IL-10 Haplotypes Research Articles

Association of genetic polymorphisms in the interleukin-10 promoter with risk of prostate cancer in Chinese

BackgroundRecent studies identified an increased risk of prostate cancer (PCa) in Caucasian men harboring polymorphisms of genes involved in innate immunity and inflammation. This study was designed to assess whether single nucleotide polymorphisms in the IL-10 promoter play a role in predisposing individuals to PCa in a Chinese population.MethodsWe genotyped three SNPs of the IL-10 promoter (-1082A/G, -819T/C and -592A/C) using polymerase chain reaction-restriction fragment length polymorphism analysis in 262 subjects with PCa and 270 age-matched healthy controls. Odds ratio and 95% confidence interval were determined by logistic regression for the associations between IL-10 genotypes and haplotypes with the risk of PCa and advanced PCa grade.ResultsNo significant differences in allele frequency or genotype distribution were observed for any of the IL-10 SNPs between PCa patients and control subjects. Significantly higher frequencies of -1082G, -819C and -592C allele and GCC haplotype were observed, however, in early stage patients in comparison to advanced PCa patients (for -1082 G, 13.9% vs 6.1%, OR = 2.48, P = 0.005; for -819 C 40.3% vs 30.8%, OR = 1.51, P = 0.043; for -512C, 40.3% vs 30.8%, OR = 1.51, P = 0.043; and for haplotype GCC 11.1%vs 5.1%, OR = 2.66, P = 0.008, respectively).ConclusionsOur results identify that IL-10 promoter polymorphisms might not be a risk factor for PCa in Chinese cohorts, but rather incidence of polymorphisms associates with PCa grade, suggesting that IL-10 expression may impact PCa progression.

Functional interleukin-10 promoter variants in coronary artery disease patients in Tunisia.

The contribution of interleukin (IL)-10 promoter variants -1082G/A, -819C/T, and -592C/A to the risk of coronary artery disease (CAD) was investigated in 291 CAD patients and 291 age- and gender-matched control subjects. IL-10 genotyping was performed using PCR-allele-specific amplification (PCR-ASA). Regression analysis was employed in assessing the contribution of the IL-10 variants to the overall CAD risk. A higher frequency of the -592A allele (p = 0.004), but not the -1082A (p = 0.828) or -819T (p = 0.952) alleles, was seen in CAD patients. A higher frequency of -592C/A (p = 0.011), and a lower frequency of -592C/C (p = 0.015) genotypes was noted in patients compared to healthy controls. Regression analysis demonstrated an association of -592C/A [OR (95% CI) = 1.82 (1.02-3.23)] and -592A/A [OR (95% CI) = 3.33 (1.27-9.09)] genotypes with 1-artery disease. Haplotype analysis revealed that none of the eight possible IL-10 haplotypes was associated with CAD or with the severity of CAD, and was confirmed by multivariate regression analysis, after adjusting for a number of confounders (smoking, systolic and diastolic blood pressure, hypertension, diabetes, glucose, cholesterol, and triglycerides). Our results suggest that the -592C/A, more so than the -1082G/A or the -819C/T IL-10 promoter variant alleles, may be considered to be a risk factor for CAD in Tunisians.

Immunosuppressive Cytokine Gene Polymorphisms and Outcome after Related and Unrelated Hematopoietic Cell Transplantation in a Chinese Population

Cytokine gene polymorphisms can affect the outcome of allogeneic hematopoietic stem cell transplantation. We analyzed 6 single nucleotide polymorphisms in 3 immunosuppressive cytokine genes, TGFβ1-509(C>T), +869(T>C), TGFβ1 receptor II (TGFβ1RII) +1167(C>T, codon389 AAC/AAT), and IL-10-1082(A>G), -819(T>C), -592(A>C), in a cohort of 138 pairs of recipients and their unrelated donors and a second cohort of 102 pairs of recipients and their HLA-identical sibling donors. TGFβ1-509 T/T genotype in the donors or T allele-positivity in the recipients was associated with a significant protective effect against acute graft-versus-host disease (aGVHD) and grades II-IV aGVHD in the unrelated transplantation cohort. In the combined cohort, multivariate analysis confirmed that donors with the TGFβ1-509 T/T genotype also conferred protection against the risk of aGVHD and grades II-IV aGVHD. In both the unrelated transplantation cohort and the sibling transplantation cohort, the IL-10-819 C/C and -592 C/C genotypes in either recipients or donors were significantly associated with a higher incidence of aGVHD. In the combined cohort, the IL-10 promoter haplotype polymorphisms at positions -1082, -819, and -592 influenced the occurrence of aGVHD and death in remission. Recipients without the A-T-A haplotype or those transplanted from donors without the A-T-A haplotype had a higher incidence of aGVHD than those who were A-T-A homozygotes or heterozygotes. Estimates for death in remission showed a clear advantage for recipients transplanted from donors with the A-T-A haplotype. In multivariate analysis, recipients without the A-T-A IL-10 haplotype had a higher risk of aGVHD (relative risk [RR] = 0.764; 95% confidence interval [CI]: 0.460-1.269; P = .096) and grades II-IV aGVHD (RR = 0.413; 95% CI: 0.245-0.697; P = .001). These results provide the first report of an association between TGFβ1, TGFβ1RII, and IL-10 polymorphic features and outcome of allo-HSCT in a Chinese population, and suggest an interaction between TGFβ1-509 genotypes and IL-10 promoter haplotype polymorphisms at positions -1082, -819, and -592 and the risk of aGVHD.

