Association of hepatocellular carcinoma risk with polymorphisms in tumour necrosis factor alpha gene in a Chinese Han population

Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related death worldwide. Studies have shown that the tumour necrosis factor alpha (TNF‐α) plays an important role in the development of HCC; however, the association between genetic variations of TNF‐α and HCC is not yet fully understood. To evaluate the correlation of TNF‐α polymorphisms with HCC, we randomly selected 327 HCC patients and 432 healthy controls, all these subjects reported Han nationality. Genotyping of four TNF‐α SNPs (rs1799724, rs1800629, rs1799964 and rs1800610) was performed using the matrix‐assisted laser desorption ionization‐time of flight mass spectrometry (MALDI‐TOF‐MS) method. Distributions of rs1799964 genotypes and rs1800610 alleles were found to be significantly different between cases and controls (p = .011, p = .001). The recessive model of rs1799964 significantly increased HCC risk (p = .0015), while the dominant and over‐dominant models of rs1800610 significantly reduced HCC risk (p = .0096, p = .014). Haplotype analysis of the four TNF‐α SNPs revealed that the TGTA haplotype was associated with a reduced HCC risk (p = .0033, OR = 0.53), while the TGTG haplotype was associated with an increased HCC risk (p = .0032, OR = 9.69). These findings indicated that specific TNF‐α polymorphisms may be associated with the susceptibility to HCC.     

Association of PTPN22 rs2476601 and EGFR rs17337023 Gene polymorphisms and rheumatoid arthritis in Zahedan,Southeast Iran

In this study we aimed to evaluate the possible association of PTPN22 rs2476601 as well as epidermal growth factor receptor (EGFR) rs17337023 gene polymorphism and rheumatoid arthritis (RA) in a sample of Iranian population. This case‐control study was performed on 120 patients with RA and 120 healthy subjects. Genomic DNA was extracted from whole blood and PTPN22 rs2476601 and EGFR rs17337023 polymorphisms were determined using tetra amplification refractory mutation system–polymerase chain reaction (T‐ARMS‐PCR). The results showed that PTPN22 rs2476601 CT genotype as well as rs2476601 T allele was a risk factor for susceptibility to RA (OR=5.89 95%CI = 1.78–19.48, P = 0.004 and OR = 4.78, 95%CI = 1.59–14.35, P = 0.003, respectively). We also found that EGFR rs17337023 AT and rs17337023 TT genotypes were risk factor for susceptibility to RA (OR = 9.94 95%CI = 3.65–26.73, P < 0.001 and OR = 3.66, 95%CI = 1.46–9.15, P = 0.005, respectively). In addition the EGFR rs17337023 T allele was a risk for predisposition to RA (OR = 1.56, 95%CI=1.06‐2.30, P = 0.030). In conclusion, we found an association between PTPN22 rs2476601 and EGFR rs17337023 polymorphisms and the risk of RA in a sample of Iranian population.     

Methylenetetrahydrofolate Reductase C667T Polymorphism is Associated with Increased Risk of Coronary Artery Disease in a Chinese Population

Coronary artery disease (CAD) is a complex disease resulting from a combination of environmental and genetic factors. We hypothesized that polymorphisms in methylenetetrahydrofolate reductase (MTHFR) rs1801133 C/T, matrix metalloproteinases (MMPs)‐2, tumour necrosis factor (TNF)‐α, macrophage migration inhibitory factor (MIF) rs755622 G/C and cyclin D1 (CCND1) rs678653 G/C contribute to CAD susceptibility. We examined the association between the five polymorphisms and the risk of CAD in a Chinese population of 435 CAD patients and 480 controls. Genotyping was performed using matrix‐assisted laser desorption ionization/time‐of‐flight mass spectrometry (MALDI/TOF MS). When the MTHFR rs1801133 CC homozygote genotype was used as the reference group, the TT or CT/TT genotypes were associated with a significantly increased risk for CAD. The CT heterozygote genotype was not associated with the risk for CAD. Logistic regression analyses revealed that MMP‐2 rs243865 C/T, TNF‐α rs1800629 A/G, MIF rs755622 G/C and CCND1 rs678653 G/C polymorphisms were not associated with the risk of CAD. These findings suggest that the MTHFR rs1801133 C/T polymorphism is associated with CAD development. Future larger studies with other ethnic populations are required to confirm current findings.     

