Association of NFKB1 and NFKBIA Polymorphisms in Relation to Susceptibility of Behçet's Disease

Behçet's disease (BD) is a chronic inflammatory autoimmune disease. Although raised levels of proinflammatory cytokines in BD have been reported, the pathogenesis is still unknown. The aim of this study was to investigate the association of NFKB1 and NFKBIA polymorphisms and their single and combined analysis effects on susceptibility of BD in Turkish population. We analysed the distribution of NFKB1 ‐94 ins/del ATTG (rs28362491) and NFKBIA 3′ UTR A→G (rs696) polymorphisms using PCR‐RFLP method in 89 patients with BD and 190 controls in this population. Statistical analysis of the results was performed by calculating OR, and 95% CI via χ² test and using Bonferroni correction. According to the significant results of both single and combined genotype analysis, the frequencies of ins/ins genotype and ins allele of rs28362491 were significantly higher in patients with BD (Pc = 0.003, 0.004, respectively). Also, higher frequencies of the rs696 variant containing AA genotype was found in patients with BD (Pc = 0.0033), whereas no statistical significant differences in distribution of the alleles of rs696 polymorphism in patients and controls. In addition, according to the combined genotype analysis, the wild type of both rs28362491 and rs696 polymorphisms (ins/ins/AA genotype) was also significantly higher in BD cases (Pc = 0.044). Our findings prove that both single and combined genotype analysis of rs28362491 and rs696 polymorphisms indicate that the wild genotypes of both two SNPs (ins/ins and AA genotypes) and ins/ins/AA combined genotype are strongly associated with enhanced risk of BD in a Turkish population.     

NFKB1 polymorphism is associated with age-related gene methylation in Helicobacter pylori-infected subjects

CpG island aberrant methylation is shown to be an important mechanism in gene silencing. The important role of NF-κB in the inflammatory response to H. pylori colonization has been indicated. We investigated the influence of NFKB1 polymorphisms, -94 ins/del (rs28362491) and -449 C>G (rs72696119), on the aberrant gene methylation under H. pylori infection. Gastric mucosal samples were obtained from sub-subjects without malignancies. Methylation status of genes (p14ARF, p16INK4a, DAPK and CDH1) was determined by methylation-specific PCR (MSP). The genotyping of NFKB1 was performed by PCR-SSCP. There was a strong allelic association between rs28362491 and rs72696119, and all H. pylori-infected -94 del/del homozygotes had a -449 GG genotype. The -94 del/del homozygosity was significantly associated with risk for development of CpG island high methylation (CIHM) (two or more gene methylations), especially DAPK and CDH1 methylations, and the number of methylated genes was significantly higher in -94 del/del homozygotes than in ins/del and ins/ins (ins carrier) H. pylori-infected elder subjects. In addition, this methylated gene number was significantly increased with age in H. pylori-infected del/del homozygotes, but not in infected ins carriers. Furthermore, the inflammation score was significantly higher in H. pylori-infected del/del homozygotes compared to ins carriers. NFKB1 -94 ins/del ATTG polymorphism (rs28362491) was significantly associated with the increased risk for the development of age-related gene methylation in non-cancerous gastric mucosa under H. pylori-induced inflammation.     

The genetic polymorphism and expression profiles of NLRP3 inflammasome in patients with chronic myeloid leukemia

