient.

Risk of seropositivity to multiple oncogenic human papillomavirus types among human immunodeficiency virus-positive and -negative Ugandan women.

To understand the prospects for human papillomavirus (HPV) mass vaccination in the setting of a developing country, we studied the co-occurrence of seropositivity to multiple high-risk (hr) HPV types among HIV-positive and HIV-negative Ugandan women. Our seroepidemiological study was conducted among 2053 women attending antenatal clinics. Sera were analysed for antibodies to eight hrHPV types of the α-7 (18/45) and α-9 (16/31/33/35/52/58) species of HPV by using a multiplex serology assay. Our results show that seropositivity for greater than one hrHPV type was as common (18 %) as for a single type (18 %). HIV-positive women had higher HPV16, HPV18 and HPV45 seroprevalences than HIV-negative women. In multivariate logistic regression analysis, age (>30 years) and level of education (secondary school and above) reduced the risk, whereas parity (>5) and HIV-positivity increased the risk for multiple hrHPV seropositivity. However, in stepwise logistic regression analyses, HIV-status remained the only independent, stand-alone risk factor [odds ratio (OR) 1.7, 95 % confidence interval (CI) 1.0-2.8). On the other hand, the risk of HPV16 or HPV18 seropositive women, as compared to HPV16 or HPV18 seronegative women, for being seropositive to other hrHPV types was not significantly different when they were grouped by HIV-status (ORHPV16/HIV+ 12, 95 % CI 4.5-32 versus ORHPV16/HIV- 22, 95 % CI 15-31 and ORHPV18/HIV+ 58, 95 % CI 14-242 versus ORHPV18/HIV- 45, 95 % CI 31-65). In conclusion, seropositivity to HPV16, HPV18 and to non-vaccine hrHPV types is common in Ugandan women, suggesting that there is little natural cross-protective immunity between the types. HIV-positivity was an independent, stand-alone, albeit moderate risk factor for multiple hrHPV seropositivity. HPV mass vaccination may be the most appropriate method in the fight against cervical cancer in the Ugandan population.

Comparison of the use of minimized cardiopulmonary bypass with conventional techniques on the incidence of retinal microemboli during aortic valve replacement surgery.

OBJECTIVES: Minimized cardiopulmonary bypass (MCPB) circuits have been shown to reduce cerebral and retinal microembolisation during coronary artery bypass graft (CABG) surgery compared to conventional CPB (CCPB) circuits. Our aim was to evaluate whether the reduction of microembolisation is sustained in aortic valve surgery, as well as to evaluate the effects of MCPB on inflammatory, endothelial, and platelet activation markers. MATERIAL AND METHODS: Patients were randomized to undergo aortic valve replacement (AVR), with or without CABG, with MPCB (n=20) or CCPB (n=20). After anaesthesia induction and termination of CPB, standardized digital retinal fluorescein angiography images were obtained on both eyes and analyzed in a blinded fashion. Blood samples were collected at eight time points until the third postoperative day. RESULTS: Fewer patients in the MCPB group showed evidence of microembolic perfusion defects on postperfusion retinal fluorescein angiographs compared to the CCPB group (37% vs. 63%, absolute difference 26%, 95% CI -5% -51%, P = 0.194). Polymorphonuclear leukocyte (PMN) elastase and von Willebrand factor release were statistically significantly reduced in the MCPB group, but there were no significant differences in other markers of inflammation, coagulation or endothelial activation. A significantly higher three-fold increase in the amount of shed blood was collected to the cell saver with a higher rate of intraoperative platelet transfusion in the MCPB group compared to CCPB. CONCLUSIONS: The use of MCPB was associated statistically insignificantly with less retinal microemboli compared to CCPB. MCPB was complicated by excess bleeding and need for transfusion. The feasibility of MCPB techniques in valve surgery requires further studies.

The effect of hysterectomy or levonorgestrel-releasing intrauterine system on cardiovascular disease risk factors in menorrhagia patients: a 10-year follow-up of a randomised trial.

OBJECTIVE: To compare, whether women with menorrhagia, treated with either hysterectomy or LNG-IUS, differ in their cardiovascular risk profile during 10-year follow-up. STUDY DESIGN: A total of 236 women were randomized to treatment by hysterectomy (n=117) or LNG-IUS (n=119). Their cardiovascular risk factors were analyzed at baseline, at 5 years, and at 10 years. As 55 originally randomized to the LNG-IUS group had hysterectomy during the follow-up, all analyzes were performed by actual treatment modality. MAIN OUTCOME MEASURES: Waist circumference, body-mass index (BMI), blood pressure, and the levels of blood lipids, serum high-sensitivity CRP (hsCRP) and tumor necrosis factor alpha (TNF-α) were measured, and the use of medication for hypertension, diabetes, hypercholesterolemia, and ischemic heart disease was analyzed. RESULTS: After 5 years, an increase in the use of diabetes medication during the follow-up was only detected in the hysterectomy group (from 1.7% to 6.7%, P=0.008 vs from 5.1% to 8.4%, P=0.08), as well as they had significantly higher serum levels of TNF-α (108.59 pg/ml vs 49.02 pg/ml, P=0.001) and hsCRP (1.55 µg/ml vs 0.78 µg/ml, P=0.038) at 5- and 10-years. There was no difference between the groups in the use of cardiovascular medication, neither was there difference in blood pressure, waist circumference, BMI, or concentrations of blood lipids. CONCLUSIONS: Hysterectomy seems to be associated with increased levels of serum inflammatory markers and increased diabetes medication, which in turn, may predispose individual to future cardiovascular events.

Changes in pre-diagnostic serum C-reactive protein concentrations and ovarian cancer risk: a longitudinal study.