Associations of the IL‐1F7 gene polymorphisms with rheumatoid arthritis in Chinese Han population

Our aim was to investigate whether genetic polymorphism of IL‐1F7 (rs3811047) was involved in the susceptibility to rheumatoid arthritis (RA) in Chinese Han population. Single nucleotide polymorphism (SNP) of IL‐1F7 gene (rs3811047) was analyzed in 184 unrelated Chinese Han patients with RA and 184 healthy controls by ligase detection reaction based on high temperature ligase detection reactions polymerase chain reaction (LDR‐PCR). There were no statistically significant differences in the genetic polymorphism (genotypes and allele frequencies) of IL‐1F7 (rs3811047) in the patients with RA compared with control. Although all of the clinical and laboratory measures were similar to each other among patients with different genotypes, RA patients carrying AA or AG genotypes had lower swollen joint count, swollen joint index, rest pain and health assessment questionnaire (HAQ) score than that in patients having GG genotype (P < 0.05). These findings show that no evidence for the involvement of a pro‐inflammatory polymorphism in the IL‐1F7 in the susceptibility to RA in China. Patients carrying A allele had less severe disease activity than those not carrying this allele, suggesting that the A allele of IL‐1F7 gene (rs3811047) may have a protective effect on RA.     

Association of the tumor necrosis factor ‐308 A/G promoter polymorphism with Tourette syndrome

Several lines of evidence suggest that certain subtypes of obsessive‐compulsive and tic disorders might be paediatric manifestations of post‐streptococcal autoimmunity caused by cross‐reactive autoantibodies. As tumor necrosis factor (TNF) is known to play a seminal role in coordinating the humoral immune response, TNF gene polymorphisms have been proposed as genetic risk factors both in obsessive‐compulsive disorder (OCD) and Tourette syndrome (TS). The aim of this study was to investigate two TNF promoter polymorphisms (‐238 A/G: rs361525 and ‐308 A/G: rs1800629) on the genetic susceptibility to OCD and TS in a child psychiatric sample (102 patients with OCD and 117 patients with TS). In the case–control set‐up, the genotype and allele frequencies were compared to a control group from the general population (n = 405). As a control child psychiatric sample, 194 children with attention‐deficit hyperactivity disorder were also genotyped. Our results revealed that the TNF ‐308 G‐allele was more frequent in children with TS compared to controls (90.2% vs 84.8%, P = 0.037). For confirmation of this genetic association, a family‐based analysis, the transmission disequilibrium test was used, which showed preferential transmission of the G‐allele to patients with TS (nominal P‐value 0.011). Moreover, this allele was also transmitted more frequently to children with tic symptoms (nominal P‐value 0.039). No association was found between OCD or obsessive‐compulsive symptoms and the studied TNF polymorphisms. Based on these findings, the TNF ‐308 G‐allele can be associated with Tourette syndrome, highlighting the potential pathophysiological role of TNF dysregulation.     

Influence of TNFα and LTα single nucleotide polymorphisms on susceptibility to and prognosis in cutaneous malignant melanoma in the British population

Cutaneous malignant melanoma (CMM) is a potentially fatal malignancy in which exposure to UV light is the most important risk factor. Several lines of evidence suggest that increased expression of tumour necrosis factor (TNF) α, upregulated by UV exposure, may contribute to tumour escape from the immune response. In this study, we addressed whether single nucleotide polymorphisms (SNPs) in the TNFα promoter and lymphotoxin (LT) α gene are associated with susceptibility to or known prognostic indicators (e.g. initial tumour growth phase, Breslow thickness, mitotic count in vertical growth phase tumours, and tumour regression) in CMM. One hundred and forty‐six British Caucasian CMM patients and 220 controls were typed for TNFα?376, ?308 and ?238 and LTα+252 SNPs by ARMS‐PCR. Only the TNFα?238 GG (P = 0.05) and GA (P = 0.03) genotypes showed slight, but significant, associations with CMM, while LTα+252 AA was associated with a higher mitotic count in vertical growth phase tumours (P = 0.02). Both TNFα?238 and LTα+252 SNPs showed linkage disequilibrium with HLA‐DQB1*0303 and *0301 alleles, variably implicated in CMM susceptibility/prognosis. In addition, TNFα?238, ?308, LTα+252 haplotypes were assigned and compared. The GGA haplotype showed a modest association with CMM (P = 0.04) and with stage of disease (P = 0.03) and initial growth phase in CMM (P = 0.02), but these associations were only significant when P‐values were uncorrected. Unlike basal cell carcinoma, these preliminary findings suggest that genetic variation associated with differential TNFα and LTα production is unlikely to play a major, independent role in susceptibility to, and perhaps prognosis in, CMM.     