NLRP3 inflammasome has been recently reported as an important risk factor in the development of cancer. But the relationship between polymorphisms of NLRP3 inflammasome related genes and chronic myeloid leukemia (CML) is rarely reported. Therefore, the aim of the present study was to investigate the association of five genetic polymorphisms (NLRP3, IL-1β, IL-18, CARD8 and NF-κB) in 267 CML patients and 344 healthy controls. We found that the AT genotype of CARD8 (rs2043211) was significantly higher compared to TT genotype in high and intermediate risk CML patients. IL-1β (rs16944) polymorphism in early molecular response at 6?months was marginally different, with more GG and less AA genotype in BCR-ABL^IS >1% group. IL-18 (rs1946518) polymorphism was significantly different with more GG genotype in BCR-ABL^IS >1% group at 6?months. We also demonstrated that WBC count of newly diagnosed patients carrying AG genotype was significantly higher than that of GG or AA genotype of IL-1β (rs16944). The onset age of patients carrying ins/ins genotype of NF-κB (rs28362491) was significantly older than that of ins/del and del/del genotype. Moreover, IL-1β or NLRP3 mRNA expression was decreased and IL-18 mRNA expression was increased significantly in CML patients compared with controls. In conclusion, the genetic polymorphisms of NLRP3 inflammasome may be served as potential predictors for CML.     

IL1β, IL18, NFKB1 and IFNG gene interactions are associated with severity of rheumatoid arthritis: A pilot study

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease which can lead to progressive and functional disability. Literature data suggest that some inflammatory proteins are dysregulated in RA patients and its genetic polymorphisms may contribute to the aetiology and pathogenesis of disease in different ethnic groups. Polymorphisms in IL1β, IL18, NFKB1 and IFNG genes were studied in different populations with RA, but the analysis indicated contradictory results. Thereby, we hypothesised that polymorphisms in these genes could have a combined effect on susceptibility to and severity of disease. We evaluated the +3953?C/T IL1β (rs1143634), –137?G/C IL18 (rs187238), –94 ins/del ATTG NFKB1 (rs28362491) and +874?T/A IFNG (rs2430561) polymorphisms in the northeastern Brazilian population. Peripheral blood samples were collected and DNA extraction was conducted. The polymorphisms were evaluated by RFLP and ARMS–PCR. An association was observed in rs1143634 which showed a protective effect against development of RA in carriers of the T allele (OR?=?0.58; 95% CI 0.36–0.92; p?=?.020). In addition, we found an association among genotypes of the rs1143634 with the HAQ index (p?=?.021) and rs2430561 with DAS28 (p?=?.029) and CDAI (p?=?.029). In relation to combined effects of these SNPs (C/C to rs1143634, G/G to rs187238, I/I to rs28362491 and AA to rs2430561) we found a significant association with decreased functional disability (HAQ index p?<?.001) and ESR (p?=?.034), indicating a lower disease activity in carriers of these genotypes. GLM analysis confirmed these associations (HAQ (F?=?5.497; p?<?.001) and ESR (F?=?2.727; p?=?.032)). Our analysis indicated that in the studied population +3953?C/T IL-1β (rs1143634), –137?G/C IL-18 (rs187238), –94 ins/del ATTG NFKB1 (rs28362491) and +874?T/A IFNG (rs2430561) polymorphisms can together contribute to RA severity although they do not individually influence the disease.     

Association analysis of polymorphisms in OAS1 with susceptibility and severity of hand,foot and mouth disease

Hand, foot and mouth disease (HFMD) is a common childhood illness that mainly affects Asian children under the age of 5 years. Human enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the most common pathogens of HFMD. It is imperative that the susceptible population is screened early and that the severe illness population can be identified via genetic variation detection in children. Four single‐nucleotide polymorphisms (SNP) [2′‐5′‐oligoadenylate synthetase1 (OAS1) rs10774671, selectin P ligand (SELPLG) rs2228315, scavenger receptor class B member 2 (SCARB2) rs41284767 and interleukin 28B (IL28B) rs12979860] were determined by Taqman assays in 333 HFMD samples and 163 control samples. The rs2228315, rs41284767 and rs12979860 polymorphisms did not differ significantly between HFMD patients and the controls, but the prevalence of the rs10774671 polymorphism was significantly different between the control children and children infected with CA16 (GG genotype vs. AA + AG genotype, P < 0.05). Children with the GG genotype were more susceptible to CA16‐type HFMD. Furthermore, the rs10774671 genotype distribution was clearly different between children with severe HFMD and those with mild HFMD [P < 0.05, OR 0.240, 95% CI (0.071–0.809)]. HFMD children with the AA+AG genotype were more likely to progress to encephalitis than were those with the GG genotype. Plasma γ‐interferon (IFN) expression levels among control children and the mild and severe HFMD children were detected by ELISA. Those with mild HFMD had higher γ‐IFN expression levels compared with those with severe HFMD (P < 0.05). In addition, there is a significant correlation between γ‐IFN levels and OAS1 rs10774671 SNP, as analysed by linear correlation assay. The GG genotype correlated with higher γ‐IFN levels (P < 0.05). In short, the OAS1 rs10774671 SNP GG genotype contributed to CA16 susceptibility and was associated with the development of mild HFMD.     

