Association of IL-1α rs17561 and IL-1 RN rs315952 polymorphisms with Tourette syndrome: a family-based study.
ABSTRACT: Immune system dysregulation has been implicated to play a key role in pathogenesis of Tourette syndrome (TS). IL-1α and IL-1RN are important inflammatory cytokines that mediate the inflammation. In this study, we investigated the relationship between single-nucleotide polymorphisms (SNPs) of IL-1α and IL-1RN and the susceptibility to TS in Chinese Han population.A total of 276 children with TS and their parents were recruited in the study. All DNA from our subjects were genotyped for SNPs of IL-1α rs17561 and IL-1RN rs315952 using predesigned TaqMan SNP genotyping assay. The genetic contributions of two polymorphisms were evaluated using transmission disequilibrium test (TDT) and haplotype relative risk (HRR) design. In addition, to increase the efficiency of the test, the haplotype-based HRR (HHRR) was performed.No significant differences were observed in allelic and genotypic frequency of rs17561 in IL-1α and rs315952 in IL-1RN between the transmitted group and non-transmitted group (for IL-1α rs17561: TDT=0.890, df=1, P=0.402; HRR=1.011, X(2)=3.016, P=0.082, 95% CI=0.999-1.024; for IL-1RN rs315952: TDT=0.095, df=1, P=0.805; HRR=0.984, X(2)=0.008, P=0.929, 95% CI=0.695-1.394). Similarly, the analysis of HHRR also did not support a significant association (for IL-1α rs17561: HHRR=1.226, X(2)=0.915, P=0.339, 95% CI=0.807-1.863; for IL-1RN rs315952: HHRR=0.963, X(2)=0.094, P=0.759, 95% CI=0.758-1.225).Our results suggest that IL-1α rs17561 and IL-1RN rs315952 polymorphisms may not be associated with susceptibility to TS in Chinese Han population. However, the results still need to be replicated in a larger sample size and different populations.
Project description:Preeclampsia (PE) is an excessive systemic inflammation response with dysfunction of endothelial. Our study was to investigate the association between genetic variations in IL-1 and the susceptibility to PE in Chinese Han population. 402 PE patients and 554 normal pregnant women of third trimester were enrolled. The polymorphisms of rs315952 in IL1RN and rs17561 in IL1A were genotyped by TaqMan allelic discrimination real-time PCR. Obviously statistic difference of the genotypic frequencies were found in both of IL1RN rs315952 and IL1A rs17561 between cases and controls (for rs315952, P = 0.001; for rs17561, P = 0.021.). For rs315952, the C allele was associated with development of PE (P = 0.003, OR = 1.319, 95%CI 1.099-1.583). Patients with CC or CT genotype were less likely to develop severe PE than patients carrying TT genotype(P < 0.001, OR = 0.24, 95%CI 0.15-0.40). For rs17561, the C allele was the risk factor for predisposition to PE (P = 0.012, OR = 1.496, 95%CI 1.089-2.055). Our results suggest IL1RN and IL1A may involve in the development of PE in Chinese Han population.
Project description:Tourette syndrome (TS) is a polygenic neuropsychiatric disease. Previous studies have indicated that dysregulation in the histaminergic system may play a crucial role in disease onset. In this study, we investigated the role of the histidine decarboxylase gene (HDC) in TS susceptibility in the Chinese Han population. After genotyping 241 TS nuclear families trios, we analyzed three tag HDC single nucleotide polymorphisms (rs854150, rs854151, and rs854157) in a family-based study using the transmission disequilibrium test (TDT) and haplotype relative risk (HRR). TDT showed no over-transmission in these SNPs across the HDC region (for rs854150: ?2 = 0.472, P = 0.537, OR = 1.097, 95%CI = 0.738-1.630; for rs854151: ?2 = 0.043, P = 0.889, OR = 1.145, 95%CI = 0.767-1.709; for rs854157:?2 = 0.984, P = 0.367, OR = 1.020, 95%CI = 0.508-2.049). HRR also showed the same tendency (for rs854150: ?2 = 0.211, P = 0.646, OR = 1.088, 95%CI = 0.759-1.559; for rs854151: ?2 = 0.134, P = 0.714, OR = 0.935, 95%CI = 0.653-1.339; for rs854157:?2 = 0.841, P = 0.359, OR = 1.206, 95%CI = 0.808-1.799). Additionally, the haplotype-based haplotype relative risk showed a negative association. Although these findings indicate an unlikely association between HDC and TS in the Chinese Han population, a potential role for HDC cannot be ruled out in TS etiology. Future research should investigate this more thoroughly using different populations and larger samples.
