Wild-type GG Genotype Research Articles

IL23R-Protective Coding Variant Promotes Beneficial Bacteria and Diversity in the Ileal Microbiome in Healthy Individuals Without Inflammatory Bowel Disease.

This study aimed to characterize the mucosa-associated microbiota in ileal Crohn's disease [CD] patients and in healthy controls in terms of host genotype and inflammation status. The mucosa-associated microbiotas of intestinal pinch biopsies from 15 ileal CD patients with mild and moderate disease and from 58 healthy controls were analysed based on 16S ribosomal sequencing to determine microbial profile differences between [1] IL23R, NOD2 and ATG16L1 genotypes in healthy subjects, [2] ileal CD patients and control subjects, and [3] inflamed and non-inflamed mucosal tissue in CD patients. The protective variant of the IL23R gene [rs11209026] significantly impacted the microbial composition in the ileum of healthy subjects and was associated with an increased abundance of phylotypes within the family Christensenellaceae as well as increases in diversity and richness. Comparative analysis of healthy and non-inflamed CD microbiome samples indicated a notable decrease in the abundance of Faecalibacterium prausnitzii as well as Shannon diversity and richness. Inflamed and non-inflamed ileal samples of CD subjects had high intra-individual stability and inter-individual variability, but no significant alterations in diversity, richness or taxa were identified. Calprotectin correlated positively with the abundance of Proteobacteria and negatively with diversity in the samples from healthy subjects. The observation of low diversity and low abundance of beneficial bacteria in healthy control subjects carrying the IL23R [rs11209026] wild-type GG genotype indicates that the gut microbiome is influenced by host genetics and is altered prior to disease diagnosis. Faecal calprotectin may be a potential non-invasive screening tool for dysbiosis in subjects without disorders of intestinal inflammation.

Impact of GGCX polymorphisms on warfarin dose requirements in atrial fibrillation patients

Background/aim: Warfarin is a common anticoagulant with large interindividual differences and a narrow therapeutic range. The polymorphisms of gamma-glutamyl carboxylase (GGCX) are important genetic factors for warfarin dose requirements. Materials and methods: Polymerase chain reaction and direct sequencing methods were used to detect the GGCX rs699664 genotype in 215 atrial fibrillation (AF) patients with warfarin administration. The effects on warfarin dose by different genotypes were analyzed. A warfarin dosing algorithm was developed based on age, height, CYP2C9, VKORC1, and GGCX genotype. Results: In 215 AF patients, there were 104 cases of wild-type GG genotype (48.4%), 92 cases of GA genotype (42.8%), and 19 cases of AA genotype (8.8%). Patients with the GGCX rs699664 A allele (GA or AA genotypes) needed higher warfarin doses than those with the GG genotype (P < 0.05). A warfarin dosing algorithm showed that age, height, CYP2C9, VKORC1, and GGCX genotype were the best variables for estimating warfarin dose (R2 = 41.2%). Another independent cohort of 60 AF patients showed a significant linear correlation between predicted warfarin maintenance dose and actual dose (R = 0.660, P < 0.01). Conclusion: AF patients with the GA and AA genotypes in GGCX rs699664 required significantly higher warfarin doses. GGCX rs699664 is a potential predictor for the warfarin dose of AF patients.

The P38α rs3804451 Variant Predicts Chemotherapy Response and Survival of Patients with Non–Small Cell Lung Cancer Treated with Platinum-Based Chemotherapy

The JNK and P38α pathways play an important role in the sensitivity and outcomes of chemotherapy. We hypothesize that functional single nucleotide polymorphisms (SNPs) of genes of these pathways modulate outcomes of patients with advanced non–small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy (PBC). We selectively genotyped 11 independent, potentially functional SNPs of 9 genes in the JNK and P38α pathways first in a discovery group of 355 patients with advanced NSCLC treated with PBC, and we evaluated their associations with progression-free survival (PFS) and overall survival (OS) by Cox proportional hazards regression analysis. Then, resultant significant SNPs were further validated in a replication group of 355 patients. In both discovery and validation groups as well as their combined analysis, the MAPK14 rs3804451GA/AA genotypes showed a strong association with a reduced PFS (adjusted hazards ratio [HR]=1.39; 95% confidence interval [CI]=1.16–1.66; P=.0003) and OS (adjusted HR=1.41; 95% CI=1.11-1.80; P=.005) compared with the wild-type GG genotype. In contrast, patients with or without the MAPK14 rs3804451A allele had no significant difference in OS in response to tyrosine-kinase inhibitor treatment (adjusted HR=0.86; 95% CI=0.56-1.33; P=.505). The present study provides evidence that the MAPK14 rs3804451 G>A variant may modulate survival outcomes in patients with advanced NSCLC treated with PBC. Larger studies of additional patient populations are needed to validate our findings.