Genetic polymorphisms of tumour necrosis factor alpha (TNF‐α) promoter gene and response to TNF‐α inhibitors in Spanish patients with inflammatory bowel disease

Tumour necrosis factor alpha (TNF‐α) has an important role in inflammatory response. Alterations in the regulation of TNF‐α have been implicated in a variety of inflammatory disorders, including Inflammatory bowel disease (IBD). Indeed, a common treatment for IBD is the use of TNF‐α inhibitors. Polymorphisms in the TNF‐α promoter region are known to affect the level of gene expression. Our aim was to investigate the influence of these single nucleotide polymorphisms (SNPs) in TNF‐α promoter gene play in the risk of IBD in a Spanish population and their individual response to anti‐TNF‐α treatment. DNA samples from patients with IBD and controls were screened for TNF‐α ?238G/A (rs361525) and ?308G/A (rs1800629) SNPs by PCR‐SSOP using a microbeads luminex assay and compared with response to TNF‐α inhibitors. There were not statistical differences in ?238G/A and ?308G/A allele and genotype frequencies between patients. However, we found an increased frequency of ?308A allele and ?308GA genotype in these nonresponders patients to TNF‐α inhibitors with respect to responders patients (Pc < 0.05). This ?308GA genotype has been classified as high producer of this cytokine. This fact could actually be interesting to explain the different response of patients with IBD with respect to TNF‐α inhibitors. TNF‐α promoter gene polymorphism does not seem to play a role in IBD susceptibility, but particular TNF‐α genotypes may be involved in the different responses to TNF‐α inhibitor treatment in Spanish patients with IBD.     

Tumour necrosis factor‐alpha (‐308G/A) promoter polymorphism is associated with ulcerative colitis in Brazilian patients

Inflammatory bowel disease consists of multifactorial diseases whose common manifestation is inflammation of the gastrointestinal tract and their pathogenesis remains unknown. This study aimed to analyse the gene polymorphisms in Brazilian patients with inflammatory bowel disease. A total of 101 patients diagnosed with inflammatory bowel disease were analysed for the tumour necrosis factor‐alpha (‐308 G/A; rs1800629) and interleukin‐10 (‐1082 G/A; rs1800896) gene polymorphisms. Genotyping was performed through polymerase chain reaction–sequence‐specific primer, then fractionated on 2% agarose gel and visualized after staining by ethidium bromide. The anatomic–clinical form of Crohn's disease (CD) predominant was the inflammatory (32.75%), followed by fistulizing (29.31%) and 27.58% stricturing. As control group, a total of 136 healthy subjects, from the same geographical region, were enrolled. The statistical analyses were performed using R program. The frequency of the A allele at tumour necrosis factor‐alpha was high in ulcerative colitis (UC) patients (51%) than in controls (22%; P > 0.01). No statistical difference was found with the genotypic and allelic frequencies of CD patients compared to controls (P = 0.54). The polymorphism ‐1082G/A of interleukin‐10 was not statistical different between the diseases compared to controls. Tumour necrosis factor‐alpha (TNF‐α) (‐308G/A) is associated with UC onset, suggesting that the presence of ‐308A allele could confer a relative risk of 3.62 more to develop UC in general population. Further studies, increasing the number of individuals, should be performed to ratify the role of TNF‐α in the inflammatory bowel disease pathogenesis.     