Project description:Recent studies demonstrated that interleukin 1 receptor antagonist (IL-1RN) plays an important role in metabolic effects. To investigate whether IL1RN polymorphisms are associated with obesity, two single nucleotide polymorphisms (SNPs) of the IL1RN gene [rs4251961 (-828, T> C) and rs315952 (Ser133Ser)] were analyzed in 122 overweigh/obese and 123 control subjects. Overweigh/obese subjects were classified according to body mass index (BMI). SNPStats was used to obtain odds ratios (ORs), 95% confidence intervals (CIs), and P values. Multiple logistic regression models (codominant1, codominant2, dominant, recessive, and log-additive) were conducted to analyze the genetic data. Synonymous SNP (rs315952) of the IL1RN gene was associated with overweigh/obese with hypertension (OR= 4.98, 95% CI= 1.74-14.19, P = 0.003 in codominant 1 model and OR= 3.98, 95% CI= 1.48-10.74, P= 0.0029 in dominant model). However, another SNP (rs4151961) did not show association with overweigh/obese or overweigh/obese with hypertension. These results suggest that exonic SNP of IL1RN (rs 315952, Ser133Ser) may be contributed to overweigh/obese with hyper-tension.
Project description:Recently, a genome-wide association study has indicated associations between single nucleotide polymorphisms in the Collagen Type XXVII Alpha 1 gene (COL27A1) and Tourette syndrome in several ethnic populations. To clarify the global relevance of the previously identified SNPs in the development of Tourette syndrome, the associations between polymorphisms in COL27A1 and Tourette syndrome were assessed in Chinese trios. PCR-directed sequencing was used to evaluate the genetic contributions of three SNPs in COL27A1(rs4979356, rs4979357 and rs7868992) using haplotype relative risk (HRR) and transmission disequilibrium tests (TDT) with a total of 260 Tourette syndrome trios. The family-based association was significant between Tourette syndrome and rs4979356 (TDT: ?2 = 4.804, P = 0.033; HRR?= 1.75, P = 0.002; HHRR = 1.32, P = 0.027), and transmission disequilibrium was suspected for rs4979357 (TDT: ?2 = 3.969, P = 0.053; HRR?= 1.84, P = 0.001; HHRR = 1.29, P = 0.044). No statistically significant allele transfer was found for rs7868992 (TDT: ?2 = 2.177, P = 0.158). Although the TDT results did not remain significant after applying the conservative Bonferroni correction (p = 0.005), the significant positive HRR analysis confirmed the possibility of showing transmission disequilibrium, which provides evidence for an involvement of COL27A1in the development of TS. However, these results need to be verified with larger datasets from different populations.
Project description:BACKGROUND: Recent evidence suggest that the innate immune system is implicated in the early events of celiac disease (CD) pathogenesis. In this work for the first time we have assessed the relevance of different proinflammatory mediators typically related to innate immunity in CD predisposition. METHODS: We performed a familial study in which 105 celiac families characterized by the presence of an affected child with CD were genotyped for functional polymorphisms located at regulatory regions of IL-1alpha, IL-1beta, IL-1RN, IL-18, RANTES and MCP-1 genes. Familial data was analysed with a transmission disequilibrium test (TDT) that revealed no statistically significant differences in the transmission pattern of the different genetic markers considered. RESULTS: The TDT analysis for IL-1alpha, IL-1beta, IL-1RN, IL-18, and MCP-1 genes genetic variants did not reveal biased transmission to the affected offspring. Only a borderline association of RANTES promoter genetic variants with CD predisposition was observed. CONCLUSION: Our results suggest that the analysed polymorphisms of IL-1alpha, IL-1beta, IL-1RN, IL-18, RANTES and MCP-1 genes do not seem to play a major role in CD genetic predisposition in our population.