SCN5A (G892A) gene is associated with AV block conduction disorder in north Indian population

Objective- Electrical abnormalities of the heart cause the cardiac arrhythmia with or without essential structural heart disease. Due to genetic variation, cardiac arrhythmia can occur in any age group patients as well as in healthy people. The present study aimed to examine the allele and genotype of SCN5A (G892A) gene in cardiac conduction disorder (especially AV block conduction disorder) cases and comparison with healthy controls. Method- A total number of 104 cases and 104 controls were enrolled in this study. DNA was extracted using salting out method followed by polymerase chain reaction amplification and restriction endonuclease digestion (using AluI restriction enzyme). Digested PCR products were identified using agarose gel electrophoresis and stained with ethidium bromide. Results- There was a strong association of SCN5A G892A polymorphisms (GA vs. GG, OR= 4.01 and AA vs. GG OR= 3.12) with cardiac conduction disorder. Further multivariate logistic regression analysis, after adjustment for age, gender showed that when compared with wild type GG genotype, carriers of the A alleles had an increase risk of cardiac conduction disorder (OR-1.89, 95%CI- 0.78-1.67, p value- <0.0001). Conclusion- In conclusion the results of the present study suggest that the SCN5A G892A gene polymorphism carries an increased risk for cardiac conduction disorder in north Indian populations.

TIM-3 Genetic Variations Affect Susceptibility to Osteoarthritis by Interfering with Interferon Gamma in CD4+ T Cells.

Osteoarthritis (OA) is the most common type of arthritis, in which T cell responses and cytokines may play critical roles in the development of the disease. TIM-3 may affect immune responses and is correlated with decreased expression of interferon gamma (INF-γ) in CD4+ T cells. In the current study, we investigated the association between polymorphisms in the TIM-3 gene and susceptibility to OA. Two polymorphisms in TIM-3, -574G/T and +4259T/G polymorphisms, were identified in OA cases and healthy donors by polymerase chain reaction-restriction fragment length polymorphism method. Data revealed that the prevalence of TIM-3 +4259T/G genotype was significantly elevated in OA patients than in the healthy donors after adjustment (Odds ratio [OR] = 2.67, 95% confidence interval [CI] 1.32-5.11, P < 0.001). Similarly, the TIM-3 +4259G allele presented a positive association with the risk of OA after adjustment (OR = 2.58, 95% CI 1.29-4.82, P = 0.003). The TIM-3 -574G/T polymorphism did not show any correlation with the disease. We further examined whether the two TIM-3 polymorphisms could affect INF-γ expression in CD4+ T cells. Data revealed that subjects carrying polymorphic +4259TG genotype had significantly higher mRNA and protein levels of INF-γ in CD4+ T cells compared to wild-type GG genotype (P < 0.001 and P < 0.01). These results indicated that TIM-3 polymorphism is associated with increased susceptibility to OA possibly by upregulating INF-γ expression in CD4+ T cells.

Association analysis of IL-17A and IL-17F polymorphisms in Chinese women with cervical cancer.