Pro‐ and anti‐inflammatory cytokine gene single‐nucleotide polymorphisms in inflammatory bowel disease

Anti‐inflammatory cytokines have an important role in disease, tumour and transplant processes. Alterations in the regulation of several cytokines have been implicated in a variety of inflammatory disorders, including IBD (inflammatory bowel disease) [Crohn′s disease (CD) and ulcerative colitis (UC)]. Cytokine polymorphisms are also known to affect the level of gene expression. Thus, the aim of this study was to determine the relationship between cytokine polymorphisms and the IBD pathologies in a Spanish population. Polymorphisms analysis was performed using PCR‐SSOP using a microbeads luminex assay. The following polymorphisms were determined: TNFα [?238G/A (rs361525) and ?308G/A (rs1800629)], IFNγ [+874A/T (rs62559044)], TGFβ [+869C/T (rs1982073) and +915G/C (rs1800471)], IL10 [?1082A/A (rs1800896), ?592A/C (rs1800872), ?819C/T (rs1800871)], IL6 [?174C/G (rs1800795)], IL12p40 [3′UTR ?1188A/C (rs3212227)], IL1α [?889C/T (rs1800587)], IL1β [?511C/T (rs1143634) and +3962C/T (rs1143633)], IL1R [Pst‐1 1970C/T] and IL1RA [Mspa‐1 11100C/T]. No statistical differences in TNFα, IFNγ, TGFβ, IL10, IL6, IL1α, IL1β, IL1R and IL1Ra genotypes and allele distributions between the IBD groups and healthy controls were found. However, we observed significant differences in the 3′UTR ?1188A/C polymorphism of IL12p40. So ?1188A allele was increased in patients with UC and the ?1188C allele (high IL12p40 production) was increased in patients with CD with respect to controls. These data are in concordance with the fact that CD has been shown to be associated with a Th1 T‐cell‐mediated inflammation model and high IL12/IFNγ production at histological affected sites. These data suggest that cytokine polymorphisms in TNFα, IFNγ, TGFβ, IL10, IL6 and IL1α, IL1β, IL1R and IL1Ra cytokine gene do not seem to be relevant in IBD susceptibility and IL12p40 3′UTR ?1188A/C polymorphism seems to be associated with a differential IBD development.     

Associative role of HLA‐DRB1 SNP genotypes as risk factors for susceptibility and severity of rheumatoid arthritis: A North‐east Indian population‐based study

Rheumatoid arthritis (RA) is a complex, multifactorial, systemic autoimmune disease. Reports are suggestive of the role of HLA especially HLA‐DRB1 alterations in RA pathogenesis. Existing data involving different geographical populations on the role of alterations in specific locus of HLA‐DRB1 in RA susceptibility and severity are equivocal, with no data available from ethnically distinct North‐east Indian population, where RA cases are alarmingly increasing. This study aimed to evaluate the association of HLA‐DRB1 gene SNPs (rs13192471, rs660895 and rs6457617) with susceptibility and severity of RA in an ethnically distinct North‐east Indian population. Whole blood was collected from clinically characterized RA cases (satisfying the American College of Rheumatology 1987 criteria) (n = 123) and community‐based age and sex‐matched healthy controls (n = 156) with informed consent. The HLA‐DRB1 SNP analysis was performed for all the RA and control cases using ARMS‐PCR using case and control genomic DNA as template. Statistical analysis was performed by SPSSv13.0 software. The HLA‐DRB1 rs660895 showed both wild (AA) and heterozygote (AG) genotype but the heterozygote allele was found to be associated with reduced risk of RA compared to controls [OR = 0.531, p = .024]. The difference in distribution of rs6457617 polymorphism between RA and control cases was comparable [OR = 0.525, p = .079]. Significantly higher distribution of variant rs13192471 genotype was observed in RA cases (69.92%) compared to controls (46.75%) (p < .001) and was associated with increased risk of susceptibility to RA [OR = 2.576, p < .001] compared to controls, as well as progression to severity in RA cases [OR = 2.404, p = .048]. Combinatorially also, the presence of rs13192471 variant genotype was associated with increased risk of RA susceptibility [OR = 8.267, p = .026] and RA severity [OR = 3.647, p = .280]. Alterations in HLA‐DRB1 are associated with RA susceptibility. HLA‐DRB1 rs13192471 SNP plays a critical role in RA susceptibility and severity in North‐east Indian cases and has prognostic significance in RA.     