BACKGROUND: Evidence suggests that inflammation may be associated with increased risk of ovarian cancer but there is paucity of studies investigating this association, especially using over-time changes in inflammatory biomarkers. MATERIALS AND METHODS: We conducted a prospective population-based case-control study nested within the Finnish Maternity Cohort (FMC). Within the FMC, 170 women with ovarian cancer who had donated serum samples to the cohort twice, ≥1 year apart, before cancer diagnoses were identified. One control per case was matched for age, parity and sampling date. RESULTS: Comparing the highest with lowest tertiles, the odds ratio (OR) of ovarian cancer using the first set of serum samples (mean lag time to cancer diagnosis 9.0 years) was 1.62 [95% confidence interval (CI) 0.93-2.83]. However, analysis conducted using the second set of serum samples donated closer to cancer diagnosis (mean lag time 6.4 years) revealed a significantly increased risk of ovarian cancer comparing extreme tertiles of C-reactive protein (CRP) concentrations; OR 1.96 (95% CI 1.11-3.4). Over time, increases in individuals' CRP concentrations were also associated with increased risk; OR 1.90 (95% CI 1.12-3.23). CONCLUSION: The results suggest that inflammation may precede ovarian cancer since increasing CRP concentrations, both across tertiles and longitudinally at the individual level, were associated with increased risk.

Cytokine gene polymorphism and Chlamydia trachomatis-specific immune responses.

Chlamydia trachomatis-induced fallopian tube damage leading to tubal factor infertility (TFI) is linked with TNF, IL-10, and probably IFNG gene polymorphisms. The aim of this study was to clarify the contribution of these cytokine gene polymorphisms to interindividual variation in C trachomatis-specific immune responses and the cross-regulation of secreted cytokines and single nucleotide polymorphisms (SNPs). Cytokine polymorphisms (IL-10 -1082A/G, -819T/C, and -592A/C, IFNG +874T/A, and TNF -308G/A) were genotyped by polymerase chain reaction in 139 women. C trachomatis-specific immune responses were measured using lymphocyte proliferation (LP) induced by C trachomatis E and F strains and chlamydial heat shock protein 60 antigens. Cytokine secretion was measured in culture supernatants of infected and uninfected mononuclear leukocytes. IL-10 -1082/-819/-592 and IFNG +874 SNPs were associated with the intensity of LP responses to C trachomatis antigens. These cytokines also interact with each other and a cumulative effect of IL-10 -1082 and IFNG +874 genotypes was seen in LP responses to C trachomatis antigens. Our data suggest that interleukin-10 and interferon-γ regulate C trachomatis-specific immune responses in humans and that genetic variation in the expression of their coding genes explains interindividual variation in host immune responses to C trachomatis infection.

Analyses of polymorphisms in the inflammasome-associated NLRP3 and miRNA-146A genes in the susceptibility to and tubal pathology of Chlamydia trachomatis infection.

Susceptibility to Chlamydia trachomatis infections is 40% host based. microRNA-146a is a negative regulator of Tolllike receptor (TLR) signaling and possesses functional polymorphisms which decrease the production of premiR-146a and mature miR-146a. Single nucleotide polymorphisms (SNPs) in NLRP3 are associated with decreased NLRP3 expression and hypoproduction of interleukin (IL)-1beta. We investigated whether the SNPs miR-146a G>C (rs2910164), NLRP3 C>T (rs4925663) and G>A (rs12065526) are associated with the susceptibility to and severity of C. trachomatis infection. The genotypes of three SNPs were tested in two cohorts: cohort 1 consists of Dutch women (n = 318) attending a sexually transmitted disease (STD) clinic and cohort 2 (n = 277) consists of subfertile (n = 184) and healthy Finnish women (n=93). While in cohort 1 the analyzed SNPs were not associated with the susceptibility to C. trachomatis infections (C. trachomatis-positive vs. C. trachomatis-negative), we showed in C. trachomatis-positive women that the NLRP3 mutant AG and AA genotypes were a risk factor for the development of symptoms (P = 0.047, OR = 2.9) and more specifically for having lower abdominal pain (genotype AA: P = 0.022, OR = 31.3). In the Finnish tubal pathology group versus the control group no statistical significant differences in the incidences of the SNPs studied were found, nor for the degree of tubal pathology. In conclusion, the mutant NLRP3 A allele is a risk factor for the development of symptoms, specifically lower abdominal pain, after a C. trachomatis infection in women attending an STD clinic.

Cytokine polymorphisms and severity of tubal damage in women with Chlamydia-associated infertility.

Chronic inflammation induced by Chlamydia trachomatis can lead to tubal factor infertility (TFI). To investigate the genetic basis of chlamydial TFI and various manifestations of tubal damage, we studied functional polymorphisms in selected cytokine genes (IL-10 -1082 A/G, -819 T/C, and -592 A/C; IFN-gamma +874 T/A; TNF-alpha -308 G/A; TGF-beta1 codons 10 T/C and 25 G/C; and IL-6 -174 G/C) in 114 women with laparoscopically verified TFI (hereafter known as "cases") and in 176 controls. Evidence of past infection with C. trachomatis was demonstrated in 96 cases by use of a combined test for humoral and cell-mediated immune responses to chlamydial elementary bodies (EBs) and chlamydial heat-shock protein 60 antigens. We found that the IL-10 -1082 AA genotype and the TNF-alpha -308 A allele increased the risk of severe tubal damage in women with infertility associated with C. trachomatis (odds ratio [OR], 7.3 [95% confidence interval {CI}, 1.3-42] and 4.0 [95% CI, 1.0-16], respectively), suggesting that differences in these genes contribute to the wide spectrum of disease manifestations.