Polymorphisms In Inflammation-related Genes Research Articles

Developmental Predictors of Suicidality in Schizophrenia: A Systematic Review.

Background/Objectives: Schizophrenia (SZ) is a severe psychiatric disorder characterized by a complex interplay of genetic, developmental, and environmental factors that significantly increase the risk of suicidal ideation (SI) and suicide attempts (SAs). This systematic review synthesizes current research on the developmental predictors of SI in individuals with SZ, aiming to delineate the multifactorial etiology of suicide within this population. Methods: A comprehensive search across Medline, PsycINFO, and EMBASE databases identified 23 eligible studies, emphasizing the varied methodological approaches and the global distribution of research efforts. Results: These studies demonstrate a robust association between early life adversities, particularly childhood trauma such as physical neglect, emotional abuse, and sexual abuse, and the increased prevalence of SI and SAs in SZ. This review also highlights the significant genetic factors associated with the development of suicidality in SZ, raising the possibility that polymorphisms in inflammation-related genes and neurodevelopmental abnormalities may influence susceptibility to SI. Notably, family history of psychiatric conditions may exacerbate the risk of SI through both hereditary and environmental mechanisms. Environmental factors, including socioeconomic status and social support, are also implicated, underscoring the role of broader socio-environmental conditions influencing outcomes. Conclusions: This review supports the integration of biopsychosocial models in understanding SI in SZ, advocating for interventions addressing the complex interplay of risk factors and the need for longitudinal studies to elucidate the dynamic interactions between risk factors over time. This comprehensive understanding is crucial for developing targeted preventive strategies and enhancing the clinical management of SZ, aiming to reduce suicidality in this vulnerable population.

Association Analysis of Polymorphisms in Inflammation-Related Genes with Non-Hodgkin Lymphoma Susceptibility

Non-Hodgkin's lymphoma (NHL) is a common hematological malignancy that develops in the lymphatic system. A20, CYLD, IFN-γ, JAK2, PI3KCA, and TP53 are known as inflammation-related genes in autoimmune diseases and cancers. In the end, 126 patients with NHL and 109 healthy individuals with well-characterized clinical profiles were enrolled. Twelve variants in the above genes were determined by the Kompetitive allele-specific PCR (KASP) assay. As a result, among genotyped 12 SNPs, the AG genotype of the rs280500 in the TYK2 gene showed significantly higher frequency in the patient group compared to healthy individuals (P=0.05). In addition, no significant differences in genotype frequencies of the other SNPs were found between the two groups. In conclusion, the rs280500 in the TYK2 gene was the risk variant for NHL susceptibility and additionally contributed to understanding the genetic basis of NHL.

Inflammation-related Gene Polymorphisms Associated With Childhood Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is a malignant hematological disease and is often accompanied by a variety of genetic abnormalities. The pathogenesis of inflammation-related single-nucleotide polymorphism (SNP) in children with ALL remains unclear. This study was to discover the association of the SNP sites of some inflammation-related genes and the susceptibility and treatment response of ALL in children, so as to provide personalized treatment for ALL in children. One hundred sixty-five childhood ALL patients and 175 age-matched healthy participants were recruited in this study. We investigated the involvement of 31 SNPs of the inflammation-related genes in the pathogenesis and treatment response of childhood ALL. Statistical analysis revealed that rs2280714 in IRF5, rs2297630 in SDF-1, rs4353135 in NLRP3, rs1946518 in interleukin-18 were related to the susceptibility to pediatric ALL. Interleukin-1β rs16944 SNP was correlated with ALL risk stage in children. Rs7633631 in CD226 and rs10818488 in TRAF1 were related to the minimal residual disease (MRD) on day 15 and day 33. Certain SNPs of inflammation genes were associated with the susceptibility and treatment response of ALL children. These findings may help in the early detection, diagnostic evaluation, and making individual chemotherapy regimen for ALL children according to the genotype of these sites at the time of initial diagnosis.

Favorable Genotypes of Type III Interferon Confer Risk of Dyslipidemia in the Population With Obesity.