Polymorphisms in genes involved in autoimmune disease and the risk of FVIII inhibitor development in Italian patients with haemophilia A

One of the most severe and important complication in the treatment of patients with haemophilia A is the formation of neutralizing antibodies (FVIII inhibitors) that inhibit the clotting activity of substituted FVIII. Both genetic and environmental factors influence the susceptibility of patients to develop inhibitors. The objective of this study was to evaluate whether polymorphisms in different genes involved in the regulation of the immune system may confer susceptibility to inhibitor development in patients with HA. We analysed the distribution of polymorphisms in the CTLA4, PTPN22, IL10, TNFalpha, FOXP3 and IRF5 genes that have been reported to be associated with a number of autoimmune disease. In addition, we evaluated the distribution of IL10 haplotypes in haemophilic patients and healthy controls to assess whether specific polymorphisms in IL10 gene were associated to the risk of inhibitor development. We focused on a cohort of Italian unrelated haemophilic patients with and without a history of inhibitors. Genotyping was carried out with standard methods including RFLP, real time PCR and direct DNA sequencing. Our data show that, considering single nucleotide variations, genotype frequencies in patients with inhibitors were not significantly different from those observed in patients without inhibitors, suggesting a lack of association between these polymorphisms and the development of inhibitors. Moreover, no relationship was found between specific combinations of IL10 alleles and the antibody production. Previous contradictory association studies may depend on the different genetic background of the population examined. Further studies may contribute to a clearer understanding of this process.

Functional Polymorphism in the Interleukin-6 and Interleukin-10 Genes in Patients with Paranoid Schizophrenia —A Case-Control Study

Schizophrenia is a multifactorial disease with changes in immunological system. Such changes are the result of cytokine-level disturbances connected with cytokine gene polymorphisms. However, research about cytokine gene polymorphisms in schizophrenia has been surprisingly limited and ambiguous. The aim of the study was to identify whether polymorphisms of interleukin (IL)-6 and IL-10 are risk factors for the development of paranoid schizophrenia in case-control study. IL-6 (-174G/C; rs 1800795) and IL-10 (-1082G/A; rs 1800896) promoter polymorphisms in patients with paranoid schizophrenia and healthy individuals were genotyped using polymerase chain reaction-restriction fragment length polymorphism method. Differences in IL-6 and IL-10 promoter haplotypes may play an important role in determining the transcription level for IL-6 and IL-10 genes in schizophrenic patients. The presence of allele C at position -174 of IL-6 promoter sequence may correlate with increasing risk of paranoid schizophrenia in the Polish population, but research on a broadened group of people is needed. The presence of allele G at position -1082 of IL-10 promoter sequence correlates with increasing risk of paranoid schizophrenia in the Polish population. The coexistence of genotype GG at position -1082 of IL-10 promoter sequence and genotype GC at position -174 of IL-6 promoter sequence correlates with increasing risk of paranoid schizophrenia in the Polish population.