Association of interleukin‐16 polymorphisms with disease progression and susceptibility in endometriosis

Interleukin‐16 (IL‐16) is a multifunctional pro‐inflammatory cytokine that was previously found in association with complex disorders, and it is now cleared that this cytokine plays a critical role in regulation of cellular functions such as homoeostasis. Due to the complexity of endometriosis and its resemblance to cancer, we designed present case–control study to determine the effects of genetic polymorphisms of the human IL‐16 gene on Iranian women's susceptibility to endometriosis. A total of 126 patients with endometriosis (stages I–IV) and 144 healthy women as control group were recruited to the study. We genotyped four single nucleotide polymorphisms of IL‐16 gene (rs11556218 T>G, rs4778889 T>C, rs4072111 C>T and rs1131445 C>T). Genotyping was performed using PCR and restriction fragment length polymorphism. Our results showed that genotype distribution in two exonic polymorphisms including rs11556218 and rs4072111 was significantly different between Endometriosis patients and healthy individuals (P < 0.05). We have also found an association between rs4072111 and rs1131445 with progression to the severe stages (III–IV) of endometriosis (P < 0.05). Finally, we may conclude that IL‐16 gene polymorphisms are highly associated with increased risk of endometriosis and could be considered as a susceptibility factor for endometriosis.     

Investigation of Cytotoxic T‐lymphocyte antigen 4 Polymorphisms in Gastric Cardia Adenocarcinoma

To assess the potential effects of Cytotoxic T‐lymphocyte antigen 4 (CTLA4) gene polymorphisms on susceptibility to gastric cardia adenocarcinoma (GCA), we genotyped four polymorphisms (rs733618 A>G, rs16840252 C>T, rs231775 G>A and rs3087243 G>A) in CTLA4 and calculated odds ratios (ORs) with the corresponding 95% confidence intervals (95% CIs) for the genotype and allele distributions between GCA cases and controls. The CTLA4 genotypes were determined by the polymerase chain reaction–ligase detection reaction (PCR‐LDR) analysis in 330 GCA patients and 608 unrelated cancer‐free controls. In this case–control study, there was no significant difference in the genotype and allele distributions of four CTLA4 polymorphisms between GCA patients and controls. However, haplotype association analysis indicated that compared with CTLA4 G_rs733618C_rs16840252G_rs231775C_rs3087243, CTLA4 G_rs733618C_rs16840252A_rs231775G_rs3087243 and A_rs733618C_rs16840252G_rs231775A_rs3087243 haplotypes conferred increased risks of GCA (OR = 6.46, 95% CI = 1.33–31.28; P = 0.012; both); however, CTLA4 A_rs733618C_rs16840252A_rs231775G_rs3087243 and A_rs733618T_rs16840252G_rs231775G_rs3087243 haplotypes conferred decreased risks of GCA (P = 0.001 and P = 0.011, respectively). These results highlight that the rare CTLA4 haplotypes may affect the development of GCA in the Chinese population.     

HLA‐DRB1 gene polymorphisms and its associations with rheumatoid arthritis in Chinese Han women of Shaanxi province,northwest of China

Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by symmetric polyarthritis. This study was designed to investigate the associations between HLA‐DRB1 gene polymorphisms and RA in the Chinese Han population of Shaanxi province, northwest of China. In total, we identified 31 high‐resolution HLA‐DRB1 alleles in 109 patients with RA. Compared with the controls, the AF of HLA‐DRB1*04:05 (P = 0.000, Pc = 0.007, OR = 3.462, 95%CI: 1.749–6.852) was significantly higher in patients with RA. In addition, the patients with RA had higher allele frequency (AF) of the HLA‐DRB1*04:03 (P = 0.030, Pc = NS, OR = 4.737, 95%CI: 1.012–22.180); DRB1*04:06 (P = 0.018, Pc = NS, OR = 5.288, 95%CI: 1.145–24.422) and the shared epitope (SE) alleles (P = 0.004, Pc = NS, OR = 2.166, 95%CI: 1.279–3.667), respectively. Moreover, positive possibilities of RF and anti‐CCP were significant higher in SE‐positive patients compared to SR‐negative patients (OR = 4.787, 95%CI: 1.101–20.824; OR = 3.775, 95%CI: 1.106–12.876, respectively). Our results indicated that HLA‐DRB1*04:05, *04:03, *04:06 and SE alleles might be susceptibility allele for RA in Chinese Han population of Shaanxi province, northwest of China.     