BackgroundStudies have indicated that the chronic state of inflammation caused by obesity leads to dyslipidemia. However, how the polymorphisms involved in these inflammatory pathways affect the lipid metabolism in people with obesity is poorly understood. We investigated the associations of inflammation-related gene polymorphisms with dyslipidemia in individuals with obesity living in China.MethodsThis case–control study in a population with obesity involved 194 individuals with dyslipidemia and 103 individuals without dyslipidemia. Anthropometric indices of obesity, fasting plasma glucose, blood pressure, blood lipids, and C-reactive protein were evaluated. The genes we tested were IL6 (interleukin 6), IL6R (interleukin 6 receptor), FOXP3 (forkhead box P3), TLR2 (toll-like receptor 2), TLR4 (toll-like receptor 4), IFNL3 (interferon lambda 3, formerly known as IL28B), and IFNL4 (interferon lambda 4, formerly known as IL29). Polymorphisms were genotyped using matrix-assisted laser desorption/ionization-time of flight mass spectrometry.ResultsThere were significant differences in the allelic and genotype frequencies of IFNL3 (IL28B) rs12971396, rs8099917, rs11882871, rs12979860, rs4803217 between non-dyslipidemia and dyslipidemia groups in people with obesity. These single nucleotide polymorphisms (SNPs) of IFNL3 were highly linked (D′ and r > 0.90), so the result of one SNP could represent the result of other SNPs. For IFNL3 rs12971396, people with the homozygous genotype (the major group) carried a higher risk of dyslipidemia than people with the heterozygous genotype (P < 0.001, OR = 4.46, 95%CI, 1.95–10.22).ConclusionsThe favorable genotypes of type III interferon, which have a beneficial role in anti-virus function, were associated with dyslipidemia in a Chinese population with obesity. Type III interferon could have a pathologic role and confer risk of dyslipidemia in people with obesity and chronic inflammation.

Immune and inflammation-related gene polymorphisms and susceptibility to tuberculosis in Southern Xinjiang population: A case-control analysis.

Genetic and immune factors play an important role in tuberculosis. Under different ethnicities and genetic backgrounds, different immune and inflammation-related gene polymorphisms may confer different susceptibility to tuberculosis. This study investigated the relationship between immune and inflammation-related gene polymorphism and susceptibility to tuberculosis in Xinjiang Uyghur population, China. In this case-control study, we enrolled 507 pulmonary tuberculosis patients and 454 healthy controls from Southern Xinjiang. single nucleotide polymorphism (SNP) genotyping was performed. The 12 SNPs of nine immune and inflammation-related genes (including TNF rs361525, IL6 rs2066992 and rs1524107, IL17A rs3748067, IL17F rs763780, VDR rs731236, rs2228570 and rs1544410, IFNGR1 rs1327474, P2RX7 rs3751143, CTAGE1 rs4331426 and Toll-like receptor 4 (TLR4) rs4986790) and their relationship with tuberculosis were evaluated. The T allele and TT genotype of IL-6 rs2066992 and rs1524107 increased the risk of active tuberculosis. The C allele of IFNGR1 rs1327474 was related to the reduced risk of tuberculosis in the Xinjiang Uyghur population. The G allele and AG/GG genotypes of TLR4 rs4986790 were associated with an increased risk of tuberculosis (p<.05). Furthermore, haplotype analysis found that the haplotype TT of interleukin (IL)-6 was a risk factor, whereas the CG type was a protective factor for active tuberculosis in the Xinjiang Uyghur population. There were three immune and inflammation-related genes (IL-6, IFNGR1 and TLR4) and a total of four SNPs (rs2066992, rs1524107, rs1327474 and rs4986790) related to the susceptibility of the Uyghur population to tuberculosis. Our findings may provide evidence for further understanding the mechanism of tuberculosis susceptibility in the Xinjiang Uyghur population.

Association of Inflammation-Related Gene Polymorphisms With Susceptibility and Radiotherapy Sensitivity in Head and Neck Squamous Cell Carcinoma Patients in Northeast China.

BackgroundInflammation-related gene polymorphisms are some of the most important determinants for cancer susceptibility, clinical phenotype diversity, and the response to radiotherapy and chemotherapy. However, the relationship between these polymorphisms and head and neck squamous cell carcinoma (HNSCC) remains unclear. The aim of this study was to investigate the role of inflammation-related gene polymorphisms in the developmental risk and radiotherapy sensitivity of HNSCC.MethodsThe Matrix-Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) genotyping system was used to genotype 612 individuals from a Chinese population for 28 inflammation-related gene polymorphisms.ResultsThe protein kinase B (AKT1) rs1130233 TT, dominance model (CT+TT vs. CC), recessive model (TT vs. CT+CC), and rs2494732 CC genotypes were associated with reduced risk of HNSCC (P=0.014; P=0.041; P=0.043). The polymeric immunoglobulin receptor (PIGR) rs291097 GA, dominance model (GA+AA vs. GG), and rs291102 dominance model (GA+AA vs. GG) were associated with increased risk of HNSCC (P=0.025; P=0.025; P=0.040). The interleukin-4 receptor-α (IL-4RA) rs1801275 AA genotype was significantly correlated with increased radiotherapy sensitivity of HNSCC patients (P=0.030). In addition, age ≤ 60 years, non-smoker status, and normal levels of squamous cell carcinoma antigen (SCC) were found to be associated with increased radiotherapy sensitivity of HNSCC patients (P=0.033; P=0.033; P=0.030).ConclusionThe AKT1 rs1130233, AKT1 rs2494732, PIGR rs291097, and PIGR rs291102 polymorphisms were significantly related to the risk of HNSCC. The IL-4RA rs1801275 polymorphism, age ≤ 60 years, non-smoker status, and normal levels of SCC were significantly associated with increased radiotherapy sensitivity of HNSCC.