We selected six tagged single nucleotide polymorphisms (SNPs) in the interleukin 17A (IL-17A) and IL-17F genes, and evaluated the relationship between the six common SNPs and environmental factors in cervical cancer patients. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the IL-17A (rs2275913, rs3748067, and rs3819025) and IL-17F (rs763780, rs9382084, and rs1266828) SNPs. The associations between IL-17A and IL-17F gene polymorphisms and risk of cervical cancer were estimated by conditional logistic regression. Compared with the control subjects, the cervical cancer patients had a lower age at first live birth, a habit of smoking, a family history of cancer, and a greater incidence of human papillomavirus-16 or 18 infections. The logistic regression analysis showed that the variant AA genotype of rs2275913 was associated with a significantly higher risk of cervical cancer than the wild-type GG genotype (OR = 1.99, 95%CI = 1.12-3.50). However, no evidence of the association was observed between rs3748067, rs3819025, rs763780, rs9382084, and rs1266828 polymorphisms and the risk of cervical cancer. We suggest that rs2275913 may play a role in the etiology of cervical cancer. These findings could be helpful in identifying individuals at increased risk of developing cervical cancer.

Associations of ERCC4 rs1800067 polymorphism with cancer risk: an updated meta-analysis.

RESULTS from previous studies concerning the association of ERCC4 rs1800067 polymorphism with risk of cancer were inconsistent. To explore the exact relation with susceptibility, we conducted the present meta-analysis. Literature of electronic databases including PubMed, Web of Science, EMBASE, Wanfang and Chinese National Knowledge Infrastructure (CNKI) were systematically searched. ORs and their 95%CIs were used to assess the strength of associations between ERCC4 polymorphism and cancer risk. There was no significant association between ERCC4 rs1800067 AA or AG genotypes and overall risk of cancer (AA vs. GG: OR=0.998, 95%CI=0.670-1.486, P=0.992; AG vs. GG: OR=0.970, 95%CI=0.888- 1.061, P=0.508). A dominant genetic model also did not demonstrate significant association of (AA+AG) genotype carriers with altered risk of overall cancer (OR=0.985, 95%CI=0.909-1.068, P=0.719). In addition, no significant association was observed between A allele of ERCC4 rs1800067 A/G polymorphism and altered cancer risk compared with G allele (OR=0.952, 95%CI=0.851-1.063, P=0.381). Subgroup analysis suggested that AA genotype carriers were significantly associated with decreased risk of glioma compared with wild-type GG genotype individuals (OR=0.523, 95%CI=0.275-0.993, P=0.048). For subgroup of lung cancer, A allele of ERCC4 rs1800067 A/G polymorphism was significantly associated with decreased risk of lung cancer compared with G allele (OR=0.806, 95%CI=0.697-0.931, P=0.003). This meta-analysis indicated that ERCC4 rs1800067 A/G polymorphism might not be associated with risk of overall cancer. However, individuals with the AA genotype were associated with significantly reduced risk of glioma compared with wild-type GG genotype; The A allele was associated with significantly reduced risk of lung cancer compared with G allele. Future large- scale studies performed in multiple populations are warranted to confirm our results.

Tim-3 polymorphism downregulates gene expression and is involved in the susceptibility to ankylosing spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory disorder primarily affecting the sacroiliac joints and the spine. T-cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3) has been established as a negative regulatory molecule that plays a critical role in controlling inflammation. Studies have shown that polymorphisms in TIM-3 gene may be associated with inflammatory diseases. The current study investigated the association between polymorphisms in the TIM-3 gene and susceptibility to AS, and it examined the effects of these polymorphisms on gene expression. Two polymorphisms in TIM-3 -574G/T and +4259T/G polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism in 282 AS patients and 298 healthy controls. Results showed that frequency of the TIM-3 -574GT genotype was significantly increased in cases than in controls (Odd ratio [OR]=2.50, 95% confidence interval [CI]: 1.39-4.48, p=0.002). Similarly, TIM-3 -574T allele revealed a positive association with the disease (OR=2.39, p=0.002). The TIM-3 +4259T/G polymorphism did not show any correlation with AS. We further evaluated TIM-3 mRNA and protein levels in CD4(+) T cells, CD8(+) T cells, and monocytes from subjects carrying different TIM-3 genotypes. Results revealed that subjects carrying polymorphic -574GT genotype had significantly lower TIM-3 mRNA and protein levels in CD4(+) T cells, CD8(+) T cells, and monocytes than those with wild-type GG genotype. These data suggest that TIM-3 polymorphism is associated with increased susceptibility to AS possibly by downregulating gene expression.

