Interleukin (IL)-8 -251 T/A and IL-10 (-1082 G/A and -819/592 C/T) polymorphisms and their expression may influence gastritis, atrophy, intestinal metaplasia (IM) and gastric cancer (GC) following H. pylori infection.Genotyping of these genes was performed (ASO-PCR) in 200, 182 and 250 with GC, functional dyspepsia (FD) and healthy controls (HC), respectively. Anti-H. pylori IgG-antibody was tested in all and serums IL-8 and IL-10 were measured randomly in 60 subjects of each group by ELISA.Pro-(IL-8)-251 AA and anti-inflammatory (IL-10)-819 TT genotypes were commoner among GC than HC (p = 0.023, OR 1.86 [1.09-3.2] and p = 0.020, OR 2.0 [1.11-3.5]) but comparable with FD. IL-8 AA and IL-10-819 T allele carriage was also commoner in H. pylori-infected GC than HC (p = 0.011, OR 2.47 [1.23-5.0], and p = 0.018, OR 2.3 (1.16-4.59). IL-10-1082 G/A genotype and haplotypes (ACC, GCC, ATA and GTA) were comparable in all groups. Circulating levels of IL-8 and IL-10 were higher among GC than HC but comparable to FD (IL-8; 57.64 [6.44-319.46] vs. 54.35 [4.24-318.96] and 26.33 [4.67-304.54] pg/ml, p < 0.001 and IL-10; 15.47 [1.01-270.87] vs. 12.28 [0.96-64.88] and 3.79 [1.24-56.65], p < 0.001 for GC vs. HC). IL-8/IL-10 ratio was lower among GC than HC but higher than FD (3.7 [0.18-38.41] vs. 6.59 [0.98-130.2], p < 0.001 and 4.22 [0.15-61.4], p < 0.01). Circulating levels of IL-8, IL-10 and IL-8/lL-10 ratios were different among H. pylori-infected and non-infected GC than HC (p < 0.001, p < 0.001 and p < 0.01).Pro-(IL-8)-251 T/A and anti-inflammatory (IL-10)-819 C/T gene polymorphisms and their circulating levels may play a role in H. pylori-associated gastric carcinogenesis in northern India.
There is considerable evidence that polymorphisms in the regulatory regions of cytokine genes are highly influenced by ethnicity. Polymorphisms in interleukin 1-beta (IL-1beta) and IL-1 receptor antagonist (IL-1Ra) genes, respectively encoding a potent inflammatory agent and an antagonist, which combines with IL-1 receptors competitively, have been associated with a number of diseases like systemic lupus erythematosus, rheumatoid arthritis, sepsis, kidney diseases, and cancer. In this study, we therefore evaluated the distribution of interleukin-1 gene cluster (IL-1beta promoter region, exon-5 and IL-1Ra) gene polymorphisms in 206 healthy north Indian subjects, using PCR-based restriction analysis. We also constructed various haplotypes and estimated the linkage disequilibrium (LD). We found that genotype and allelic frequencies for these cytokines were conspicuously different when compared among different ethnic populations. The haplotype 'T-E1-1' predominated (41.7%) while the least common was 'C-E2-2' (2%) in our population. Genetic linkage between three loci of IL-1 gene showed strong association among the variants in controls (D'=0.42, p<0.001). Our results suggest that the frequency and distribution of the polymorphisms in India are substantially different from other populations and ethnic groups. Thus they signify an impact of ethnicity and provide a basis for future epidemiological and clinical studies.
Chemokines and their receptors acts as mediators of migration of immune cells to the site of inflammation and deregulated inflammatory response is associated with increased risk of cancer. We performed a case-control study to analyze the frequencies of CCL2 (I/D, rs3917887), -2518 (A > G, rs1024611), and CCR2 (G > A, rs1799864) polymorphisms for prostate cancer (PCa) risk. In this hospital-based case-control study, histologically confirmed 195 PCa patients and 250 unrelated healthy controls of similar ethnicity were genotyped by PCR-RFLP. The result showed that heterozygous ID (odds ratio (OR) = 1.71; p = 0.010) carrier genotype of CCL2 gene were at increased risk for developing PCa. Variant allele D carriers (ID + DD) demonstrated a 1.67-fold increased risk (OR = 1.67; p = 0.010), suggesting a dominant effect model involved in PCa risk. Similarly, variant allele D of CCL2 gene also had a higher risk (OR = 1.53; p = 0.040) for developing PCa. High risk to PCa was also observed with respect to diplotypes, I-G (OR = 1.83; Bonferroni corrected p value (P c) = 0.004) and D-A (OR = 2.11; P c = 0.004) of CCL2 I/D and -2518 (A > G). In association of genotypes with clinic-pathological grade of tumor, homozygous DD (OR = 7.40; P c = 0.042) and variant allele carrier ID + DD (OR = 2.42; P c = 0.036) genotypes of CCL2 gene conferred risk in high Gleason grade tumor of PCa. We observed a significantly enhanced risk for PCa due to interaction between CCL2 I/D, -2518 (A > G), and CCR2 (G > A) genotypes. However, -2518 (A > G) and CCR2 V64I (G > A) gene polymorphisms were not significantly associated with PCa risk. Our results supported that CCL2 I/D gene variant contribute to the susceptibility and clinic-pathological characteristic of PCa and could be considered as an important risk factor for this malignancy in North Indian men.