Human leukocyte antigen‐G polymorphisms influence the clinical outcome in diffuse large B‐cell lymphoma

The role of HLA‐G is extensively studied in cancer due to its inhibition of the immune response. Several polymorphisms in the HLA‐G gene have been reported to significantly affect its expression. We, therefore, investigated whether functionally relevant HLA‐G polymorphisms, HLA‐G‐725C/G/T, and HLA‐G 14‐base pair, have any influence on the susceptibility to diffuse large B‐cell lymphoma (DLBCL) and its clinical course. The polymorphisms were genotyped in 207 previously untreated patients with DLBCL and 150 unrelated controls. A significant difference in genotype distribution of HLA‐G polymorphic genotypes between the patients and controls was found. The frequencies of the HLA‐G?725GG or the HLA‐G?725GC genotype were lower, and those of the HLA‐G ins/ins genotype were higher in the patients compared with the controls. Patients carrying the HLA‐G‐725CC genotype presented a higher probability of overall survival (OS) than subjects with other genotype combinations of HLA‐G‐725C/G/T (P = 0.003). The homozygous HLA‐G del/del had a lower probability of OS than subjects carrying the HLA‐G deletion/insertion (del/ins) or the HLA‐G ins/ins genotype (P = 0.009). Two HLA‐G genotype‐based risk groups were defined according to the genotype distribution. The high‐risk (HR) group presented a shorter OS than low‐risk (LR) patients (P = 0.001). In a multivariate analysis adjusted for International Prognostic Index (IPI) factors, both the intermediate high/high IPI‐risk group (P < 0.0001) and the HR genotype group (P = 0.004) independently increased the risk of death. This is the first study indicating an important role of HLA‐G polymorphisms for the clinical course of DLBCL. The potential influence of HLA‐G polymorphisms on the susceptibility to DLBCL thus deserves further study. © 2015 Wiley Periodicals, Inc.     

Association of TIM‐1 5383‐5397ins/del and TIM‐3 ‐1541C>T polymorphisms with multiple sclerosis in Isfahan population

Multiple sclerosis (MS) is an organ‐specific autoimmune disease in central nervous system, affecting about 2.5 million people around the world. Probable involvement of two newly identified immunoregulator molecules, TIM‐1 and TIM‐3, has been reported in autoimmune diseases. In this study, for the first time, the association of TIM‐1 5383‐5397ins/del and TIM‐3 ‐1541C>T polymorphisms with MS in an Iranian population was considered. The results of our study showed that there is no significant association between TIM‐1 5383‐5397ins/del and MS (P = 0.38); however, the frequency of CT genotype of TIM‐3 ‐1541C>T in patient group was significantly higher than the control group, and there was a significant association between CT genotype and MS (P = 0.009, OR = 4.08).     