Cyclin D1 G870A polymorphism and the risk of hepatocellular carcinoma in a Chinese population

Cyclin D1, encoded by the gene CCND1, is a regulatory protein in the cell cycle transition from G1 phase to S phase. A common polymorphism (G870A) in the exon 4 of CCND1 gene affects splicing of the CCND1 transcript and may cause uncontrollable cellular growth. Therefore, the CCND1 G870A polymorphism may influence an individual's susceptibility to the development of certain tumors. The present study was performed to test the association between G870A polymorphism in the CCND1 gene and hepatocellular carcinoma (HCC) risk in a Chinese population. We extracted the peripheral blood samples from 220 patients with HCC and 220 age- and gender-matched healthy controls. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and direct DNA sequencing were performed to detect the polymorphism. The CCND1 genotype distribution among HCC patients was not significantly different from that among healthy controls (P=0.08). Compared with the wild-type GG genotype, neither the variant AA genotype nor the variant genotypes containing the A allele were associated with risk of HCC. However, stratification analysis by HBV carrier status revealed that the variant genotypes containing the A allele were associated with a significantly increased risk of HCC among HBsAg-positive individuals (adjusted OR=3.87; 95 % CI=1.12, 13.30). These results suggest that the CCND1 G870A polymorphism may increase the risk of HBV-related HCC in the Chinese population.

Genetic Polymorphisms of Surfactant Protein D rs2243639, Interleukin (IL)-1β rs16944 and IL-1RN rs2234663 in Chronic Obstructive Pulmonary Disease, Healthy Smokers, and Non-Smokers

Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease that involves the activity of various inflammatory cells and mediators. It has been suggested that susceptibility to COPD is, at least in part, genetically determined. The primary aim of this study was to investigate the association between surfactant protein D (SFTPD) rs2243639, interleukin (IL)-1β rs16944 and IL-1 receptor antagonist (IL-1RN) rs2234663 gene polymorphisms and COPD susceptibility, as well as examining the association between the various IL-1RN/IL-1β haplotypes and pulmonary function tests (PFT). Secondly, we aimed to examine the influence of SFTPD rs2243639 polymorphism on serum surfactant protein D (SP-D) level. A total of 114 subjects were recruited in this study and divided into three groups: 63 COPD patients, 25 asymptomatic smokers, and 26 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed for the detection of SFTPD rs2243639 and IL-1β rs16944 polymorphisms. Detection of variable numbers of an 86-bp tandem repeat (VNTR) of IL-1RN was done using PCR. Serum SP-D level was measured using enzyme linked-immunosorbent assay. PFTs were measured by spirometry. Carriers of the SFTPD AG and AA polymorphic genotypes constituted 71.4% of COPD patients versus 48% in asymptomatic smokers, with a statistically significant difference between the two groups (p=0.049). Smokers who were carriers of the polymorphic SFTPD rs2243639 A allele (AG and AA genotypes) have a 2.708 times risk of developing COPD when compared with wild-type GG genotype carriers [odds ratio (OR) 2.708 (95% CI 1.041-7.047)]. Forced expiratory flow (FEF) 25-75% predicted was higher in IL-1RN*1/*1 when compared with *1/*2 (p=0.013). FEF25-75% predicted in carriers of haplotype IL-1RN *1/IL-1β T (49.21±10.26) was statistically significantly higher than in carriers of IL-1RN *2/IL-1β T (39.67±12.64) [p=0.005]. Forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC) in carriers of haplotype IL-1RN *1/IL-1β T (64.09±6.39) was statistically significantly higher than in carriers of IL-1RN *2/IL-1βT (59.44±7.71) [p=0.048]. There was no association between SFTPD rs2243639 genotypes and serum SP-D level. Smokers who are carriers of the SFTPD AG and AA polymorphic genotypes may be at a higher risk of developing COPD when compared with wild-type GG genotype carriers. IL-1RN rs2234663/IL-1β rs16944 haplotypes influence FEF25-75% predicted and FEV1/FVC. SFTPD rs2243639 polymorphism did not influence serum SP-D levels in our group of recruited subjects.