Selection for Genetic Variation Inducing Pro-Inflammatory Responses under Adverse Environmental Conditions in a Ghanaian Population

BackgroundChronic inflammation is involved in the pathogenesis of chronic age-associated, degenerative diseases. Pro-inflammatory host responses that are deleterious later in life may originate from evolutionary selection for genetic variation mediating resistance to infectious diseases under adverse environmental conditions.Methodology/Principal FindingsIn the Upper-East region of Ghana where infection has remained the leading cause of death, we studied the effect on survival of genetic variations at the IL10 gene locus that have been associated with chronic diseases. Here we show that an IL10 haplotype that associated with a pro-inflammatory innate immune response, characterised by low IL-10 (p = 0.028) and high TNF-α levels (p = 1.39×10−3), was enriched among Ghanaian elders (p = 2.46×10−6). Furthermore, in an environment where the source of drinking water (wells/rivers vs. boreholes) influences mortality risks (HR 1.28, 95% CI [1.09–1.50]), we observed that carriers of the pro-inflammatory haplotype have a survival advantage when drinking from wells/rivers but a disadvantage when drinking from boreholes (pinteraction = 0.013). Resequencing the IL10 gene region did not uncover any additional common variants in the pro-inflammatory haplotype to those SNPs that were initially genotyped.Conclusions/SignificanceAltogether, these data lend strong arguments for the selection of pro-inflammatory host responses to overcome fatal infection and promote survival in adverse environments.

P441 Association of IL-10 promoter genotypes and haplotypes with idiopathic recurrent spontaneous miscarriage

International Journal of Gynecology & ObstetricsVolume 107, Issue S2 p. S539-S539 Poster presentations P441 Association of IL-10 promoter genotypes and haplotypes with idiopathic recurrent spontaneous miscarriage N. Mtiraoui, N. MtiraouiSearch for more papers by this authorW. Zammiti, W. ZammitiSearch for more papers by this authorT. Mahjoub, T. MahjoubSearch for more papers by this author N. Mtiraoui, N. MtiraouiSearch for more papers by this authorW. Zammiti, W. ZammitiSearch for more papers by this authorT. Mahjoub, T. MahjoubSearch for more papers by this author First published: 20 November 2009 https://doi.org/10.1016/S0020-7292(09)61933-0AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume107, IssueS2Abstracts of XIX FIGO World Congress of Gynecology and ObstetricsOctober 2009Pages S539-S539 RelatedInformation

Genetics of susceptibility to infection with enteric pathogens

This review examines recent developments in human genetic susceptibility to enteropathogens that cause infectious diarrhea. The affinity of specific norovirus genogroups to different histoblood group antigens (HBGAs) on secretor cells has been studied in different epidemiologic studies. HBGAs are also used as receptors by Vibrio cholerae with different degrees of affinity between biotypes. Polymorphisms in the CD14, lactoferrin and osteoprotegerin promoter genes were associated to diarrhea in travelers. Single nucleotide polymorphisms in the IL-8 genes are also associated to increased risk for enteroaggregative Escherichia coli and Clostridium difficile infection. IL-10 haplotypes were associated to enterotoxigenic E. coli associated diarrhea in exposed individuals. A family-based study showed a significant association of the LPLUNC1 gene and cholera. The major histocompatibility complex class II antigens are associated to different degrees of susceptibility and resistance to Salmonella, Cryptosporidium and Entamoeba infection. Variants in genes that encode molecules that mediate attachment, pathogen recognition, inflammatory cytokine response, innate and acquired immunity are being identified as determinants of host genetic susceptibility to infectious diarrhea.

Association of gastric disease with polymorphisms in the inflammatory-related genes IL-1B, IL-1RN, IL-10, TNF and TLR4

This study aimed to investigate if single nucleotide polymorphisms (SNPs) in a series of inflammatory genes were associated with the development of the most common pathologies thought to precede gastric cancer development namely; Helicobacter pylori (H. pylori)-associated gastritis and intestinal metaplasia. A total of 250 patients were genotyped for 11 SNPs in the IL-1B, IL-1RN, TNF, TLR4 and IL-10 genes. The study population comprised H. pylori uninfected ('normal') control patients (n=96), H. pylori-positive gastritis (n=91) and intestinal metaplasia patients (n=63). Genotyping was performed using Taqman allelic discrimination assays. Odds ratios for gastric disease groups were adjusted for potential confounding factors. No differences were identified in frequency of carriage, or homozygosity, for any of the 'risk' alleles investigated across the patient groups. No evidence was found to suggest an association with increased risk of developing either chronic gastritis or intestinal metaplasia with SNPs in the IL-1B, IL-1RN, TNF, TLR4 and IL-10 genes or haplotypes tested. This study found no evidence of an association with increased risk of developing either chronic gastritis or intestinal metaplasia with the SNPs or haplotypes tested.