IL‐12B Gene Polymorphisms and IL‐12 p70 Serum Levels Among Patients with Rheumatoid Arthritis

Rheumatoid arthritis (RA) is one of the autoimmune diseases, where different polymorphisms in cytokine genes play a pathogenic role. IL‐12 is now recognized as a critical cytokine in terms of regulating the balance between Th1 and Th2 cells. We investigated the role of single nucleotide polymorphisms (SNPs) (rs3212227 (A/C) and rs17860508 (CTCTAA/GC)) of the IL‐12B gene in the genetic susceptibility to RA and in the severity of the disease. Six hundred and thirty‐four Caucasian RA patients and 341 healthy matched controls were studied using PCR‐RFLP method and high‐resolution melting analysis. Concentration of IL‐12 cytokine level in serum was evaluated using ELISA. The genotype frequency did not deviate from HWE in each examined group. Frequencies of the rs3212227 CC genotype were statistically higher in patients with RA compared with the healthy control group in both codominant and recessive models (P = 0.037; P = 0.04, respectively). The frequency of rs3212227 C allele also showed similar tendency (P = 0.07). IL‐12 level in serum was significantly higher in RA group compared with control (P < 0.0001). We observed that increased IL‐12 serum level was correlated with higher number of tender and swollen joints, ExRA presence and higher levels of haemoglobin, CRP and PLT. Also higher IL‐12 level in serum was observed within RA patients with hypertension. Present findings indicated that IL‐12p40 + 1188A/C polymorphism as well as IL‐12p70 protein levels may be associated with RA in the Polish population.     

Levels of Interleukin‐(IL)‐12p40 are Markedly Increased in Brucellosis Among Patients with Specific IL‐12B Genotypes

Brucellosis remains a major zoonosis worldwide. Brucella antigens induce the production of T‐helper 1 (Th1) cytokines such as interleukin‐12 (IL‐12) in humans. We aimed to investigate the association of two single nucleotide polymorphisms (SNPs) in the gene encoding the IL‐12p40 cytokine (IL‐12B) with brucellosis and to examine the functionality of these SNPs through measuring serum levels of IL‐12p40. We genotyped IL‐12B gene rs3212227, A>C; rs6887695 G>C polymorphisms in a case‐control study on a total of 281 subjects including 153 patients with active brucellosis and 128 healthy controls, using RFLP and serum IL‐12p40 levels, were assessed by ELISA. The rs3212227 minor allele (C) and homozygote genotype (CC) were more frequent in controls compared with patients with brucellosis (P = 0.006, OR = 0.608, 95%CI = 0.429–0.861 for the C allele; P = 0.024, OR = 0.443, 95% CI: 0.218–0.900 for the CC genotype). Comparison of IL‐12B genotypes and serum levels of the IL‐12p40 revealed that rs3212227 AA genotype, with higher frequency in patients than in controls, was associated with increased levels of the cytokine (P = 0.0001). Furthermore, the distribution of haplotype and genotype combinations in our study suggested that rs3212227C/rs6887695C haplotype or CC/GC or CC/CC genotype combinations may protect controls against Brucella infection by contributing to a functional downregulation of the serum IL‐12p40 production in vivo, as shown by ELISA (P < 0.05). Overall, our study demonstrated that rs3212227 A variant was associated with higher levels of serum IL‐12p40 and could possibly contribute to an inherited predisposition to brucellosis.     

Association between interleukin‐21 gene polymorphisms (rs12508721) and HBV‐related hepatocellular carcinoma