The study of t-PA, u-PA and PAI-1 genes polymorphisms in patients with abdominal aortic aneurysm

The most important feature of abdominal aortic aneurysm (AAA) pathogenesis is an enzymatic degradation of elastic lamellae and extracellular matrix proteins particularly with participation of matrix metalloproteinases. Plasmin, which is responsible for the dissolution of fibrin in blood vessels, plays also a key role in the cascade for activation of the metalloproteinases. The purpose of this study was to evaluate the influence of selected polymorphisms in genes coding for tissue plasminogen activator (−7351 C/T polymorphism), urokinase-type plasminogen activator (1788 C/T polymorphism) and plasminogen activator inhibitor 1 (−675 4G/5G and −844 G/A polymorphism) on the susceptibility to AAA. We performed a case–control study of 153 polish patients hospitalized due to AAA and compared them with matched healthy control subjects. The polymorphisms were ascertained through genotyping by polymerase chain reaction and restriction digestion of amplified fragments or through high-resolution melting analysis. In this study we have found lower frequency of wild-type GG genotype of the −844G/A PAI-1 polymorphism in cases than in controls, what may suggest the protective effect of this genotype for the risk of AAA development. None of the remaining polymorphisms tested were associated with AAA occurrence.

IL-6 gene promoter polymorphisms and risk of coronary artery disease in a Chinese population.

We investigated the relationships between single nucleotide polymorphisms (SNPs) of the interleukin (IL)-6 gene 174 G>C (rs1800795), 572 G>C (rs1800796), and 597 G/A (rs1800797) and coronary artery disease (CAD) risk in a Chinese population. This case-control study recruited 296 CAD patients and 327 controls between January 2009 and May 2012. Genotyping of IL-6 174 G>C (rs1800795), 572 G>C (rs1800796), and 597 G/A (rs1800797) was performed on a 384-well plate format using the Sequenom MassARRAY platform. CAD patients were more likely to be older and male, with a higher body mass index, diabetes, and hypertension, and presented higher triglycerides, and lower total cholesterol, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. We found that the IL-6 174CC genotype was associated with a significantly increased risk of CAD compared to the wild-type GG genotype in a codominant model [odds ratio (95% confidence interval) = 1.94 (1.13-3.37)], whereas IL-6 174 G>C polymorphisms presented an increased risk of CAD in dominant and recessive models. However, we did not find that the IL-6 572 CC and 597 AA genotypes were correlated with an increased risk of CAD. IL-6 174 G>C rs1800795 was associated with CAD risk in a Chinese population. Further large-scale studies are required to determine whether IL-6 SNPs interact with environmental factors in the development of CAD.

Influence of the c.1517G>C genetic variant in the XRCC1 gene on pancreatic cancer susceptibility in a Chinese population.

We investigated the influence of the c.1517G>C genetic variant in the X-ray repair complementing group 1 gene (XRCC1) on pancreatic cancer (PC) susceptibility in Chinese patients. A total of 390 PC patients and 392 controls were enrolled in this case-control study. The genotypes of c.1517G>C genetic variants were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Our findings suggested that the allele and genotype frequencies in PC patients were significantly different from those in cancer-free controls. The CC genotype was associated with an increased risk of PC compared to the wild-type GG genotype (odds ratio=2.43, 95% confidence interval 1.43-4.13, X2=11.19, P=0.001). The C allele may contribute to the development of PC (C vs G, odds ratio=1.32, 95% confidence interval 1.06-1.64, X2=6.25, P=0.012). Results from this study indicate that the c.1517G>C genetic variant of the XRCC1 gene is significantly associated with PC susceptibility in the Chinese population.

