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The objective was to assess the impact of genetic variation on cervical cytokine concentrations of interleukin (IL)-1α, IL-1β, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α), and first, to determine if these variants interact with polymorphisms in Toll-like receptor 4 (TLR4) that were previously shown to associate with pro-inflammatory cervical cytokine concentrations, and second, to determine if findings are affected by bacterial vaginosis (BV). We examined 183 single nucleotide polymorphisms (SNPs) in 13 cytokine genes and receptors for associations with cervical cytokine levels in 188 African American and European American women. We tested for associations of gene-gene interactions between SNPs in TLR4 and cytokine gene and receptor polymorphisms with cervical pro-inflammatory cytokines. None of the single locus associations were significant after correction for multiple testing in either European Americans or African Americans. However, there were significant gene-gene interactions between IL-1R2 rs485127 and two SNPs in TLR4 (rs1554973 and rs7856729) with IL-1β after correction for multiple testing. Our study demonstrates that interactions between TLR4 and IL-1R2 are associated with cervical pro-inflammatory cytokine concentrations. These results provide important insights into the possible regulatory mechanisms of the inflammatory response in the presence and absence of microbial disorders such as BV. Additionally, the observed differences in allele frequencies between African Americans and those of European descent may partially explain population disparity in pregnancy-related phenotypes that are cytokine concentration-dependent., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Few studies have examined the coordinated regulation of the extensive network of cytokines, chemokines, and growth factors involved in the immune response to bacterial vaginosis (BV) during pregnancy. We compared these patterns between women with (BV(+)) and without (BV(-)) bacterial vaginosis and between women of African and of European ancestry. This cohort included 83 Whites (28 BV(+) and 55 BV(-)) and 80 Blacks (41 BV(+) and 39 BV(-)). Pairwise correlations were determined for 28 factors that included cytokines, chemokines, and growth factors. In Whites, there were significantly more correlations involving immunoregulatory cytokines in BV(-) compared with BV(+) women. In Blacks, there were no significant differences in the correlation patterns between BV(+) and BV(-) women. Overall, in BV(-) women, there were no significant differences in the correlation patterns between Whites and Blacks. Conversely, in BV(+) women, Blacks have a stronger correlated response to infection than Whites. This indicates that Whites and Blacks have different correlated immune responses to BV that may at least partially explain the disparity observed in the prevalence of this disease.

Background: Preterm birth (PTB) is hypothesized to be an inflammatory response disease. However, no single factor alone is likely to explain PTB risk. It is more probable that coordinated networks of cytokines affect risk., Methods: Therefore, we examined the relationships between amniotic fluid (AF) cytokines/chemokines and related biomarkers in PTB and normal term deliveries in African Americans and Caucasians. Data were obtained from African American (41 preterm labor and 91 term labor) and Caucasian (105 preterm labor and 100 term labor) pregnant mothers. Pro-inflammatory cytokines and related molecules interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor- (TNF)-alpha, TNF soluble receptors (sTNFR1 and sTNFR2), and anti-inflammatory cytokine IL-10 that were all previously associated with PTB were studied. Correlations between biomarkers were calculated; differences of correlation coefficients between AF from African American and Caucasian samples in preterm labor and term labor were measured., Results: Multiple differences were observed between African American and Caucasian preterm and term birth groups. In term birth the strongest differences were between pro- and anti-inflammatory correlations, whereas in PTB differences were equally distributed between pro-inflammatory/anti-inflammatory and pro-inflammatory/pro-inflammatory correlations. Three correlation patterns differed significantly between AF from PTB African Americans with and without microbial invasion of the intra-amniotic cavity (MIAC); no differences were observed in Caucasians with MIAC., Conclusion: Correlation analyses of cytokine measurements suggest coordinated interplay during pregnancy; significant differences exist between African Americans and Caucasians. Such analyses can serve as a means of understanding risk factors in these populations.