P08: Effects of inflammation-related cytokine gene polymorphisms on gastric cancer risk among atomic bomb survivors

RERF epidemiology studies found that risks of certain cancers among atomic-bomb (A-bomb) survivors, including gastric cancer, increased with past exposure dose to atomic radiation, and that these risks remain high even today. RERF immunology studies implied that radiation exposure greatly affected host immune systems of A-bomb survivors, further providing for the possibility that altered immune response in this population, specifically inflammatory response and immunological host defense, might be involved in the development of various cancers. In fact, we have reported that the enhancement of persistent inflammation with increased age was further accelerated among people exposed to A-bomb radiation. In this study, we examined relationship between gastric cancer risk and radiation dose based on 43 SNPs of inflammation-related genes ( IL1B, IL6, IL8, IL10, BAT1, NFKBIL1, LTA, TNF, and LST1 ), in a case-control study of 238 cases and 1757 controls within a subcohort of the RERF Adult Health Study. We found statistically significant association between IL10 , LTA , and TNF SNPs and risk of gastric cancer, but not between other SNPs and risk of gastric cancer. Three SNPs on the LTA-TNF loci were associated with elevated risk of gastric cancer. Additionally, our genome analysis identified a single haplotype block within the IL10 gene locus, which was indicated by four htSNPs (generating two major alleles, IL10-ATTA and IL10-GGCG ). We found that risk of gastric cancer significantly varied by IL-10 haplotype in both non-exposed and exposed individuals, and that risk-enhancing effects of radiation were evident in all the haplotypes. Our findings offer further evidence that variation in the IL10 and TNF loci affects gastric cancer risk.

Extended IL10 haplotypes and their association with HIV progression to AIDS

Interleukin-10 (IL-10) is a pleiotropic cytokine with both immunosuppressive and immunostimulatory functions. Its roles in infections and autoimmunity may have resulted in selective pressures on polymorphisms within the gene, leading to genomic coexistence of several semi-conserved haplotypes involved with diverse pathogen interactions during genomic evolution. Previous studies focused either exclusively on promoter haplotypes or on individual SNPs. We genotyped 21 single nucleotide polymorphisms in the human IL10 gene and examined this variation compared to other mammalian species sequences. Haplotype heterogeneity in human populations is centered around 'classic' 'proximal' promoter polymorphisms: -592, -819 and -1082. High-producing GCC haplotypes are by far the most numerous and diverse group, the intermediate IL-10 producing ACC-inclusive haplotypes seem to be related most closely to the ancestral haplotype, and the ATA-inclusive haplotypes cluster a separate branch with strong bootstrap support. We looked at associations of corresponding haplotypes with HIV progression. A haplotype trend regression confirmed that individuals carrying the low-producing ATA-inclusive haplotypes in European Americans progress to AIDS faster, and most likely explain the role of IL10. Our findings are consistent with the hypothesis that existing polymorphisms in this gene may reflect a balance of historic adaptive responses to autoimmune, infectious and other disease agents.

Interaction between BCL2 and Interleukin-10 Gene Polymorphisms Alter Outcomes of Diffuse Large B-Cell Lymphoma following Rituximab Plus CHOP Chemotherapy

Rituximab may overcome bcl-2-mediated chemoresistance through the inhibition of interleukin-10 (IL-10)-mediated loops, thus down-regulating bcl-2 expression. We examined the effects of genetic variation in BCL2/IL10 gene loops on treatment outcomes of diffuse large B-cell lymphoma when treated with either CHOP or rituximab plus CHOP (R-CHOP) chemotherapy. Four genotypes were tested including BCL2 -938 C>A (rs2279115), +21 A>G (rs1801018), IL10 -819 T>C (rs1800871), and -592 A>C (rs1800872) in patients receiving either R-CHOP (n = 125) or CHOP (n = 110). IL10 SNPs, -819 TT/TC or -592 AA/AC genotypes correlated with improved CHOP response rates (P = 0.04). Neither polymorphism separately influenced the failure-free survival (FFS) or overall survival in patients, but the IL10 haplotype was associated with treatment outcomes after R-CHOP for FFS (P = 0.03) or progression (P = 0.007), whereas the -938 AA BCL2 genotype significantly affected overall survival (P = 0.04). An interactive effect between BCL2 and IL10 SNPs was significant in the group with both -938 AA BCL2 genotype and 1 to 2 copies of CC IL10 haplotype. This group showed a better FFS (P = 0.01) and a lower probability of progression (P = 0.004) compared with other genotype groups when treated with R-CHOP chemotherapy. These data indicated that R-CHOP chemotherapy resistance in diffuse large B-cell lymphoma may involve interactions between the BCL2 and IL10 genes.