The SERPINA4 rs2070777 AA Genotype is Associated with an Increased Risk of Recurrent Miscarriage in a Southern Chinese Population.

BackgroundMany inflammation-related gene polymorphisms are associated with susceptibility to recurrent miscarriage. SERPINA4 is involved in inflammation and is associated with susceptibility to a variety of diseases, but its relevance in recurrent miscarriage is unclear. Therefore, this study aimed to investigate the relationship between SERPINA4 gene polymorphisms and susceptibility to recurrent spontaneous abortion.MethodsTwo SERPINA4 polymorphisms were genotyped in 631 patients with recurrent miscarriage and 771 controls by TaqMan real-time polymerase chain reaction, and the strength of each association was evaluated through 95% confidence intervals (CIs) and odds ratios (ORs).ResultsThe results showed that SERPINA4 rs2070777 AA genotypes were associated with an increased risk of recurrent miscarriage (AA vs AT/TT adjusted OR=1.409, 95% CI=1.032–1.924, P=0.0309), and we also found a significant association between the rs910352 T allele in the SERPINA4 gene and susceptibility to recurrent miscarriage (CT vs CC adjusted OR=1.579, 95% CI=1.252–1.992, P=0.0001; TT vs CC adjusted OR=1.524, 95% CI=1.134–2.049, P=0.0052). The combined analysis of two SNPs of the SERPINA4 gene revealed that carriers with one to two unfavorable genotypes were associated with a higher risk for recurrent miscarriage compared with individuals with no unfavorable genotypes (adjusted OR=1.257, 95% CI=1.019-1.550). Moreover, our study indicates that having one to two unfavorable genotypes is associated with an increased risk of recurrent miscarriage in women 35–40 years of age.ConclusionOur study suggests that SERPINA4 rs2070777AA genotypes might contribute to an increased risk of recurrent miscarriage in a southern Chinese population.

Inflammation-related gene polymorphisms associated with Parkinson\u2019s disease: an updated meta-analysis

BackgroundStrong evidence supports the involvement of inflammation processes in the development and progression of Parkinson’s disease (PD), where increasingly correlations have been identified between genetic variations in inflammation-related genes and PD. However, data varies between studies. Therefore, we conducted a meta-analysis to clarify associations between inflammation-related gene polymorphisms and PD risk.MethodsAll studies were identified through online databases. Pooled and stratified groups based on racial descent were assembled to evaluate associations between polymorphisms and PD.ResultsThe pooled results showed that protective effects for PD were observed for (1) IL-1α -889 C/T in Asian populations (T vs. C, OR = 0.831, P = 0.031; TT + CT vs. CC, OR = 0.827, P = 0.049); (2) IL-6 -176 G/C in Caucasian populations (CC + GC vs. GG, OR = 0.656, P = 0.000; GC vs. GG, OR = 0.673, P = 0.000); (3) IL-8 -251 A/T (T vs. A, OR = 0.812, P = 0.041; TT vs. AT + AA, OR = 0.663, P = 0.012), particularly in Caucasian populations (TT vs. AT + AA, OR = 0.639, P = 0.010); (4) IL-10 -819 T/C (C vs. T, OR = 0.742, P = 0.034); (5) IL-18 -607 C/A (AA + CA vs. CC, OR = 0.597, P = 0.015; CA vs. CC, OR = 0.534, P = 0.005), and (6) CCR2 +190 G/A (AA vs. GA + GG, OR = 0.552, P = 0.018; AA vs. GG; OR = 0.554; 95% CI 0.336–0.914, P = 0.005). An increased risk of PD was associated with IL-10 -1082 G/A in Asian populations (A vs. G, OR = 1.731, P = 0.000; AA + GA vs. GG, OR = 1.910, P = 0.000). No significant associations with PD were observed for polymorphisms in IL-1β -511 C/T, IL-10 -592 C/A, IL-18 -137 G/C, TNFα -863 C/A, TNFα -857 C/T, TNFα -308 G/A, IFNΥ +874 T/A, and MCP1/CCL2 +2518 A/G.ConclusionsWe suggest that IL-1α -889, IL-6 -176, IL-8 -251, IL-10 -1082, IL-10 -819, IL-18 -607, and CCR2 +190 polymorphisms may be associated with PD risk; however, further studies must verify these conclusions.