We have examined the association between cervical cytokine, chemokine and growth factor concentrations with bacterial vaginosis (BV) in pregnant white and black women. A nested case-control analysis was performed to examine 28 cervical cytokine, chemokine and growth factor concentrations in 83 white women (55 with normal flora and 28 with BV) and 81 black women (39 with normal flora and 42 with BV). White women with BV had significantly lower IP10 (P=0.001) and MCP1 (P=0.006) concentrations compared to women with normal flora. Black women with BV had higher IL-1alpha (P<0.001) concentrations than those with normal flora. In women with normal flora, whites had significantly higher levels of IL-1alpha (P=0.047), IL-6 (P=0.010), IL-10 (P=0.016) and PDGF-BB (P=0.010) than blacks. There were no significant concentration differences between white and black women with BV. These results demonstrate significant differences in cytokine and chemokine concentrations between women with and without BV. Ethnic differences in cytokine concentrations were also observed in women with normal flora, indicating that white and black women with normal flora have different cytokine levels, but respond to BV in a similar manner.

More than 20 years after the identification of Helicobacter pylori as a human pathogen, gastric cancer continues to be a leading cause of cancer deaths worldwide. Genetic association studies have the potential for helping to identify those at greatest risk for developing gastric cancer subsequent to infection by H. pylori. IL1B promoter polymorphisms have been supported by several meta-analyses as being associated with gastric cancer risk. In this review, we discuss challenges in experimental design of gene association studies in gastric cancer, with attention to gene-environment interactions that may lead to inconsistency in findings across populations.

Differences in incidence and outcome of cancer among ethnic groups may be explained by biological and/or socio-economic factors. Genetic variations that affect chronic inflammation, a potentially important risk factor for carcinogenesis, may differ across ethnic groups. Such differences may help explain cancer disparities among these groups. Single nucleotide polymorphisms (SNPs) within cytokine genes can affect cytokine levels and the degree of inflammation. Associations between cancer and some cytokine SNPs have been suggested. However, these have not been consistently replicated among populations, suggesting that SNP function may differ according to ethnicity, or that SNPs alone do not completely account for regulation of inflammation. We examined seven polymorphisms in African-American (n = 294) and Caucasian (n = 299) newborns in Louisiana: IL1B-511C > T, IL1B-31T > C, IL1B + 3954C > T, IL1RN*2, IL10-1082G > A, IL10-592C > A, and TNF-308G > A. African-American newborns had significantly higher frequencies of IL1B-511T, IL1B-31C, IL10-1082A and IL10-592A alleles and complete linkage equilibrium between IL1B + 3954 and IL1B-31. In contrast, IL1B + 3954T, IL1RN*2, and TNF-308A were more frequent in Caucasian newborns and exhibited strong linkage disequilibrium between IL1B + 3954 and IL1B-31. All allelic frequencies were significantly different between groups. We hypothesize that these dissimilarities may contribute to differences in the inflammatory response and cancer incidence and mortality between African-Americans and Caucasians in Louisiana.

One in three people has been infected with Mycobacterium tuberculosis (MTB), and the risk for MTB infection in HIV-infected individuals is even higher. We hypothesized that HIV-positive individuals living in tuberculosis-endemic regions who do not get infected by Mycobacterium tuberculosis are genetically resistant. Using an “experiment of nature” design that proved successful in our previous work, we performed a genome-wide association study of tuberculin skin test positivity using 469 HIV-positive patients from prospective study cohorts of tuberculosis from Tanzania and Uganda to identify genetic loci associated with MTB infection in the context of HIV-infection. Among these individuals, 244 tested were tuberculin skin test (TST) positive either at enrollment or during the >8 year follow up, while 225 were not. We identified a genome-wide significant association between a dominant model of rs877356 and binary TST status in the combined cohort (Odds ratio = 0.2671, p = 1.22x10-8). Association was replicated with similar significance when examining TST induration as a continuous trait. The variant lies in the 5q31.1 region, 57kb downstream from IL9. Two-locus analyses of association of variants near rs877356 showed a haplotype comprised of rs877356 and an IL9 missense variant, rs2069885, had the most significant association (p = 1.59x10-12). We also replicated previously linked loci on chromosomes 2, 5, and 11. IL9 is a cytokine produced by mast cells and TH2 cells during inflammatory responses, providing a possible link between airway inflammation and protection from MTB infection. Our results indicate that studying uninfected, HIV-positive participants with extensive exposure increases the power to detect associations in complex infectious disease. [ABSTRACT FROM AUTHOR]