IL6 and CRPhaplotypes are associated with COPD risk and systemic inflammation: a case-control study

BackgroundElevated circulating levels of C-reactive protein (CRP), interleukin (IL)-6 and fibrinogen (FG) have been repeatedly associated with many adverse outcomes in patients with chronic obstructive pulmonary disease (COPD). To date, it remains unclear whether and to what extent systemic inflammation is primary or secondary in the pathogenesis of COPD.The aim of this study was to examine the association between haplotypes of CRP, IL6 and FGB genes, systemic inflammation, COPD risk and COPD-related phenotypes (respiratory impairment, exercise capacity and body composition).MethodsEighteen SNPs in three genes, representing optimal haplotype-tagging sets, were genotyped in 355 COPD patients and 195 healthy smokers. Plasma levels of CRP, IL-6 and FG were measured in the total study group. Differences in haplotype distributions were tested using the global and haplotype-specific statistics.ResultsRaised plasma levels of CRP, IL-6 and fibrinogen were demonstrated in COPD patients. However, COPD population was very heterogeneous: about 40% of patients had no evidence of systemic inflammation (CRP < 3 mg/uL or no inflammatory markers in their top quartile). Global test for haplotype effect indicated association of CRP gene and CRP plasma levels (P = 0.0004) and IL6 gene and COPD (P = 0.003). Subsequent analysis has shown that IL6 haplotype H2, associated with an increased COPD risk (p = 0.004, OR = 4.82; 1.64 to 4.18), was also associated with very low CRP levels (p = 0.0005). None of the genes were associated with COPD-related phenotypes.ConclusionOur findings suggest that common genetic variation in CRP and IL6 genes may contribute to heterogeneity of COPD population associated with systemic inflammation.

Association of IL10 and other immune response- and obesity-related genes with prostate cancer in CLUE II.

Chronic intra-prostatic inflammation and obesity are thought to influence prostate carcinogenesis. Thus, variants in genes in these pathways could be associated with prostate cancer risk. We genotyped 17 common single nucleotide polymorphisms (SNPs) in RNASEL, TLR4, IL1B, IL6, IL8, IL10, TNF, CRP, ADIPOQ, LEP, PPARG, and TCF7L2 in 258 white prostate cancer cases and 258 matched controls nested in CLUE II. Single-locus analyses were conducted using conditional logistic regression. TagSNPs were selected in IL10, CRP, and TLR4 and haplotype analyses were done. The A allele of IL10 -1082G>A (rs1800896), known to result in lower levels of this anti-inflammatory cytokine, was positively associated with risk (AG vs. GG, OR = 1.69, 95% CI: 1.10-2.60; AA vs. GG, OR = 1.81, 95% CI: 1.11-2.96; P (trend) = 0.02). Associations of IL10 haplotypes with prostate cancer were explained by high linkage disequilibrium between two tagSNPs (rs1800890 and rs3024496) and -1082G>A. A TLR4 candidate SNP (rs4986790; AG/GG vs. AA, OR = 0.60, 95% CI: 0.33-1.08; P(trend) = 0.09), known to have decreased expression and be associated with lower circulating levels of inflammatory mediators, and tagSNP (rs10116253; CC vs. TT, OR = 3.05, 95% CI: 1.11-8.41), but not haplotypes, were associated with risk. None of the other candidate SNPs or haplotypes was statistically significantly associated with risk. Our prospective study suggests that genetic variation in IL10 and possibly TLR4 is associated with prostate cancer risk. Although none of the SNPs in the obesity genes tested was associated, this does not rule out a complex role of obesity and its metabolic consequences in prostate cancer etiology.

IL-10 promotor haplotypes associated with susceptibility to and severity of bacterial corneal ulcers

Interleukin-10 plays an important role in modulating inflammation and antimicrobial defences. In animal models for bacterial corneal ulcers, high IL-10 levels were associated with a better clinical outcome. We investigated whether IL-10 promotor haplotypes, known to determine IL-10 expression in vitro, are associated with susceptibility to and/or clinical outcome of bacterial corneal ulcers in patients.IL-10 promotor polymorphisms C-819T, G-1082A, A-2763C, and A-2849G for 83 patients with bacterial corneal ulcers and 115 healthy controls were determined by restriction fragment length PCR analysis. For 63 patients and all healthy controls the most frequently occurring IL-10 promotor haplotypes were inferred from these data using the program SNPHAP. A significant underrepresentation of the A-2849A genotype was observed in patients as compared to healthy controls. Both the -2763A allele and the IL-10.1 promotor haplotype were associated with a poor clinical outcome, whereas a favourable clinical outcome was seen in patients carrying the IL-10.2 promotor haplotype. Together, IL-10 promotor haplotypes associated with low IL-10 levels seem to protect against the onset of bacterial corneal ulcers. Once a corneal ulcer has developed, patients carrying IL-10 haplotypes associated with a high IL-10 expression may have a favourable outcome.