A promoter polymorphism (rs3806798) of interleukin‐15 gene is associated with chronic hepatitis B virus infection in the Chinese Han population

This study aimed to investigate the association between the polymorphisms of IL‐15 gene and susceptibility to chronic hepatitis B virus (HBV) infection in the Chinese Han population. A total of 234 patients with chronic HBV infection and 150 age‐ and sex‐matched healthy controls in the Chinese population were enrolled in this case–control study. Genotyping of ten single nucleotide polymorphisms (SNPs) in the IL‐15 gene was carried out via Sequenom MassARRAY system. The association analysis demonstrated that SNP rs3806798 (A/T) had a significant difference in the distribution between patients and healthy controls (P = 0.033). Moreover, a significantly increased risk of HBV infection was found to be associated with IL‐15 rs3806798 A allele among male patients and HBeAg‐negative patients, compared with IL‐15 rs3806798 T allele (P = 0.003; P = 0.046, respectively). Furthermore, haplotype analysis revealed that haplotype ATAGG (rs3806798, rs12508866, rs1519551, rs6819823 and rs2857261, respectively) in block 1 was significantly associated with HBV infection (P = 0.022). In conclusion, we found an association between IL‐15 rs3806798 and the risk of chronic HBV infection in a sample of Chinese Han population.     

Association of Interleukin‐1 beta and tumor necrosis factor‐alpha genetic polymorphisms with gastric cancer in India

Interleukin 1 beta (IL‐1β) and Tumor necrosis factor alpha (TNF‐α) are key inflammatory cytokines whose polymorphisms have been correlated with increased susceptibility to gastric cancer (GC). Since geographical and racial differences exist in cancer rates, our study was aimed to evaluate the first possible association of polymorphisms in these genes with GC risk in West Bengal, India. Polymorphisms in IL‐1β and TNF‐α genes were genotyped in 120 GC patients and 135 healthy individuals. Combined effect of the SNPs in both genes with GC risk was determined through allele dosage analysis (ADA) and the survival data were analyzed by Log Rank Test. The study results revealed that IL‐1β rs1143627: T > C, rs16944: C > T (p = 0.001;OR = 1.85; 95% CI 1.30‐2.63) and rs1143633: G > A (p < 0.0001; OR = 2.53; 95% CI 1.67‐3.83) and TNF‐α rs1800630: C > A, rs1799964: T > C (p < 0.0001; OR = 2.31; 95% CI 1.54‐3.46) polymorphisms significantly contributed toward GC risk. Moreover, ADA showed that carriage of 7 “effective” risk alleles conferred a risk of almost 10‐fold in comparison to individuals carrying less than 3 “effective” risk alleles. Our survival analysis also indicated a significant association between IL‐1β rs1143627: T > C and rs16944: C > T and patient survivability. The presence of H. pylori enhanced the risk in individuals with IL‐1β rs1143627:CC and rs16944:TT genotypes. Further, meta‐analysis revealed significant association of IL‐1β rs1143627: T > C (p = 0.026; OR = 4.165; 95% CI 1.18‐14.65) and rs16944: C > T (p = 0.01; OR = 5.49; 95% CI 1.48‐20.37) in presence of H. pylori with gastric cancer in Asian population though no significant difference (p > 0.05) was found when compared to absence of H. pylori Environ. Mol. Mutagen. 59:653–667, 2018. © 2018 Wiley Periodicals, Inc.     