Many diseases are differentially distributed among human populations. Differential selection on genetic variants in ancestral environments that coincidentally predispose to disease can be an underlying cause of these unequal prevalence patterns. Selected genes may be pleiotropic, affecting multiple phenotypes and resulting in more than one disease or trait. Patterns of pleiotropy may be helpful in understanding the underlying causes of an array of conditions in a population. For example, several fibroproliferative diseases are more prevalent and severe in populations of sub-Saharan ancestry. We propose that this disparity is due to selection for an enhanced Th2 response that confers resistance to helminthic infections, and concurrently increases susceptibility to fibrosis due to the profibrotic action of Th2 cytokines. Many studies on selection of Th2-related genes for host resistance to helminths have been reported, but the pleiotropic impact of this selection on the distribution of fibrotic disorders has not been explicitly investigated. We discuss the disproportionate occurrence of fibroproliferative diseases in individuals of African ancestry and provide evidence that adaptation of the immune system has shaped the genetic structure of these human populations in ways that alter the distribution of multiple fibroproliferative diseases. [ABSTRACT FROM AUTHOR]

We examined the association of 166 single nucleotide polymorphisms (SNPs) in cytokines and cytokine related genes with cytokine concentrations (IL-1β, IL-8, and IL-10) in the amniotic fluid (AF). These cytokines have been associated with spontaneous preterm birth (PTB) and their genetic regulation may play a role in disease risk. These associations were studied in both PTB and term births in African Americans and Caucasians; maternal and fetal genotypes were studied separately. Analyses modeled genotype, pregnancy status, and marker by pregnancy status (case/control) interaction with cytokine concentration as outcome. Our results indicate that AF cytokines (IL-1β and IL-10) were associated with interactions between pregnancy status and both maternal and fetal SNPs, with the most significant interactions being observed for African Americans with IL-1β concentration (maternal at IL1RAP rs1024941 p < 10−3, fetal IL1RAP rs3773953 p < 10−3). AF IL-10 concentrations also showed evidence for association with SNPs in both ethnicities with the most significant interaction in Caucasian maternal samples (IL10 rs1800896 p < 10−3). Our data indicate that the genetic regulation of cytokine concentrations in PTB likely differs by ethnicity. AF cytokine concentrations were associated with interactions between genotype and PTB in African Americans, but less so in Caucasians. [ABSTRACT FROM AUTHOR]