IL-10 and TNF-α promoter haplotypes are associated with childhood Crohn’s disease location

To determine the distribution and frequencies of the genotypes and haplotypes of the genes encoding for the glucocorticoid receptor (GR), the tumor necrosis factor (TNF)-alpha and the interleukin (IL)-10 in childhood Crohn's disease (CD) and to assess the impact of the corresponding DNA variants on clinical and disease phenotypes. Ten variants in GR, TNF-alpha and IL-10 were genotyped in 113 childhood CD cases and 95 healthy subjects, both of French-Canadian origin. For the GR polymorphisms (R23K and N363S) and IL-10 variants in the 5'flanking region (-1082 G > A, -819 T > C and -592 A > C), no difference was observed in allele and genotype frequencies between CD patients and controls. At the haplotype level, we found three IL-10 haplotypes previously described in Caucasians (GCC, ACC and ATA) and three novel haplotypes only present in IBD patients. When we analyzed the haplotype distribution with the anatomical location of the disease, the GCC haplotype was associated with the colonic and the ACC haplotype with the terminal ileum location, respectively. The genotyping of five polymorphisms in the promoter region of the TNF-alpha gene (-1031 T > C, -863 A > C, -857 T > C, -308 A > G and -238 A > G) revealed a significant overrepresentation of homozygous -1031 CC among CD patients (OR = 9.9) and an association with the colonic location. For TNF-alpha, eleven haplotypes were inferred, including two frequent ones, TCCGG and CACGG, which were significantly observed more frequently in controls and cases, respectively. This is one of the first studies investigating the association between haplotype structure and disease location in a CD pediatric cohort. Our results will help to increase our understanding of the genetic determinants of childhood CD.

IL-10 Gene Polymorphisms, Periodontal Disease and Intrauterine Growth Restriction: A Pilot Study

IL-10 has several immuno-protective functions in the placenta The expression of IL-10 is genetically determined. The aim of this study was to investigate whether maternal periodontal disease and IL-10 gene polymorphisms, are associated with intra uterine growth restriction (IUGR). A total of 160 pregnant women were recruited from the Antenatal Clinic, St Mary's Hospital, Manchester, UK and enrolled into a prospective pilot study. The study included 92 Caucasians, 41 Asians and 27 Afro Caribbeans. The periodontal examination involved recording bleeding on probing and pocket depth indices on all teeth. ARMS-PCR was used for genotyping IL-10 gene at position −1082, −819 and −592. Birth weight was assessed using the individualised birth weight ratio (IBR), with intrauterine growth restriction IUGR defined as an IBR below the 5th percentile, x2 test was performed for statistical analysis. The −1082 A/A genotype, is associated with more increased BOP% sites (23% vsl4%, P = 0.069), and significantly with more IUGR in Afro-Caribbean women (75% vs 9%, P = 0.002). Moreover, the combination between the −1082 A genotype and increased percentages of bleeding sites have increased the risk of IUGR in Afro Caribbean women. However, this genotype had only a marginal influence on IUGR (P = 0.07) and no influence on periodontal disease in Caucasian women (P = 0.55). There was no significant association between IUGR, periodontal disease and IL-10 gene polymorphisms at position −819 and −592. Also, there was no significant difference between IL-10 haplotypes, periodontal disease and IUGR in any of the ethnic groups examined. Future studies, with a larger sample size, are required to ascertain the genetic association between IL-10 gene polymorphisms maternal periodontal disease and IUGR in different ethnic groups.