Association between genetic polymorphisms in pre-miR-146a and pre-miR-196a2 and genetic damage levels among coke oven workers

To investigate the association of rs2910164 G > C polymorphism and rs11614913 T > C polymorphism in pre-miR-146a and pre-miR-196a2 with genetic damage levels in coke oven workers. A total of 575 nonsmoking workers who have worked for more than one year in a coke-oven plant at Wuhan, Hubei Province were enrolled in this study in September to October, 2010. The general characteristics as well as blood and urine samples were collected. The genetic damage levels were detected by cytokinesis-block micronucleus cytom assay and represented as micronucleus (MN) frequencies of binucleate cells in peripheral blood lymphocytes. The rs2910164 G > C polymorphisms in pre-miR-146a and rs11614913 T > C polymorphisms in pre-miR-196a2 were genotyped by using TaqMan assay. The plasma concentrations of benzo[a]pyrene-diolepoxide (BPDE)-albumin adducts were determined by using ELISA. All data were analyzed, the frequency ratio (FR) and 95%CI were calculated. Totally, 575 workers were taken into consideration. The rs2910164 C allele was associated with increased MN frequencies in the coke oven workers (P trend = 0.025), and the MN frequencies were higher in rs2910164 CC genotype carriers (4.38 ± 3.46) than in wild-type rs2910164 GG genotype carriers (4.02 ± 3.09) (FR = 1.18, 95%CI:1.04-1.34). The further stratified analyses by working years, gender, alcohol consumption, and the levels of BPDE-albumin adducts showed that the effects of rs2910164 C allele in increasing MN frequencies were robust in subjects who were males (FR = 1.11, 95%CI:1.02-1.20), nondrinkers (FR = 1.07, 95%CI:1.00-1.14), working years less than 20 (FR = 1.12, 95%CI:1.03-1.22), and workers with lower BPDE-albumin adducts levels (FR = 1.11, 95%CI:1.02-1.21) (P trend = 0.011, 0.044, 0.006 and 0.020, respectively). In addition, the MN frequencies were higher in workers with rs11614913 TC genotype (4.27 ± 2.91) than workers with rs11614913 TT genotype (3.90 ± 3.32) (FR = 1.12, 95%CI:1.02-1.23).Workers carried both rs2910164 GG and rs11614913 TT genotypes were set as a control, and the MN frequencies of workers with both rs2910164 CC and rs11614913 CC genotypes (5.32 ± 4.94) were 1.51 (1.21-1.89) times higher than the control (3.75 ± 3.01). The rs2910164 C allele in pre-miR-146a and rs11614913 C allele in pre-miR-196a2 were associated with increased genetic damage levels in coke oven workers.

Thiopurine Effectiveness in Patients with Crohnʼs Disease

Thiopurines are efficacious in the treatment of Crohn's disease and were recently shown to induce T-cell apoptosis by modulation of Rac1 activation. To assess whether polymorphisms in Rac1 and other apoptosis-related genes, combined with clinical parameters, can predict response to thiopurines. A retrospective cohort of 156 thiopurine-treated patients with Crohn's disease was genotyped for 11 single-nucleotide polymorphisms (SNPs): 9 SNPs in Rac1, 1 SNP in the Fas ligand -843 T>C, and 1 SNP in the Caspase-9 93 C>T. Clinical data were extracted from the medical charts. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between demographic, clinical, and genetic variables and thiopurine response rates were calculated. The overall response rate to thiopurines was 74% (115/156). The Rac1 SNP rs34932801 heterozygote genotype GC was associated with a lower response rate compared with the wild-type GG genotype (46% versus 76%; OR = 0.26; 95% CI, 0.08-0.91; P = 0.036). Only wild-type homozygotes were found for 5 Rac1 SNPs. None of the other 3 Rac1 SNPs were associated with response to thiopurines. Patients with Montreal B3 behavior pattern responded worse than those with a B1 behavior pattern (59%, versus 80%; OR = 0.37; 95% CI, 0.17-0.83; P = 0.016). Sephardic Jews had a lower response rate to thiopurines compared with Jews of Ashkenazi or mixed ancestry (60% versus 82%; OR = 0.32; 95% CI, 0.15-0.69, P = 0.003). Rac1 SNP rs34932801carriage, Montreal B3 disease behavior, and a Sephardic Jewish origin were associated with unfavorable response to thiopurines. Corroboration of these associations in larger cohorts is warranted.