Interleukin‐21 (IL‐21), as a multifunctional cytokine, plays an important role in many diseases, such as cancer, inflammatory and autoimmune diseases. We aimed to investigate the relationship between polymorphisms of IL‐21 gene and susceptibility of hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) in a Chinese population. Studied subjects were divided into three groups: 100 patients with HBV‐related HCC, 115 patients with chronic HBV infection and 127 healthy controls. Genomic DNA was isolated from peripheral blood, and the polymerase chain reaction–ligase detection reaction (PCR‐LDR) method was used to genotype the SNPs (rs2221903, rs907715 and rs12508721) within IL‐21 gene. Our results showed that IL‐21 polymorphisms were associated with the risk of HCC and chronic HBV infection when compared with healthy controls. The rs2221903A/G AG genotype was associated with a higher risk of chronic HBV infection when compared with healthy controls [AG versus AA + GG, P = 0.036, OR = 1.898, 95%CI = 1.038–3.471]. The rs12508721C/T TT genotype was related with a lower risk of chronic HBV infection and HBV‐related HCC than in healthy controls [TT versus CT + CC, P = 0.026, OR = 0.451, 95%CI = 0.221–0.920; P = 0.049, OR = 0.482, 95%CI = 0.231–1.005]. No significant difference in the genotype and allele distrubutions of rs907715G/A SNP was observed in the HBV‐related HCC group, chronic HBV‐infected group and the healthy control group when compared to each other. Our findings suggest that the rs12508721T/C and rs2221903A/G polymorphisms of IL‐21 gene are associated with the susceptibility of HBV‐related HCC and chronic HBV infection. The genetic variant may in fact cause protection against the HBV‐related HCC. However, the function in these SNPs of IL‐21 gene needs to clarify the mechanisms involved in the pathogenesis of HBV‐related HCC further.     

Donor derived HLA-G polymorphisms have a significant impact on acute rejection in kidney transplantation

Human leucocyte antigen G (HLA-G) is a non-classical HLA-class I antigen that exerts immunoregulatory functions. The polymorphisms 14-base pair (bp) insertion/deletion (ins/del) (rs1704) and +3142C > G (rs1063320) could modify the expression level of HLA-G.We genotyped 175 kidney recipients (41 with acute rejection and 134 without rejection) and additionally the corresponding donors for both polymorphisms in order to assess their impact on acute rejections one year after transplantation. In addition, we analyzed soluble HLA-G (sHLA-G) levels in sera of 32 living kidney donors and compared the sHLA-G levels in terms of the present genotype.In kidney transplant recipients we did not observe an impact of the 14-bp ins/ins and the +3142GG genotypes on acute rejection. In contrast, we found a higher frequency of these genotypes in the donors of the no-rejection collective compared to the rejection collective (4.9% vs. 24.6%; p = 0.010; 9.8% vs. 31.3%; p = 0.006). Soluble HLA-G levels were highest in healthy kidney donors homozygous for the 14-bp insertion.We conclude that the HLA-G polymorphisms of the donor are of importance for susceptibility of acute rejection in kidney transplantation. We suggest that the 14-bp ins/ins and the +3142GG genotypes are protective against kidney transplant rejection.     

Association of Nod‐like receptor protein‐1 (rs2670660) and Toll‐like receptor‐4 (rs4986790) with non‐segmental vitiligo: A case–control study in South Indian population