Predictive value of interleukin‐10 promoter genotypes and haplotypes in determining the susceptibility to nephropathy in type 2 diabetes patients

The IL-10 promoter polymorphisms -1082G/A, -819C/T, and -592C/A have been consistently associated with type 2 diabetes (T2DM). We examined whether these polymorphisms variants are also associated with progression of diabetic nephropathy (DN). These promoter variants were genotyped in 917 T2DM patients comprising 515 DN patients and 402 control patients without nephropathy (DWN), together with 748 non-diabetic control subjects. Haplotype analysis and multivariate regression analysis were employed in assessing the contribution of IL-10 haplotypes to DN risk, using genotype, clinical and biochemical profile, and their interactions as predictors of DN. Carriers of mutant -592A and -819T alleles, and -819T/T, -592A/A, and -819C/T genotypes were more frequent in T2DM. However, the -819C/T genotype appeared to be protective of DN, since lower frequency -819T allele and -819C/T genotype were seen in DN patients. Regression analysis identified -1082G/-819T/-592A (GTA) and -1082G/-819T/-592C (GTC) haplotypes as DN-protective haplotypes. Relative to the -1082G/-819C/-592C haplotype, GTA [P = 0.044; odds ratio (OR) = 0.54, 95% confidence interval (CI): 0.30-0.98] and GTC (P = 0.045; OR = 0.56, 95% CI: 0.31-0.99) haplotypes were associated with decreased odds ratio (OR) for DN, after controlling for a number of covariates (age, sex, body mass index (BMI), hypertension, glucose, HbA(1c), DN duration, total cholesterol). Our results indicate that genetic variations at the IL-10 promoter influence the risk of nephropathy in T2DM patients and thus represent a potential DN genetic-susceptibility locus worthy of replication.

Cytokine Gene Polymorphisms and Outcome of Patients with Hodgkin Lymphoma: A Prospective Study of the Groupe D'Etude Des Lymphomes De L'Adulte

Background. Although Hodgkin lymphoma is a highly curable malignancy, about 15% and 30% of patients with respectively localized or disseminated disease do not respond or relapse after initial treatment. Several scoring systems using conventional biological and clinical parameters have been developed for limited and advanced stages in order to adapt the therapeutic strategy. However, the identification of patients with adverse outcome needs to be improved. Cytokines have an important role in the pathogenesis of Hodgkin lymphoma. Several studies have shown that plasma cytokine dosage at diagnosis has prognostic relevance. Various cytokine genes variants are known to influence cytokine productions and have been associated with lymphoma outcomes. We then evaluated the influence of cytokine gene polymorphisms on response to treatment and outcome in patients with Hodgkin lymphoma.Methods. Between 1998 and 2002, we prospectively investigated the prognostic role of plasma cytokines and soluble receptors in Hodgkin lymphoma patients (Casasnovas et al. JCO 2007). A sample was collected at diagnosis specifically to investigate single nucleotide polymorphisms (SNPs) in cytokine genes. Ten SNPs that could be functionally important in seven genes (IL10, TNF-alpha, IL6, IL1B, IL1RN, INF-gamma, CCL17) were studied. DNA was extracted from venous blood samples. All genotyping experiments were performed in duplicate using Taqman technology (ABI Prism 7000, Applied Biosystems): IL10 rs1800890 (−3584>A), 448 pts; IL10 rs1800896 (−1116A>G), 459 pts; IL10 rs1800871 (−853C>T), 446 pts; IL10 rs1800872 (−626C>A), 447 pts; TNFalpha rs1800629 (−487G>A), 464 pts; IL6 rs1800795 (−236G>C), 201 pts; IL1B rs16944 (−1060T>C), 198 pts; ILRNrs419598 (Ex5–35T>C), 199 pts; INF-gamma rs2430561 (+874A>T), 200 pts; CCL17rs223828 (−431T>C), 198 pts. We estimated the prognostic value of each individual SNP and the IL10 haplotype for response to treatment, relapse and overall survival (OS).Results. The median age of the 464 patients studied was 32 years (range, 15–93); 263 (57%) were male. At diagnosis, 335 patients (72%) were in Ann Arbor stage I–II and 206 (44%) presented with B symptoms. Histology was nodular sclerosis in 384 patients (84%). Treatment consisted of 4 to 6 courses of anthracycline-based chemotherapy (CT) followed by involved-field radiotherapy for stages I–II and 8 courses of anthracycline-based CT for stages III–IV. Complete response (CR) and uncertain CR (uCR) were observed in 417 patients (90%), partial response in 15 (3%) and stable and progressive disease in 32 (7%). Relapse occurred in 71 patients (15%) and 35 patients (8%) died, 24 of whom (5%) of Hodgkin lymphoma. After a median follow-up of 3.6 years months, the 4-year progression free survival (PFS) and OS were 83.4% and 93.6%, respectively. Regarding treatment response, only the IL10-1082AA genotype was associated with a better CR + uCR than other IL10 genotypes (95% vs. 88% p=0.02). Neither individual SNPs or IL10 haplotype influenced OS and PFS.Conclusions. In this large series of Hodgkin lymphoma patients with particularly favorable outcome, the IL10-1082AA genotype was associated with better response to initial treatment. These data indicate that some genes associated with non-Hodgkin lymphoma outcome do not predict Hodgkin lymphoma outcome and that other target need to be analyzed to decipher the putative role of host's immunogenetic background in this disease.