Monocyte chemotactic protein-1 and CC chemokine receptor 2 polymorphisms and prognosis of renal cell carcinoma

Monocyte chemoattractant protein-1 (MCP-1) and its receptor CC chemokine receptor 2 (CCR2) play a major role in inflammation and proliferation of cancers. We investigated a possible association between polymorphisms in MCP-1 and CCR2 genes (MCP-1 -2518A/G and CCR2 190G/A or V64I) and the risk as well as prognosis of renal cell carcinoma (RCC). Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism in 416 RCC cases and 458 age-matched healthy controls. Frequency of MCP-1 2518GG genotype for cases and controls was 0.384 and 0.286, respectively; individuals carrying the GG genotype had a 1.89-fold increased risk of RCC than those with AA genotype (95 % confidence interval [CI] 1.24-2.81, p = 0.002; data were adjusted for age and sex). Frequency of CCR2 190AA (64I/64I) genotype for cases and controls was 0.175 and 0.076, respectively; subjects having AA genotype had a 2.68-fold increased risk of RCC compared to those with the wild-type GG genotype (95 %CI 1.71-4.17, p = 4.3 × 10(-6); data were adjusted for age and sex). When analyzing the survival rate of RCC, patients with MCP-1 -2518GG genotype revealed significantly shorter survival time compared to cases with MCP-1 -2518AA and AG genotypes (p = 0.003). Similarly, RCC cases carrying CCR2 190AA genotype showed significantly shorter survival rate than patients with GG or GA genotypes (p < 0.001). These data suggested that MCP-1 -2518A/G and CCR2 190G/A polymorphisms are new risk factors for RCC and could be used as prognostic markers for this malignancy.

Tagging SNPs in the ERCC4 gene are associated with gastric cancer risk

ERCC4 plays an essential role in the nucleotide excision repair (NER) pathway, which is involved in the removal of a wide variety of DNA lesions. To determine whether the ERCC4 tagging SNPs (tSNPs) are associated with risk of gastric cancer, we conducted a hospital-based case-control study of 350 cases and 468 cancer-free controls. In the logistic regression (LR) analysis, we found a significantly decreased risk of gastric cancer associated with the rs744154 GC/CC genotypes [adjusted odds ratio (OR)=0.56, 95% confidence interval (CI)=0.42–0.75, false discovery rate (FDR) P=0.003] compared with the wild-type GG genotype. Haplotype-based association study revealed that the CGC haplotype that containing the rs744154 C allele can decrease the risk of gastric cancer compared with the most common haplotype GGT (adjusted OR=0.61, 95% CI=0.46–0.81). Using the multifactor dimensionality reduction (MDR) analysis, we identified that the SNP rs744154 and smoking status were the best two predictive factors for gastric cancer with a testing accuracy of 55.76% and a perfect cross-validation consistency (CVC) of 10 (P=0.001). Furthermore, the smokers with the rs744154 GC/CC genotypes showed a decreased risk of gastric cancer (adjusted OR=0.55, 95% CI=0.35–0.85) compared with the smokers with the GG genotype using multivariate LR analysis. The above findings consistently suggested that genetic variants in the ERCC4 gene may play a protective role in the etiology of gastric cancer, even in the smokers.

Angiotensin-converting enzyme gene 2350 G/A polymorphism and susceptibility to atrial fibrillation in Han Chinese patients with essential hypertension

OBJECTIVE:The angiotensin-converting enzyme gene is one of the most studied candidate genes related to atrial fibrillation. Among the polymorphisms of the angiotensin-converting enzyme gene, the 2350 G/A polymorphism (rs4343) is known to have the most significant effects on the plasma angiotensin-converting enzyme concentration. The aim of the present study was to investigate the association of the angiotensin-converting enzyme 2350 G/A polymorphism with atrial fibrillation in Han Chinese patients with essential hypertension.METHODS:A total of 169 hypertensive patients were eligible for this study. Patients with atrial fibrillation (n = 75) were allocated to the atrial fibrillation group, and 94 subjects without atrial fibrillation were allocated to the control group. The PCR-based restriction fragment length polymorphism technique was used to assess the genotype frequencies.RESULTS:The distributions of the angiotensin-converting enzyme 2350 G/A genotypes (GG, GA, and AA, respectively) were 40.43%, 41.49%, and 18.08% in the controls and 18.67%, 46.67%, and 34.66% in the atrial fibrillation subjects (p = 0.037). The frequency of the A allele in the atrial fibrillation group was significantly greater than in the control group (58.00% vs. 38.83%, p = 0.0007). Compared with the wild-type GG genotype, the GA and AA genotypes had an increased risk for atrial fibrillation. Additionally, atrial fibrillation patients with the AA genotype had greater left atrial dimensions than the patients with the GG or GA genotypes (p<0.01 and p<0.05, respectively).CONCLUSIONS:The results obtained in this study indicate that the angiotensin-converting enzyme 2350 G/A polymorphism is associated with atrial fibrillation and that the A allele shows an increased risk for atrial fibrillation in Han Chinese patients with essential hypertension.