Background: The interleukin-1 (IL-1) family of cytokines is involved in the inflammatory and repair reactions of skeletal muscle during and after exercise. Specifically, plasma levels of the IL-1 receptor antagonist (IL-1ra) increase dramatically after intense exercise, and accumulating evidence points to an effect of genetic polymorphisms on athletic phenotypes. Therefore, the IL-1 family cytokine genes are plausible candidate genes for athleticism. We explored whether IL-1 polymorphisms are associated with athlete status in European subjects. Methods: Genomic DNA was obtained from 205 (53 professional and 152 competitive non-professional) Italian athletes and 458 non-athlete controls. Two diallelic polymorphisms in the IL-1β gene (IL-1B) at -511 and +3954 positions, and a variable number tandem repeats (VNTR) in intron 2 of the IL-1ra gene (IL-1RN) were assessed. Results: We found a 2-fold higher frequency of the IL-1RN ½ genotype in athletes compared to non-athlete controls (OR = 1.93, 95% CI = 1.37-2.74, 41.0% vs. 26.4%), and a lower frequency of the 1/1 genotype (OR = 0.55, 95% CI = 0.40-0.77, 43.9% vs. 58.5%). Frequency of the IL-1RN 2/2 genotype did not differ between groups. No significant differences between athletes and controls were found for either -511 or +3954 IL-1B polymorphisms. However, the haplotype (-511)C-(+3954)T-(VNTR)2 was 3-fold more frequent in athletes than in non-athletes (OR = 3.02, 95% CI = 1.16-7.87). Interestingly, the IL-1RN 1/2 genotype was more frequent in professional than in nonprofessional athletes (OR = 1.92, 95% CI = 1.02-3.61, 52.8% vs. 36.8%). Conclusions: Our study found that variants at the IL-1ra gene associate with athletic status. This confirms the crucial role that cytokine IL-1ra plays in human physical exercise. The VNTR IL-1RN polymorphism may have implications for muscle health, performance, and/or recovery capacities. Further studies are needed to assess these specific issues. As VNTR IL-1RN polymorphism is implicated in several disease conditions, athlete status may constitute a confounding variable that will need to be accounted for when examining associations of this polymorphism with disease risk. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to examine correlations between vaginal inflammatory cytokines (IL-1α, IL-1β, IL-6 and IL-8) and pregnancy-related traits (gestational age, birth-weight, BMI, weight gain during pregnancy and vaginal pH). Differences in correlation coefficients were examined among bacterial vaginosis (BV) status and the presence or absence of mycoplasmas. A total of 105 women between the 22nd and 34th week of pregnancy were enrolled in this study. There was a strong negative correlation between IL-1α and weight gain during pregnancy (r =−0.877, p <0.001) and a strong positive correlation between IL-6 and BMI (r =0.670, p =0.024) in women with normal vaginal flora and mycoplasmas. These correlations were not present in women who had normal flora and no mycoplasmas. In women with BV and no mycoplasmas, there were significant correlations of gestational age with IL-6 (r =0.727, p =0.027) and IL-8 (r =0.689, p =0.040); however, these correlations were not significant in women with mycoplasmas. Our findings support the conclusion that correlations between inflammatory cytokines and pregnancy-related traits are dependent on context, suggesting that expression is labile. In particular, BMI and gestational age correlation differs depending on BV status and the presence or absence of BV-related mycoplasmas such as Mycoplasma hominis and Ureaplasma urealyticum. [Copyright &y& Elsevier]

Objective: We hypothesize that genetic variations (single nucleotide polymorphisms-SNPs) in the tumor necrosis factor-α (TNF-α), TNF receptors (TNFRI and TNFRII), interleukin-6 (IL-6) and IL-6 receptor (lL-6R) genes predict high-risk status for spontaneous preterm birth (sPTB) in European-American women. In this study we examine the allelic and genotypic variations and the gene-gene interactions in the TNF-α, TNFRs, IL-6, and IL-6R genes in maternal DNA samples by using a case-control model. Study design: Maternal DNA from cases of sPTB after preterm labor (n = 101) and controls (normal term labor and delivery) (n = 321) were genotyped for SNPs in the TNF-α (6), TNFRI (6), TNFRII (7), IL-6 (5), and IL-6R (3) loci. SNPs were tested for both allele and genotype differences (eases vs controls) with the use of standard genetic epidemiologic methods. Multilocus interaction was assessed with multifactor dimensionality reduction analysis (MDR) to test all single and multilocus combinations for the ability to predict sPTB. Results: Few significant allelic and genotypic associations were detected between cases and controls in maternal DNA. Single locus analysis documented independent association of SNPs at -7294 (allele and genotype) of TNFRI and 24660 (genotype) TNFRII loci with sPTB. MDR revealed a significant 3 locus model that includes SNPs-3448 of TNF-α, -7227 of IL-6, and 33314 of IL-6R. This interactive model allowed the successful prediction of pre- to low-risk genotypes is 3.50 (95% CI 2.52-4.87, P < .001). Conclusion: This is the first report to document a multilocus interaction in sPTB that predicts 65.2% of the cases in a European-American sample. Although putatively significant associations with sPTB were seen at a few single locus sites in TNFRI and TNFRII, they were not as predictive as the 3-locus model produced by MDR, suggesting the use of multilocus analyses in gene association studies of complex disease such as sPTB. [ABSTRACT FROM AUTHOR]