Single Nucleotide Polymorphisms in the Human TNFα Gene Are Associated with Neutropenia and Anemia in a Cohort of Patients with Myelodysplastic Syndrome

A phenotypic hallmark of the myelodysplastic syndromes (MDS) is ineffective hematopoiesis, resulting in anemia, neutropenia, and thrombocytopenia. The extent to which the stromal microenvironment interacts with MDS progenitors to influence the natural history of the disease is unknown. A number of proinflammatory cytokines, including TNFα, and IL-6, are increased in MDS patients versus normal subjects. In addition, the TNF and IL-6 genes have functional single nucleotide polymorphisms (SNPs) that are linked to cytokine hypersecretion. However, the influence of these SNPs on the MDS phenotype remains poorly defined. Our central hypothesis is that both cell autonomous and cell non-autonomous factors cooperate to define the MDS phenotype. We postulate that underlying host factors do not predispose to the development of MDS but act as genetic modifiers of disease severity, particularly with regard to the degree of cytopenias, severity of infectious complications, and disease progression. In the current study, we analyzed the frequency of the TNFα -308G/A and -238G/A, IL-6 -174G/C, and macrophage migration inhibitory factor (MIF) -173G/C and -794 CATT repeat promoter region polymorphisms and determined whether these SNPs were associated with adverse clinical and laboratory outcomes in a large cohort of MDS patients. Genotype analysis on DNA samples from 328 MDS patients was performed and the respective TNF, IL-6 and MIF haplotype frequencies were correlated with the following outcomes: age, IPSS score, karyotype, blast percentage, FAB classification, survival, anemia, neutropenia, and thrombocytopenia. As shown in Table 1, multivariate analysis of the TNFα -308G/A SNP revealed that the AA genotype (high-expressing) was significantly associated with an abnormally low ANC (<1500) as well as frank neutropenia (ANC<1000) (p<0.05 for each comparison, Cox regression).GenotypeANC<1500ANC<1000AA5/5 (100%)*4/5 (80%)*GA36/104 (35%)22/104 (21%)GG86/219 (39%)57/219 (26%)Table 1. TNF-308A/A genotype is associated with neutropenia in MDS. *p<0.05 for each ANC level analyzed.As shown in Table 2, multivariate analysis of the TNFα -238G/A SNP revealed that the presence of a high-expressing genotype (AA + GA) was significantly associated with NCI Grade II or greater anemia (Hgb<10g/dl) (p<0.05, Cox regression). After controlling for the presence of red blood cell transfusions, the frequency of the A allele in patients with Hgb<10g/dl remained statistically significant (p<0.05). Furthermore, whereas the A allele was present in 14% of anemic individuals (Hgb<12.5g/dl, n=41), no patients with a normal Hgb (n=26) carried the A allele (p=0.03, Chi square). This also remained significant after controlling for red cell transfusions (p=0.02).Table 2. The presence of an A allele in the TNF-238G/A SNP is associated with NCI Grade II anemia in MDS. *p<0.05.GenotypeHgb<10g/dlGA + AA26/41 (63%)*GG136/287 (47%)In contrast, the frequencies of the IL-6 or MIF SNPs did not have a statistically significant effect on any of the measured outcomes. To evaluate the effect of TNFα on erythroid colony formation, human peripheral blood CD34+ cells from healthy adults were cultured in semi-solid media in the presence of IL-3 (10ng/ml), erythropoietin (1U/ml), SCF (50ng/ml) and increasing doses of TNFα (0–100ng/l) and erythroid burst-forming units (BFU-E) measured on days 7 and 14. In the presence of 25 and 100ng/ml TNFα, the percentage of BFU-E colonies was reduced by 50%. Furthermore, the erythroid colony suppressing affects of TNFα were reversed to baseline in a dose-dependent manner with the addition of the anti-TNF agent infliximab. These data indicate that the presence of high-expressing polymorphic alleles in the TNFα gene promoter is independently associated with both neutropenia and the severity of anemia in a large cohort of MDS patients. TNFα-overexpression may function as a cell non-autonomous factor that interacts synergistically with intrinsic defects within MDS progenitors to promote hypoplasia within the hematopoietic lineage, potentially increasing the severity of cytopenias in patients with MDS.