Effect of IL2RA and IL2RB gene polymorphisms on lung cancer risk

BackgroundInflammation is crucial for lung cancer development. Variants of multiple genes in inflammation pathways may lead to susceptibility to lung cancer. In the present study, we aimed to assess the influence of polymorphisms in inflammation-related genes (IL2RA and IL2RB) on lung cancer risk. MethodsA total of 507 patients with lung cancer and 503 healthy controls were genotyped for seven polymorphisms of IL2RA and IL2RB using the Agena MassARRAY platform. We evaluated the relationship of the genotypes with lung cancer susceptibility using odds ratio (OR), 95% confidence interval (95% CI) and chi square test. ResultsWe found that IL2RA rs12722498 was significantly associated with a decreased risk of lung cancer in dominant (p = 0.040, OR = 0.71, 95% CI = 0.51–0.98), additive (p = 0.016, OR = 0.68, 95% CI = 0.50–0.93) and allele (p = 0.019, OR = 0.69, 95% CI = 0.51–0.94) models. After stratification analysis, the results showed that IL2RA rs12569923 (non-smokers), IL2RA rs791588 (≤60 years old, non-drinkers, BMI < 24 kg/m2), IL2RA rs12722498 (≤60 years old, non-drinkers, BMI < 24 kg/m2, female) and IL2RB rs2281089 (female, stage) significantly decreased the risk of lung cancer. Additionally, the haplotypes of rs12569923 and rs791588 in IL2RA had strong relationships with lung cancer in the subgroups of BMI < 24 kg/m2, age ≤ 60 years old, non-smokers and non-drinkers. ConclusionOur results showed that the IL2RA and IL2RB polymorphisms were associated with lung cancer risk in the Chinese Han population, which suggests roles for IL2RA and IL2RB polymorphisms in lung cancer.

The Association of Gastritis and Peptic Ulcer With Polymorphisms in the Inflammatory-related Genes IL-4 and IL-10 in Iranian Population

The current study aimed at assessing the relationship between gastritis and peptic ulcer susceptibility and inflammation-related gene polymorphisms in Iranian patients.Gastritis and peptic ulcer are common medical complications with serious outcomes on the quality of life. Inflammatory responses of gastric mucosa are associated with helicobacter pylori, but most infected patients remain asymptomatic. There is strong evidence that inflammatory response is a major part of its etiology. The current case-control study aimed atexamining genetic polymorphisms in inflammatory cytokines interleukin (IL)-4, and IL-10 using polymerase chain reaction-variable number tandem reaped (PCR-VNTR) and PCR-restriction fragment length polymorphism(RFLP) methods, respectively in 603 genotyped patients admitted to Mohammadi Hospital in Bandar Abbas, Iran(198 patients with gastritis, 84 with peptic ulcer, and 321 patients as controls). No significant associations were detected in genotype and allele frequencies of IL-10 and IL-4 between the case (with gastritis and peptic ulcer) and control groups. In conclusion, the results of the analyses suggested that these polymorphisms may not predispose the carriers to gastritis and peptic ulcer development.

Inflammatory Gene Polymorphisms in Lung Cancer Susceptibility.