Project description:Interleukin 1 (IL-1) is an important mediator of inflammation and tissue damage in inflammatory bowel disease (IBD). The balance between IL-1 and IL-1Ra as a natural inhibitor plays a vital role in a variety of diseases. Here, we investigated whether changes seen during IBD are induced spontaneously in mice lacking a functional IL-1rn gene. Histological staining was performed on the jejunum and ileum of BALB/c IL-1rn+/+ and IL-1rn-/- mice to characterize crypt-villus height, villus width, and number of goblet cells per villus. Pro-inflammatory cytokines, immune cell infiltration and matrix-degrading enzymes, together with the production of intestinal enzymes and the integrity of tight and adherent junction proteins were determined using immunohistochemistry. In the small intestine of BALB/c IL-1rn-/- mice the villus heights were significantly reduced; and in the ileum this was accompanied by a decrease in villi width. There was also an increase in goblet cell number and mucin production compared to wild-type mice. IL-1α and IL-1β immunopositivity were increased, whilst IL-1R1 expression was decreased in IL-1rn-/- mice. IL-15 and TNFα were also increased in older IL-1rn-/- mice. Increased polymorphonuclear and macrophage infiltration were seen in IL-1rn-/- mice, whilst expression of matrix-degrading enzymes and digestive enzymes were unchanged, except for dipeptidyl peptidase IV which was increased in younger IL-1rn-/- mice compared to wild type mice. The expression of tight and adhesion junctions were also dramatically decreased in IL-1rn-/- mice. In conclusion, IL-1rn-/- mice developed spontaneous abnormalities which displayed features associated with IBD, demonstrating a clear role for IL-1 in IBD.
Project description:OBJECTIVE:Autism spectrum disorders (ASD) have a complex pathophysiology including genetic, inflammatory and neurodevelopmental components. We aim to investigate the relationship between ASD and gene polymorphisms of stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor-4 (CXCR4), which may affect inflammatory and neurodevelopmental processes. METHODS:101 children diagnosed with ASD aged 2-18 and their biological parents were included in the study. All participants were assessed using an information form and the Children were assessed using Childhood Autism Rating Scale (CARS). SDF-1 G801?A and CXCR4 C13?T polymorphisms were detected by genetic techniques. The results were evaluated using the transmission disequilibrium test (TDT) and haplotype relative risk (HRR). RESULTS:Following TDT evaluation for CXCR4, the assumption of equality was not rejected (?2=1.385, p=0.239). HRR for the C allele was 1.037 [HRR (95%CI)=0.937 (0.450-2.387), ?2=0.007, p=0.933] and HRR for the T allele was 0.965 [HRR (95%CI)=0.965 (0.419- 2.221), ?2=1.219, p=0.270], but the findings were statistically insignificant. Based on TDT evaluation for SDF1, the assumption of equality cannot be rejected (?2=0, p=0.999). HRR for the A allele was 0.701 [HRR (95%CI)=0.701 (0.372-1.319), ?2=1.219, p=0.270] and HRR for the G allele was 1.427 [HRR (95%CI)=1.427 (0.758-2.686), ?2=1.219, p=0.270], but the findings were statistically insignificant. CONCLUSION:The genetic screening of blood samples from mother, father and child trios could not show a significant association between SDF1/CXCR4 genes and ASD on the basis of TDT and HRR tests. More extensive genetic studies are now needed to investigate the relationship between SDF1/CXCR4 gene polymorphisms and ASD.
Project description:<h4>Background</h4>The study aimed to evaluate the relationship of IL-1B/IL-1RN polymorphisms to the predisposition of head and neck cancer (HNC) in a Chinese Han population.<h4>Methods</h4>Nine single-nucleotide polymorphisms (SNPs) in IL-1B/IL-1RN were genotyped based on Agena MassARRAY platform. Logistic regression models were used to analyze the genetic association between these SNPs and HNC risk by calculating odds ratios (ORs) and 95% confidence intervals (CI). Haplotype analysis were performed using Haploview program and logistic regression model.<h4>Results</h4>The genetic association between rs1143643 in IL-1B and the higher risk of HNC was found (OR?=?1.23, 95% CI 1.04-1.46) in the overall. IL-1RN rs17042888 was related to a reduced risk of HNC in the subjects aged?>?46 years (OR?=?0.70, 95% CI: 0.50-0.98) and in females (OR?=?0.71, 95% CI 0.52-0.98), while rs1143643 increased the predisposition of HNC among females (OR?=?1.76, 95% CI 1.13-2.74). Furthermore, rs1143643 had an increased susceptibility to thyroid carcinoma (OR?=?1.61, 95% CI 1.10-2.34). Moreover, compared with stage I-II, the frequency of IL-1RN rs452204-AG genotype was lower in patients with stage III-IV.<h4>Conclusions</h4>IL-1B (rs1143643) and IL-1RN (rs17042888 and rs452204) polymorphisms might be related to the individual susceptibility of HNC in the Chinese Han population. These results might help to improve the understanding of IL-1B and IL-1RN genes in the occurrence of HNC.