Objective: To understand the differences in genetic interactions among tumor necrosis factor-alpha, interleukin-6 and their receptor gene variants between black and white patients in spontaneous preterm birth. Study Design: Maternal and fetal DNA (n = 1195) were collected from cases (preterm birth < 36 weeks'' gestation; n = 448), controls (> 37 weeks'' gestation; n = 747), and genotyped for single nucleotide polymorphisms in tumor necrosis factor-alpha, tumor necrosis factor receptor 1, and tumor necrosis factor receptor 2, interleukin-6, and interleukin-6 receptor loci. Multifactor dimensionality reduction analysis was used to test all single and multilocus combinations for the ability to predict pregnancy outcome. Results: In white patients, multilocus interactions in maternal DNA between single nucleotide polymorphisms at −7227 (interleukin-6), 22,215 (interleuki-6 receptor) and −3448 (tumor necrosis factor-alpha) was predictive of approximately 59.1% (P < .02; odds ratio, 2.3 [95% confidence interval = 1.6-3.4]) of pregnancy outcome. In white fetal DNA and black maternal DNA, no significant interactive models were observed. In black patients, the best epistatic model was in fetal DNA between single nucleotide polymorphisms at 17,691 (tumor necrosis factor-receptor 1) and at −3448 (tumor necrosis factor-alpha) and was predictive of pregnancy outcome 68.3% of the time (P < .01; odds ratio, 5.0 [95% confidence interval = 2.6-9.6]). Conclusion: Analyses of multilocus interactions found/associated different models in black and white patients in both maternal and fetal DNA with preterm birth as outcome. Significant maternal-fetal interactions were not detected in either race. [Copyright &y& Elsevier]

Objective: Preterm birth rate in the United States is higher in blacks than whites. It has been hypothesized that a differential inflammatory response may explain this disparity. The objective of this study is to examine the inflammatory cytokine, tumor necrosis factor (TNF)-α and soluble TNF receptor concentrations (sTNFR1 and sTNFR2) in the amniotic fluid of black and white women at delivery. Study Design: Amniotic fluid samples were collected during active labor from 158 cases (preterm births, gestational age 220/7 weeks to 360/7 weeks, 52 black and 106 white) and 175 controls (term births, gestational age 370/7 weeks to 420/7 weeks, 87 black and 88 white) at Centennial Women''s Hospital, Nashville, TN. Amniotic fluid TNF-α, sTNFR1, and sTNFR2 concentrations and the molar ratios of TNF-α to its receptors were compared between cases and controls within each racial group. Results: Median TNF-α concentration was associated with preterm birth when whites and blacks were analyzed together, with cases having higher values (191.5 pg/mL) than controls (68.9 pg/mL; P < .001). There were no significant associations with sTNFR1 or sTNFR2 concentrations between cases (2409.4 and 2934.3 pg/mL, respectively) and controls (2759.9 and 3084.1 pg/mL, respectively) when the racial groups were analyzed together (P = .08, P = .4, respectively). Black cases associated with higher TNF-α concentrations (1287.0 pg/mL in cases and 67.3 pg/mL in controls; P < .001). In whites there was no association between TNF-α and preterm birth (P = .3). The molar ratio of TNF-α/total sTNFR (R1 plus R2) associated with higher TNF-α in black cases, compared with black controls (P < .001). There was no significant association between white cases and controls for ligand receptor ratios (P = .3). Conclusion: The TNF-α/sTNFR profile in pregnancy differs between racial groups, suggesting a difference in bioavailability of TNF-α. The larger molar ratio of TNF-α/sTNFR in black cases may be indicative of a TNF-α mediated pathological process of preterm birth in blacks but not in whites. [Copyright &y& Elsevier]