Non‐segmental vitiligo (NSV) is an autoimmune skin disease. Genetics plays a predominant part in disease pathogenesis. Nucleotide‐binding and oligomerization domain (NOD)‐like receptors and pyrin‐containing protein (NLRP) and Toll‐like receptors (TLR) are pattern recognition receptors in mediating innate immunity. They participate in presenting pathogens and mediating the immune responses. NLRP and TLRs are involved in mediating immune response in various dermatological diseases. Understanding the influence of genetic polymorphisms of NLRP and TLRs associated with immune homeostasis might help us to understand the complex etiopathogenesis of NSV. Thus, we aimed to study the association of NLRP‐1 (rs2670660) and TLR‐4 (rs4986790) and the synergistic effects on disease spectrum, disease activity of NSV in South Indian population. This research was designed as a case–control genetic study with 264 patients and 264 controls. Genotyping of NLRP‐1 (rs2670660) and TLR‐4 (rs4986790) was performed by Taqman 5’ allele discrimination assay and ARMS‐PCR. Plasma levels of proteins were measured by enzyme‐linked immunosorbent assay (ELISA). A statistically significant difference was observed with the frequency of homozygous GG genotype of NLRP‐1 (rs2670660) (17.8% in cases vs. 5.3% in controls) (p < 0.0001; OR‐3.73; 95% CI‐1.94–7.14). Allele G was significantly frequent in 38% of the cases than in controls with 30% (p = 0.004; OR‐1.46; 95% CI‐1.13–1.89). Plasma NLRP‐1 level was significantly higher in patients compared to controls (p < 0.05). Amongst cases, the plasma NLRP‐1 levels did not show any difference with respect to their genotypes (p > 0.05). In TLR‐4 (rs4986790), no significant difference in the frequency of genotypes and allele between cases and controls (p = 0.80) was observed; nevertheless, plasma TLR‐4 was analogous between cases and controls (p > 0.05). Influence of genotype on plasma TLR‐4 showed no significant difference in TLR‐4 levels between GG and ancestral genotype AA, whilst heterozygous AG genotype showed a significant increase of TLR‐4 compared to AA and GG (p = 0.02) amongst NSV cases. The obtained results suggest that NLRP‐1 (rs2670660), and not TLR‐4 ((rs4986790), is associated with increased risk of NSV in South Indian population.     

Association between TLR2 polymorphisms (− 196–174 Ins/Del,R677W,R753Q,and P631H) and schizophrenia in a Tunisian population

Since immune dysregulation has been well studied in schizophrenia pathophysiology, recent studies showed a potent role of TLR2 in neuroinflammation process underlying schizophrenia pathogenesis. However, the genetic predisposition is still unclear. Thus, we hypothesized that TLR2 polymorphisms − 196–174 Ins/Del (rs111200466), R753Q (rs5743708), R677W (rs121917864), and P631H (rs5743704) could be involved in schizophrenia predisposition. A case–control study was performed on a Tunisian population composed of 250 healthy controls and 250 patients genotyped by PCR–RFLP. Genotype and allele distribution were evaluated with sex, schizophrenia subtypes, and other clinical features. We also assessed a haplotype analysis for TLR2 polymorphisms with schizophrenia. Our results showed higher ins/del genotype frequency in healthy women compared to patients (p = 0.006; OR = 0.2). In the other hand, logistic regression showed higher ins/del genotype frequency in controls compared to paranoid patients (p = 0.05; OR = 0.48, adjusted). Frequencies of CT and T allele of R677W were significantly higher in patients compared to controls (p < 10⁻⁴, OR = 10.39; p < 10⁻⁴, OR = 4, adjusted, respectively). R753Q polymorphism was exclusively detected in patients (GA + AA = 2.5%) particularly in men with disorganized subtype. P631H did not show any association with schizophrenia. Finally, haplotype analysis showed that InsGTC and delGTC were associated with higher risk of schizophrenia (p = 0.0001, OR = 8.58; p = 0.04, OR = 5.01, respectively). In the Tunisian population, our results suggested that TLR2 R677W could be associated with susceptibility for schizophrenia, while − 196–174 Ins/Del suggested a trend of protection in women. Otherwise, R753Q could have an effect on schizophrenia especially for disorganized subgroup.

     

Human leukocyte antigen (HLA)-G during pregnancy part II: Associations between maternal and fetal HLA-G genotypes and soluble HLA-G