Chronic inflammation has been implicated in carcinogenesis, with increasing evidence of its role in lung cancer. We aimed to evaluate the role of genetic polymorphisms in inflammation-related genes in the risk for development of lung cancer. A nested case-control study design was used, and 625 cases and 625 well-matched controls were selected from participants in the β-Carotene and Retinol Efficacy Trial, which is a large, prospective lung cancer chemoprevention trial. The association between lung cancer incidence and survival and 23 polymorphisms descriptive of 11 inflammation-related genes (interferon gamma gene [IFNG], interleukin 10 gene [IL10], interleukin 1 alpha gene [IL1A], interleukin 1 beta gene [IL1B], interleukin 2 gene [IL2], interleukin 4 receptor gene [IL4R], interleukin 4 gene [IL4], interleukin 6 gene [IL6], prostaglandin-endoperoxide synthase 2 gene [PTGS2] (also known as COX2), transforming growth factor beta 1 gene [TGFB1], and tumor necrosis factor alpha gene [TNFA]) was evaluated. Of the 23 polymorphisms, two were associated with risk for lung cancer. Compared with individuals with the wild-type (CC) variant, individuals carrying the minor allele variants of the IL-1β-511C>T promoter polymorphism (rs16944) (CT and TT) had decreased odds of lung cancer (OR= 0.74, [95% confidence interval (CI): 0.58-0.94] and OR= 0.71 [95% CI: 0.50-1.01], respectively, p= 0.03). Similar results were observed for the IL-1β-1464 C>G promoter polymorphism (rs1143623), with presence of the minor variants CG and CC having decreased odds of lung cancer (OR= 0.75 [95% CI: 0.59-0.95] and OR= 0.69 [95% CI: 0.46-1.03], respectively, p= 0.03). Survival was not influenced by genotype. This study provides further evidence that IL1B promoter polymorphisms may modulate the risk for development of lung cancer.

Polymorphisms in inflammation-related genes and the risk of primary varicose veins in ethnic Russians.

Inflammation was shown to be activated in varicose veins, although its role in the development of vein wall transformation remains inconclusive. We aimed to investigate the influence of 13 inflammation-related single nucleotide polymorphisms (SNPs) TNF rs1800629 and rs3093661, IL1A rs1800587, IL1RN rs4251961, IL6 rs1800795 and rs1800796, IFNG rs2430561, IL10 rs1800896, TGFB1 rs1800469, HIF1A rs11549465, NFKB1 rs28362491, and rs4648068 on the risk of primary varicose veins (PVVs) in ethnic Russians. We genotyped 709 patients with PVVs and 278 individuals without a history of chronic venous disease and performed a single SNP and a haplotype analysis. Several associations with P < 0.05 were revealed in our study. Variant allele HIF1A rs11549465 T, TNF rs3093661 A, and NFKB1 rs28362491 ATTG deletion showed the reverse association with PVV risk, and allele IL6 rs1800795 C was associated with the increased risk of the studied pathology. Haplotype analysis revealed associations of TNF haplotypes rs3093661 A-rs1800629 G and IL6 rs1800795 C-rs1800796 G with the decreased and the increased risk of PVVs, correspondingly. However, all the observed associations failed to reach statistical significance after the correction for multiple testing, which was set at a level of 10-3 due to many tests performed. Our study therefore provides evidence that investigated polymorphisms do not play a major role in susceptibility to PVVs.

Inflammation-Related Gene Polymorphisms Associated With Primary Immune Thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by a reduced platelet count and an increased risk of bleeding. Although immense research has improved our understanding of ITP, the pathogenesis remains unclear. Here, we investigated the involvement of 25 single-nucleotide polymorphisms (SNPs) of the inflammation-related genes, including CD24, CD226, FCRL3, IL2, IRF5, ITGAM, NLRP3, CARD8, PTPN22, SH2B2, STAT4, TNFAIP3, and TRAF1, in the pathogenesis and treatment response of ITP. We recruited 312 ITP inpatients and 154 healthy participants in this case–control study. Inflammation-related SNP genotyping was performed on the Sequenom MassARRAY iPLEX platform. The expression of TNFAIP3 mRNA was determined by quantitative real-time RT-PCR. All SNPs in healthy controls were consistent with Hardy–Weinberg equilibrium. Statistical analysis revealed that rs10499194 in TNFAIP3 was significantly associated with a decreased risk of ITP after Bonferroni multiple correction (codominant, CT vs. CC, OR = 0.431, 95% CI = 0.262–0.711, p = 0.001; dominant, TT/CT vs. CC, OR = 0.249, 95% CI = 0.141–0.440, p = 0.000). Besides, TNFAIP3 expression was significantly higher in patients with CT and pooled CT/TT genotypes compared with CC genotype (p = 0.001; p = 0.001). Interestingly, rs10499194 was also associated with corticosteroid-sensitivity (codominant, CT vs. CC, OR = 0.092, 95% CI = 0.021–0.398, p = 0.001; dominant, TT/CT vs. CC, OR = 0.086, 95% CI = 0.020–0.369, p = 0.001; allelic, T vs. C, OR = 0.088, 95% CI = 0.021–0.372, p = 0.001). Furthermore, no significant association was found between inflammation-related SNPs and the severity or refractoriness of ITP after Bonferroni multiple correction. Our findings suggest that rs10499194 may be a protective factor for susceptibility and corticosteroid sensitivity in ITP patients.