Project description:OBJECTIVE:To verify whether the variable number of tandem repeat (VNTR) polymorphism in the IL-1RN gene that encodes the interleukin (IL)-1 receptor antagonist (IL-1Ra) plays a role in the outcome of gastrointestinal diseases associated with Helicobacter pylori (H. pylori) infection. METHODS:Patients with normal endoscopy (n = 71), inflammation of the upper gastrointestinal tract only (n = 196), gastric ulcer (n = 28), duodenal ulcer (n = 76), and gastric cancer (n = 19) were studied. H. pylori infection was diagnosed by the urease test, histological examination, and polymerase chain reaction. The IL-1 receptor antagonist gene (IL-1RN intron 2 VNTR) was analyzed by polymerase chain reaction. Gastritis was scored according to the updated Sydney system of classification. RESULTS:H. pylori infection was an independent risk factor for mild (odds ratio [OR] = 5.53 [95% confidence interval [CI] = 2.63-11.64; P < 0.05]), moderate (OR = 83.93 [95% CI = 29.7-237.18; P < 0.05]) and marked (OR = 47.47 [95% CI = 5.39-418.05; P < 0.05]) gastritis. The carriage of IL-1RN*2/*2 had a significant protective effect of H. pylori infection (OR = 0.31 [95% CI = 0.17-0.57; P < 0.05]). H. pylori infection was identified as an independent risk of inflammation, duodenal ulcer, and gastric ulcer. The carriage of IL-1RN*2/*2 was an independent risk factor for gastric cancer (OR = 5.81 [95% CI = 1.06-31.98; P < 0.05]); nonetheless, the carriage of allele 2 (IL-1RN*2/*2 plus IL-1RN*L/*2) had an independent protective effect on duodenal ulcer (OR = 0.45 [95% CI = 0.22-0.91; P < 0.05]). CONCLUSIONS:Allele 2 of the VNTR IL-1RN polymorphism had a protective effect against duodenal ulcer and H. pylori infection; however, it increased the risk of gastric cancer.
Project description:The present study investigated the distribution of genotypes within single nucleotide polymorphisms (SNPs) in genes, related to PVR pathogenesis across European subpopulations. Genotype distributions of 42 SNPs among 96 Slovenian healthy controls were investigated and compared to genotype frequencies in 503 European individuals (Ensembl database) and their subpopulations. Furthermore, a case-control status was simulated to evaluate effects of allele frequency changes on statistically significant results in gene-association studies investigating functional polymorphisms. In addition, 96 healthy controls were investigated within 4 SNPs: rs17561 (IL1A), rs2069763 (IL2), rs2229094 (LTA), and rs1800629 (TNF) in comparison to PVR patients. Significant differences (P < 0.05) in distribution of genotypes among 96 Slovenian participants and a European population were found in 10 SNPs: rs3024498 (IL10), rs315952 (IL1RN), rs2256965 (LST1), rs2256974 (LST1), rs909253 (LTA), rs2857602 (LTA), rs3138045 (NFKB1A), rs3138056 (NFKB1A), rs7656613 (PDGFRA), and rs1891467 (TGFB2), which additionally showed significant differences in genotype distribution among European subpopulations. This analysis also showed statistically significant differences in genotype distributions between healthy controls and PVR patients in rs17561 of the IL1A gene (OR, 3.00; 95% CI, 0.77-11.75; P = 0.036) and in rs1800629 of the TNF gene (OR, 0.48; 95% CI, 0.27-0.87; P = 0.014). Furthermore, we have shown that a small change (0.02) in minor allele frequency (MAF) significantly affects the statistical p value in case-control studies. In conclusion, the study showed differences in genotype distributions in healthy populations across different European countries. Differences in distribution of genotypes may have had influenced failed replication results in previous PVR-related SNP-association studies.