Association of genetic polymorphisms in Sipal with circulating tumor cells in patients with breast cancer

Objective To investigate the correlation between the polymorphisms (rs931127 and rs746429) in signal-induced proliferation-associated 1 ( Sipal ) gene and circulating tumor cells in patients with breast cancer.Methods The polymorphisms of Sipal were detected by using polymerase chain reaction (PCR)-DNA sequencing in 124 primary breast cancer patients and 120 healthy controls.The circulating tumor cells were detected by real-time quantitative PCR.Results The polymorphisms were not associated with the circulating tumor cells of the breast cancer patients ( P ＞ 0.05 ).rs931127 and rs746429 polymorphisms of Sipal were not significantly associated with age,estrogen receptor status,progesterone receptor status,and C-erbB2 overexpression of patients with breast cancer (P ＞ 0.05). However,patients with the rs931127 homozygous for the wild-type GG genotype were less likely to have positive lymph node involvement (22.6％) than those with heterozygous GA (48.3％) and mutant AA genotype (71.0％)(P ＜ 0.01 ).Patients with the rs746429 homozygous for the wild-type CC genotype were less likely to have positive lymph node involvement (31.4％) than patients with heterozygous CT (64.2％ ) and mutant TT genotype too (44.4％ ) ( P ＜ 0.01 ).Conclusion The variants rs746429 and the rs931127 allele were not associated with the circulating tumor cells of the breast cancer patients,but associated with lymph node involvement.rs931127 A allele and rs746429 T allele in patients with breast cancer may be associated with lymphatic metastasis. Key words: Breast cancer; Metastasis; Single nucleotide polymorphism; Sipa1

Age- and gender-specific effects on NRAMP1 gene polymorphisms and risk of the development of active tuberculosis in Tunisian populations

Studies that have assessed NRAMP1 polymorphisms and their association with susceptibility to tuberculosis (TB) in humans have yielded conflicting results. In this study, we evaluated the association between NRAMP1 gene polymorphisms and the risk of the development of active TB in Tunisian populations. The distribution of 3'-UTR and D543N polymorphisms in 223 TB patients (168 patients with pulmonary TB (PTB) and 55 patients with extrapulmonary TB (EPTB)) and 150 healthy donors was determined by PCR-restriction fragment length polymorphism (RFLP) method. We found that AA and AG genotypes appeared to be associated with susceptibility to PTB (odds ratio (OR) 10.8, 95% confidence interval (CI) 1.37-230.8; p corrected for the number of genotypes (pc)=0.018) and EPTB (OR 4.37, 95% CI 1.64-11.82; pc=0.0024), respectively, in patients aged less than 30 years. However, wild-type GG genotype appeared to be associated with resistance against PTB in females (OR 0.1, 95% CI 0.01-0.74; pc=0.03). The 3'-UTR del/del genotype appeared to be associated with susceptibility to PTB in patients aged less than 30 years (OR 3.75, 95% CI 1.5-9.52; pc=0.003). In contrast, TGTG+/del might be associated with resistance against the development of active PTB (OR 0.23, 95% CI 0.08-0.65; pc=0.003). A-del haplotype appeared to be associated with susceptibility to PTB (OR 1.79, 95% CI 1.11-2.9; pc=0.04). Collectively, our results suggest an association of NRAMP1 3'-UTR and D543N polymorphisms with susceptibility to mycobacterial infection in Tunisian populations in relation to age and sex.