Inflammation-Related Gene Polymorphisms Associated with Susceptibility to Primary Immune Thrombocytopenia

INTRODUCTIONPrimary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by a reduced platelet count and an increased risk of bleeding. Although immense research has improved our understanding of ITP and led to impressive therapeutics, the pathogenesis is still not completely clear and a large subset of patients are refractory to first- and second-line therapies.In this study, we investigated the involvement of a cluster of inflammation-related genes, including CD24, FCRL3, CD226, IL2, IRF5, ITGAM, NLRP3, CARD8, PTPN22, SH2B3, STAT4, TNFAIP3, and TRAF1 genes.METHODSIn this case-control study, 261 ITP inpatients (92 males and 169 females) with a mean age of 39.59 ± 17.52 years were recruited from Qilu Hospital, Shandong University between January 2007 to April 2016. In addition, 154 healthy participants (60 males and 94 females) with a mean age of 44.82 ± 13.63 years were enrolled as a control group. Inflammation-related single nucleotide polymorphism (SNP) genotyping was performed on the Sequenom MassARRAY iPLEX platform. SNPs included CD24 rs8734/rs52812045, FCRL3 rs11264799, rs7528684, rs945635, rs3761959, CD226 rs763361, IL2 rs6822844, IRF5 rs2004640, rs2280714, rs10954213, ITGAM rs1143679, NLRP3 rs35829419, rs4353135, rs10754558, CARD8 rs2043211, PTPN22 rs33996649, rs1310182, SH2B3 rs3184504, STAT4 rs7574865, rs10181656, TNFAIP3 rs6920220, rs10499194, rs2230926, rs5029939, TRAF1 rs10818488. SPSS (Ver 22.0, Chicago, IL) was used to perform statistical analysis. The results of genotyping were analyzed with t or ¦Ö2 tests. A Fisher’s exact test was performed when expected frequencies were less than 5. Univariate and multivariate analyses were then performed by non-conditional logistic regression adjusting for age and gender. P values < 0.05 were considered significant. The two-tailed significance level was set at 0.05.RESULTSGenotype frequencies of these inflammation-related SNPs in healthy controls were consistent with the Hardy-Weinberg equilibrium (p > 0.05). Genotype distributions in ITP patients and controls are detailed in Table 1. Statistical analysis revealed a significant difference in TNFAIP3 rs10499194 and CD24 rs52812045 between patients and controls (Table 1). Genotype frequencies of other SNPs were not significantly different (p > 0.05). However, when allelic frequencies were compared, significant differences were not found in any genotyped SNPs (p > 0.05).ITP is classified by duration into newly diagnosed (less than 3-month duration), persistent (3- to 12-month duration) and chronic (1-year duration). According to ordinal logistic regression, the genotype frequency of IRF5 rs2004640 was significantly different between the 3 ITP phases. Compared with heterozygous carriers, homozygous carriers of major allele were found in higher frequency in newly diagnosed patients. The OR for GG vs. GT was 0.472 (95%CI = 0.289-0.770, p = 0.003).Patients with clinically relevant bleeding who require mandated treatment or additional therapeutic intervention are defined as having severe ITP. The inflammation-related SNPs were not significantly different between severe and non-severe patients (p > 0.05).Interestingly, genotype frequency distribution of CARD8 rs2043211 was significantly higher in refractory patients than in non-refractory patients (OR = 4.191, 95%CI = 1.026-14.567, p = 0.040), while allelic frequencies were not significantly different. We also compared corticosteroid-sensitive and corticosteroid-resistant ITP patients. We found that the genotype frequency of NLRP3 rs4353135 was significantly different between the two groups, and heterozygous genotype was more frequent in corticosteroid-sensitive patients (OR = 0.413, 95%CI = 0.203-0.841, p = 0.015). No significant difference was observed in other polymorphisms.CONCLUSIONSOur study identifies SNPs that differ based on the presence of ITP (TNFAIP3 rs10499194 and CD24 rs52812045), the phase of ITP (IRF5 rs2004640), refractoriness (CARD8 rs2043211), and corticosteroid sensitivity (NLRP3 rs4353135) in Chinese Han population. These important findings may lead to more tailored treatment strategies for ITP patients. Further study will dissect how these SNPs exert their roles to affect the pathogenesis of ITP. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Inflammatory Cytokines and Alzheimer's Disease: A Review from the Perspective of Genetic Polymorphisms.