Human leukocyte antigen (HLA)-G is a class Ib molecule with restricted tissue distribution expressed on the extra-villous trophoblast and seems to have immunomodulatory functions during pregnancy. Studies have linked HLA-G polymorphisms to pregnancy complications such as preeclampsia and recurrent miscarriage. Levels of soluble HLA-G (sHLA-G) in blood plasma from non-pregnant donors seem to be associated with these polymorphisms. In the current study, we have genotyped 246 mothers and their offspring for HLA-G polymorphisms in the 3′-untranslated region (3′UTR) and measured sHLA-G in maternal blood plasma samples from gestational week 20 and at term, as well as in fetal umbilical cord blood samples. This is the first large study simultaneously performing HLA-G genotyping of mother and offspring and measuring sHLA-G in both maternal and umbilical cord blood. The results showed that increasing numbers of 14 bp ins (rs66554220) alleles in the mother–child genotype combinations were associated with higher maternal sHLA-G levels at term when restricting the analysis to 14 bp ins/del heterozygous mothers (p = 0.015). Furthermore, increasing numbers of 14InsG haplotypes (14 bp ins/del and +3142C/G (rs1063320) polymorphism) in mother–child genotype combinations were associated with higher levels of sHLA-G at term in heterozygous 14DelC/14InsG mothers (p = 0.005). In conclusion, the results indicate that there is an association between combined feto-maternal HLA-G genotypes and sHLA-G levels in maternal blood plasma.     

14-bp ins/del polymorphism and +3142C>G SNP of the HLA-G gene have a significant impact on acute rejection after liver transplantation

Expression of human leukocyte antigen G (HLA-G) has been associated with increased graft survival and decreased rejection episodes. It has been described that the HLA-G 14-base pair (bp) insertion/deletion (ins/del) (rs66554220) and +3142C>G (rs1063320) gene polymorphisms modify the expression level of HLA-G. The aim of the study was to investigate whether these HLA-G polymorphisms have an impact on acute rejection after liver transplantation. In total, 146 liver transplant recipients (57 with acute rejection and 89 without acute rejection) and 99 corresponding liver donors were genotyped for both polymorphisms. In liver transplantation the 14-bp ins/ins and the +3142GG genotypes are more frequent in recipients without rejection compared to recipients with rejection (3.5% vs. 31.5%, p = <0.001; 12.3% vs. 41.6%, p = <0.001) demonstrating an association with protection from acute rejection. In contrast, in liver donors we could not reveal an association. We conclude that 14-bp ins/ins and +3142GG genotypes of HLA-G in liver transplant recipients are of importance for prediction of acute rejection after liver transplantation. Thus genotyping of liver recipients for both polymorphisms might be useful to stratify liver transplant recipients according to the risk of acute liver transplant rejection.     

Variations in genes involved in regulation of the nuclear factor – κB pathway and the risk of acute myeloid leukaemia

Genes involved in regulation of the nuclear factor – kappa B (NF‐κB) pathway are suggested to play a role in the pathogenesis of acute myeloid leukaemia (AML). The present study aimed to assess the association between the NF‐κB1, TRAF3 and TLRs genes single nucleotide polymorphisms (SNPs) and disease susceptibility as well as progression in patients with AML. For this purpose 62 patients and 126 healthy individuals were genotyped for NF‐κB1 (rs28362491), TRAF3 (rs11160707; rs12147254), TLR2 (rs201786064), TLR4 (rs4986790; rs4986791) and TLR9 (rs5743836; rs187084) alleles. Three SNPs were found to be associated with the risk for the AML development. The TRAF3 (rs12147254) AA homozygosity (RR = 2.770, P = 0.0392), TLR9 (rs5743836) C wild‐type allele (RR = 2.542, P = 0.0096) as well as TLR9 (rs187084) T allele (RR = 13.396, P < 0.0001) and its homozygosity (RR = 11.805, P < 0.0001) were more frequent among patients with AML than healthy individuals. The associations of the rs187084 SNP were significant for both sexes. Moreover, patients who relapsed were more frequently characterized with the presence of the rs187084 TLR9 TT genotype (P = 0.045) or the rs12147254 TRAF3 A variant (P = 0.066). In conclusion, polymorphisms within the TLR9 and TRAF3 genes are associated with predisposition to AML and may affect the progression of the disease in the Polish population.     