Background Cell surface biomarker CD44 plays an important role in breast cancer cell growth, differentiation, invasion, angiogenesis and tumour metastasis. Therefore, we aimed to investigate the role of CD44 gene polymorphisms in breast cancer risk and prognosis in North Indian population. Materials & Methods A total of 258 breast cancer patients and 241 healthy controls were included in the case-control study for risk prediction. According to RECIST, 114 patients who received neo-adjuvant chemotherapy were recruited for the evaluation of breast cancer prognosis. We examined the association of tagging SNP (rs353639) of Hapmap Gujrati Indians in Houston (GIH population) in CD44 gene along with a significant reported SNP (rs13347) in Chinese population by genotyping using Taqman allelic discrimination assays. Statistical analysis was done using SPSS software, version 17. In-silico analysis for prediction of functional effects was done using F-SNP and FAST-SNP. Results No significant association of both the genetic variants of the CD44 gene polymorphisms was found with breast cancer risk. On performing univariate analysis with clinicopathological characteristics and treatment response, we found significant association of genotype (CT+TT) of rs13347 polymorphism with earlier age of onset (P = 0.029, OR = 0.037). However, significance was lost in multivariate analysis. For rs353639 polymorphism, significant association was seen with clinical tumour size, both at the genotypic (AC+CC) (P = 0.039, OR = 3.02) as well as the allelic (C) (P = 0.042, OR = 2.87) levels. On performing multivariate analysis, increased significance of variant genotype (P = 0.017, OR = 4.29) and allele (P = 0.025, OR = 3.34) of rs353639 was found with clinical tumour size. In-silico analysis using F-SNP, showed altered transcriptional regulation for rs353639 polymorphism. Conclusions These findings suggest that CD44 rs353639 genetic variants may have significant effect in breast cancer prognosis. However, both the polymorphisms- rs13347 and rs353639 had no effect on breast cancer susceptibility.
Abstract Background: Tumor necrosis factor (TNF)‐α is a proinflammatory cytokine associated with inflammatory diseases, while GSTM1 and T1 enzymes catalyze detoxification of products of oxidative stress and hence reduce inflammation. Thus, both may play important roles in the pathogenesis of inflammatory bowel disease (IBD). The present study aimed to evaluate the effect of polymorphism of the TNF‐α promoter at the −308 site, GSTM1 and GSTT1 in patients with IBD and healthy controls from northern India. Method: Genotyping was performed in 114 patients with IBD (22 Crohn’s disease [CD] and 92 ulcerative colitis [UC]) in TNF‐α and 105 (20 CD and 85 UC) in GSTM1 and T1 and 164 healthy controls using polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) and multiplex PCR methods. Results: Patients with IBD were comparable to healthy controls in relation to age and gender. Genotypic and allelic frequencies of TNF‐α were comparable among patients with IBD and healthy controls. GSTM1 null genotype was more frequent in UC than in healthy controls (52/85 vs 49/164; P < 0.001) and GSTT1 null genotype was more frequent both in UC and CD as compared to healthy controls (77/85 and 18/20 vs 26/164, respectively; P < 0.001 for both). Frequency of combined null genotype in GSTM1 and T1 was more frequently associated with IBD than healthy controls (4/20 vs 8/164; P = 0.029, OR = 4.875 and 28/85 vs 8/164; P < 0.001, OR = 9.579, respectively). Conclusions: ‘Null’ genotypes of GSTM1 and T1 are associated with IBD and the combination of the two GST genotypes further increases the risk, possibly due to gene–gene interaction. TNF‐α is unlikely to be an important determinant of susceptibility to IBD in the Indian population.
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