Neuroinflammatory processes are a central feature of Alzheimer's disease (AD) in which microglia are over-activated, resulting in the increased production of pro-inflammatory cytokines. Moreover, deficiencies in the anti-inflammatory system may also contribute to neuroinflammation. Recently, advanced methods for the analysis of genetic polymorphisms have further supported the relationship between neuroinflammatory factors and AD risk because a series of polymorphisms in inflammation-related genes have been shown to be associated with AD. In this review, we summarize the polymorphisms of both pro- and anti-inflammatory cytokines related to AD, primarily interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha, IL-4, IL-10, and transforming growth factor beta, as well as their functional activity in AD pathology. Exploration of the relationship between inflammatory cytokine polymorphisms and AD risk may facilitate our understanding of AD pathogenesis and contribute to improved treatment strategies.

Polymorphisms in HLA-DQ genes, together with age, sex, and Helicobacter pylori infection, as potential biomarkers for the early diagnosis of gastric cancer.

Polymorphisms in inflammation-related genes are factors associated with the development of gastroduodenal diseases in Helicobacter pylori-infected individuals. We aimed to analyze polymorphisms in HLA-DQ, together with other host and H.pylori variables as risk factors for precancerous and cancerous gastric lesions. 1052 individuals were studied, including nonatrophic gastritis (NAG), intestinal metaplasia (IM), gastric cancer (GC) or duodenal ulcer (DU) patients, and healthy volunteers. Patients with alleles DQA*01:01 (OR 0.78), *01:02 (OR 0.29), *01:03 (OR 0.31), and DQB*02:01/02 (OR 0.40) showed a reduced risk for GC. A multivariate logistic regression analyses showed that patients with homozygote genotypes DQA1*03:01 (OR 7.27) and DQA1*04:01 (OR 8.99) and DQB1*05:01:01 (OR 12.04) were at significantly increased risk for GC. Multivariate analyses also demonstrated that age (OR>10.0) and gender (OR>2.0) were variables that influenced significantly the risk for GC, while H.pylori infection (OR>2.5) increased the risk for IM. We identified HLA-DQ alleles associated with IM and GC, and confirm that age, sex, and H.pylori infection are variables that also influence the risk for disease. The use of multiple markers, HLA-DQ alleles, age, sex, and H.pylori infection may be useful biomarkers for the early diagnosis of patients with IM and GC.

Influence of cigarette smoking and inflammatory gene polymorphisms on glycated hemoglobin in the Japanese general population.

ObjectiveInflammation is closely involved in the development of type 2 diabetes, and cigarette smoking acts as potent inducer of inflammation. We therefore investigated interactions between inflammation-related gene polymorphisms and cigarette smoking on glycated hemoglobin (HbA1c) in the Japanese general population.MethodWe conducted a cross-sectional study using data collected from 2619 Japanese (1274 males and 1345 females) 40–69 years of age who participated in baseline survey of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study (2005–2008). Eight polymorphisms in seven genes (interleukin [IL]-1β, IL-2, IL-4, IL-8, IL-10, IL-13 and tumor necrosis factor-α) were determined using the Invader assay. The interactions of smoking and gene polymorphisms on HbA1c levels were analyzed using multiple linear and logistic regression models and analysis of covariance with adjustment for potential confounders.ResultsAmong the eight polymorphisms, only one significant interaction was detected for IL-1β T-31C (P < 0.0001). Among the subjects carrying TT genotype, current heavy smokers (≥ 20 cigarettes/day) had higher HbA1c (5.83 [95% confidence interval 5.67–5.99] %) versus all other smoking status groups (never 5.49 [5.41–5.56] %, former 5.54 [5.43–5.65] %, current moderate [< 20 cigarettes/day] 5.50 [5.30–5.69] %), whereas such differences were not observed in the subjects with C allele. The logistic regression analyses regarding high-normal HbA1c levels showed a similar pattern of results.ConclusionSmoking status did not interact with any other inflammation-related polymorphisms except for IL-1β T-31C. Heavy smokers harboring the TT genotype of IL-1β T-31C polymorphism show a greater adverse effect of smoking on HbA1c levels among Japanese middle-aged subjects.

CD14 and IL18 gene polymorphisms associated with colorectal cancer subsite risks among atomic bomb survivors.