C‐reactive protein levels and common polymorphisms of the interleukin‐1 gene cluster and interleukin‐6 gene in patients with coronary heart disease

C‐reactive protein (CRP) is an inflammatory marker associated with increased cardiovascular risk. Production of CRP is regulated by interleukin (IL)‐1β, IL‐1 receptor antagonist and IL‐6. In 160 patients with coronary heart disease (CHD) confirmed by angiography, we examined the relationship between CRP level and five polymorphisms in genes coding for these cytokines: IL‐1B(?511), IL‐1B(+3954), a variable number tandem repeat (VNTR) polymorphism in intron 2 of IL‐1RN [IL‐1RN(VNTR)], IL‐6(?174) and IL‐6(?572). CRP values were logarithmically normalized (log‐CRP) for statistical calculations. In univariate analysis, carrier status for the IL‐1B(+3954)T allele and IL‐1RN(VNTR) allele 2 [IL‐1RN(VNTR)*2] correlated with higher (P < 0.01) and lower (P < 0.05) log‐CRP values, respectively. Among the potential confounding factors analysed, smoking, body mass index, total cholesterol (P < 0.05 for all) and diabetes (P = 0.056) were positively correlated with CRP level. After adjustment for non‐genetic covariates, CRP levels remained significantly (P < 0.01) higher in carriers of IL‐1B(+3954)T than in non‐carriers: mean log‐CRP (with 95% confidence interval) was 0.443 (0.311–0.574) for CT or TT genotypes compared with 0.240 (0.107–0.373) for the CC genotype, which corresponded to back‐transformed CRP levels of 2.77 and 1.74 mg l^?1, respectively. Adjusted association was also significant for IL‐1RN(VNTR)*2 (P < 0.01), with lower CRP levels in the presence of allele 2: the mean log‐CRP value was 0.252 (0.115–0.388) for carriers and 0.421 (0.290–0.552) for non‐carriers (CRP 1.79 and 2.64 mg l^?1, respectively). When alleles of both polymorphisms were entered into the model simultaneously, the association remained significant for IL‐1B(+3954)T (P < 0.05), but not for IL‐1RN(VNTR)*2. We conclude that IL‐1B(+3954)T is associated with higher CRP levels in patients with CHD, and we found that this association was significant after adjustment for major risk factors. Our data also suggest a possible relationship of IL‐1RN(VNTR)*2 with lower CRP levels in the same patients.     

Single‐nucleotide polymorphisms of IRF8 gene are associated with systemic lupus erythematosus in Chinese Han population

Interferon regulatory factor 8 (IRF8) has been shown to have diverse roles in the regulation of the immune system. Two recent studies had revealed the association between the single‐nucleotide polymorphisms (SNPs; rs11644034 and rs2280381) of IRF8 and systemic lupus erythematosus (SLE) in a multiethnic population. The purpose of this study was to evaluate whether the association could be replicated in a Chinese Han population. Genotypes were determined by a multiplex polymerase chain reaction–ligase detection reaction (PCR–LDR) in 358 patients and 357 geographically matched healthy controls. Significant differences in genotype frequency were found between SLE and control individuals (rs11644034: AA vs. GG, P = 0.014, odds ratio (OR) = 0.980, 95% confidence internal (CI): 0.964–0.996; rs2280381: CC vs. TT, P = 0.005, OR = 0.150, 95% CI: 0.033–0.676). Conditional logistic regression analysis showed that the association of rs2280381 remained significant (P adjusted = 0.028) after adjustment for rs11644034, but not vice versa (P adjusted = 0.361).When stratifying patients with SLE according to clinical subtypes, SNP rs2280381 was found to be associated with low complement in patients with SLE. However, SNP rs11644034 was not found to be associated with SLE clinical subgroups. Analysis of the haplotypes revealed that haplotype G‐T and G‐C were also significantly associated with SLE (P = 0.002 and P = 0.012, respectively). Our study indicated that the IRF8 gene polymorphisms might be associated with susceptibility to SLE and with disease‐related clinical manifestations in Chinese Han population.