TIM‐1 rs41297579 G>A (−1454) and TIM‐4 rs7700944 gene polymorphisms as possible risk factor for rheumatoid arthritis: relation to activity and severity

T his study was aimed to evaluate the impact of both TIM‐1 rs41297579 G>A (?1454) and TIM‐4 rs7700944 polymorphisms on susceptibility to rheumatoid arthritis (RA) in a cohort of Egyptian population and to evaluate for the first time their relation to activity, severity, disease‐related disability and erosion. TIM‐1 rs41297579 G>A (?1454) and TIM‐4 rs7700944 gene polymorphisms were typed by RFLP for 128 patients with RA and 125 healthy controls. The A allele, A‐containing genotypes (GA and AA) of the TIM‐4 and GA haplotype were present with significant higher frequency in patients with RA than healthy controls (P_c < 0.001). These findings suggest that the A allele, A‐containing genotypes (GA and AA) and GA haplotype may be a susceptibility risk factor for RA [OR = 5.83 (3.6–9.4), OR = 9.41 (5.0–17.6) and OR = 4.21 (1.07–19.2), respectively]. No associations were found between TIM genotypes and disease activity, severity or presence of erosion. However, the RA patients with GA genotype of TIM‐4 have higher grade of rheumatoid factor (RF) positivity (P = 0.018), and have worse disease‐related disability (P = 0.007) and worse pain (0.025). TIM‐4 rs7700944 and not TIM‐1 rs41297579 G>A (?1454) is associated with RA in the present cohort of Egyptian and may be a risk factor for development of RA in Egyptian. Both SNPs have no effect on disease activity, severity or erosion. However, TIM‐4 GA genotype is associated with higher grade of RF positivity and worse disease‐related disability and pain.     

NRAMP1 (SLC11A1) gene polymorphisms that correlate with autoimmune versus infectious disease susceptibility in tuberculosis and rheumatoid arthritis

NRAMP1 gene has multiple pleiotropic effects on macrophage activation pathways. These pleiotropic effects may increase resistance to infections such as tuberculosis (TB), but may also lead to susceptibility of autoimmune diseases such as rheumatoid arthritis (RA). It has been hypothesized that allele 3 would be associated with autoimmune diseases, whereas allele 2 would be associated with infectious diseases, and genetic factors that enhanced survival in the epidemics of TB might have led to susceptibility for the development of RA. We analysed four NRAMP1 gene polymorphisms including 5′ promoter (GT)_n (rs34448891), INT4 (469 + 14G/C) (rs3731865), 3′UTR (1729 + 55del4) (rs17235416) and D543N (codon 543, Asp to Asn) (rs17235409) in 112 patients with TB, 98 patients with RA, 80 healthy controls for TB and 122 healthy controls for RA using ARMS‐PCR and PCR‐RFLP. We found a significant association between INT4 and RA (P = 0.004, odds ratio: 2.06, 95% CI: 1.24–3.41), but no significant differences between 5′ promoter, D543N, 3′UTR polymorphisms and RA. There were no associations between NRAMP1 gene polymorphisms and TB. Similarly, no significant differences were observed between NRAMP1 polymorphisms and rheumatoid factor positivity and erosive disease in RA and localization of TB. INT4 polymorphism may be associated with RA in Turkish patients.     

Genetic association of interleukin‐2, interleukin‐4, interleukin‐6, transforming growth factor‐β, tumour necrosis factor‐α and blood concentrations of calcineurin inhibitors in Turkish renal transplant patients