Colorectal cancer (CRC) is a common malignancy worldwide, and chronic inflammation is a risk factor for CRC. In this study, we carried out a cohort study among the Japanese atomic bomb (A-bomb) survivor population to investigate any association between immune- and inflammation-related gene polymorphisms and CRC. We examined the effects of six single-nucleotide polymorphisms of CD14 and IL18 on relative risks (RRs) of CRC. Results showed that RRs of CRC, overall and by anatomic subsite, significantly increased with increasing radiation dose. The CD14–911A/A genotype showed statistically significant higher risks for all CRC and distal CRC compared with the other two genotypes. In addition, the IL18–137 G/G genotype showed statistically significant higher risks for proximal colon cancer compared with the other two genotypes. In phenotype–genotype analyses, the CD14–911A/A genotype presented significantly higher levels of membrane and soluble CD14 compared with the other two genotypes, and the IL18–137 G/G genotype tended to be lower levels of plasma interleukin (IL)-18 compared with the other two genotypes. These results suggest the potential involvement of a CD14-mediated inflammatory response in the development of distal CRC and an IL18-mediated inflammatory response in the development of proximal colon cancer among A-bomb survivors.

Interleukin-1B signalling leads to increased survival of gastric carcinoma cells through a CREB-C/EBPβ-associated mechanism.

Polymorphisms in inflammation-related genes have been associated with a risk of gastric carcinoma (GC). However, the biological mechanisms underlying these associations are still elusive. Our objective was to determine whether chronic inflammation-associated IL1Β signalling, as seen in the context of Helicobacter pylori infection, could be linked to gastric carcinogenesis by modulating the behaviour of gastric epithelial cells. The effect of IL1B was assessed by studying the expression and activation status of the IL1Β-activated transcription factors C/EBPβ and CREB in GC cell lines. Interaction between CREB and C/EBPβ was explored through interference RNA, chromatin immunoprecipitation and chemical inhibition. CREB and C/EBPβ expression was analysed in 66 samples of primary GC and in normal gastric mucosa. GC cell growth was analysed in vitro by BrdU incorporation and in vivo employing a chicken embryo chorioallantoic membrane model. We found that IL1B regulates the expression/activation status of both C/EBPβ and CREB in GC cells through an ERK1/2-dependent mechanism. Our results show that CREB is a direct transactivator of CEBPB, acting as an upstream effector in this regulatory mechanism. Furthermore, we found CREB to be overexpressed in 94 % of GC samples and significantly associated with C/EBPβ expression (P < 0.05). Finally, we demonstrated both in vitro and in vivo that CREB can mediate IL1B-induced GC cell proliferation. Our results support the hypothesis that the effect of chronic inflammation on gastric carcinogenesis, as seen in the context of genetically susceptible individuals infected with Helicobacter pylori, includes the modulation of signalling pathways that regulate survival mechanisms in epithelial cells. IL1B is able to increase the expression/activation status of CREB and its target gene C/EBPβ, which are mandatory for GC cell survival. Our results may help inform new strategies for the prevention and treatment of GC, including the control of chronic inflammation.

Interactions of early adversity with stress-related gene polymorphisms impact regional brain structure in females.

Early adverse life events (EALs) have been associated with regional thinning of the subgenual cingulate cortex (sgACC), a brain region implicated in the development of disorders of mood and affect, and often comorbid functional pain disorders, such as irritable bowel syndrome (IBS). Regional neuroinflammation related to chronic stress system activation has been suggested as a possible mechanism underlying these neuroplastic changes. However, the interaction of genetic and environmental factors in these changes is poorly understood. The current study aimed to evaluate the interactions of EALs and candidate gene polymorphisms in influencing thickness of the sgACC. 210 female subjects (137 healthy controls; 73 IBS) were genotyped for stress and inflammation-related gene polymorphisms. Genetic variation with EALs, and diagnosis on sgACC thickness was examined, while controlling for race, age, and total brain volume. Compared to HCs, IBS had significantly reduced sgACC thickness (p = 0.03). Regardless of disease group (IBS vs. HC), thinning of the left sgACC was associated with a significant gene-gene environment interaction between the IL-1β genotype, the NR3C1 haplotype, and a history of EALs (p = 0.05). Reduced sgACC thickness in women with the minor IL-1β allele, was associated with EAL total scores regardless of NR3C1 haplotype status (p = 0.02). In subjects homozygous for the major IL-1β allele, reduced sgACC with increasing levels of EALs was seen only with the less common NR3C1 haplotype (p = 0.02). These findings support an interaction between polymorphisms related to stress and inflammation and early adverse life events in modulating a key region of the emotion arousal circuit.