Cytokines are essential for the control of the immune response as most of the immunosuppressive drugs target cytokine production or their action. The calcineurin inhibitors (CNIs) cyclosporine (CsA) and tacrolimus are immunosuppressive drugs widely used after renal transplantation to prevent allograft rejection. They are characterized by large interindividual variability in their pharmacokinetics; therefore, monitoring their blood concentrations is important to predict their optimal dosage following transplantation. Calcineurin inhibitors inhibit the phosphatase activity of calcineurin, thereby suppressing the production of other cytokines such as transforming growth factor (TGF‐β), tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐6, IL‐2, and IL‐4. The aim of this study was to investigate the relationship between polymorphisms of cytokines and blood concentrations of CNIs in renal transplant patients. The study included 53 CsA‐treated renal transplant patients and 37 tacrolimus‐treated renal transplant patients. Cytokine polymorphisms were analysed using polymerase chain reaction (PCR) sequence‐specific primers with the cytokine CTS‐PCR‐sequence‐specific primers Tray Kit; University of Heidelberg. Blood concentrations of CNIs were determined with Cloned Enzyme Donor Immunoassay (CEDIA) method. Patients with TC genotype of TGF‐β at codon 10 had lower CsA blood concentrations than the TT and CC genotypes (P = 0.005) at 1 month in CsA treatment group. The ratio of blood concentration/dose of CsA for patients with TGF‐β1‐codon 10 TC genotype was lower than for patients with TT, CC genotypes, and the dose given to these patients was higher in the first month (P = 0.046). The ratio of blood concentration/dose of CsA for patients with IL‐2‐330 GG genotype was higher than for patients with GT, TT genotypes, and the dose given to these patients was lower at first month and sixth months (P = 0.043, P = 0.035 respectively). The tacrolimus blood concentrations were significantly higher in patients with the genotype GG of IL‐2‐330 (P = 0.012) at the third month. Patients who had the TC genotype TGF‐β codon 10 had lower CsA blood concentrations and this group had higher acute rejection (P = 0.033). These results suggest that the genotyping for TGF‐β‐codon 10, IL‐2‐330 and IL‐6‐174 polymorphisms may help individualized immunosuppressive dosage regiments.     

Polymorphisms of ST2‐IL18R1‐IL18RAP gene cluster: a new risk for autoimmune thyroid diseases

Interleukin 33 (IL33) / ST2 pathway and ST2‐interlukin18 receptor1‐interlukin18 receptor accessory protein (ST2‐IL18R1‐IL18RAP) gene cluster have been involved in many autoimmune diseases but few report in autoimmune thyroid diseases (AITD). In this study, we investigated whether polymorphisms of IL33, ST2, IL18R1, and IL18RAP are associated with Graves' disease (GD) and Hashimoto's thyroiditis (HT), two major forms of AITD, among a Chinese population. A total of 11 SNPs were explored in a case–control study including 417 patients with GD, 250 HT patients and 301 controls, including rs1929992, rs10975519, rs10208293, rs6543116, rs1041973, rs3732127, rs11465597, rs1035130, rs2293225, rs1035127, rs917997 of IL 33, ST2‐IL18R1‐IL18RAP gene cluster. Genotyping of these SNPs was performed using matrix‐assisted laser desorption / ionization–time‐of‐flight mass spectrometer (MALDI‐TOF‐MS) platform from Sequenom. The frequencies of allele A and AA+AG genotype of rs6543116 (ST2) in HT patients were significantly increased compared with those of the controls (P = 0.029/0.021, OR = 1.31/1.62). And in another SNP rs917997, AA+AG genotype presented an increased frequency in HT subjects compared with controls (P = 0.046, OR = 1.53). Furthermore, the haplotype GAGCCCG from ST2‐IL18R1‐IL18RAP gene cluster (rs6543116, rs1041973, rs1035130, rs3732127, rs1035127, rs2293225, rs917997) was associated with increased susceptibility to GD with an OR of 2.03 (P = 0.022, 95% CI = 1.07–3.86). Some SNPs of ST2‐IL18R1‐IL18RAP gene cluster might increase the risk of susceptibility of HT and GD in Chinese Han population.     

Polymorphism in cathelicidin gene (CAMP) that alters Hypoxia‐inducible factor (HIF‐1α::ARNT) binding is not associated with tuberculosis

Polymorphisms in the CAMP gene (cathelicidin) have not been tested in tuberculosis susceptibility. We tested polymorphisms rs9844812 (HIF‐1α::ARNT binding site) and rs56122065 (CAMP) plus rs1800972 (DEFB1). SNP rs1800972 was associated with extrapulmonary tuberculosis (EPTB) in a codominant model (genotype CG, P = 0.037, OR 4.82; 95% CI: 0.92–47.42; statistical power, 82%), but not PTB (P = 0.101) in a Mexican population.