Cyclin D1 (G870A) polymorphism and risk of cervix cancer: a case control study in north Indian population

Cyclin D1 (CCND1) is a key regulatory protein, playing a critical role in the transition from G1 to S phase of the cell cycle. We have evaluated the association between CCND1 A870G polymorphism and risk of cervix cancer in north Indian women by using PCR-RFLP method. This association was estimated by computing odds ratio (ORs) and a 95% Confidence Intervals (95% CI) using a Multivariate Logistic Regression Analysis. No significant association was observed between CCND1 genotypes and overall risk of cervix cancer. But when stratified histologically, statistically significant (OR: 3.7, 95% CI: 1.56-8.87, P: 0.001) increased risk of squamous cell carcinoma (SCC) was observed for individuals with AA genotype. Thus our findings suggest that CCND1 (G870A) polymorphism may be associated with increased risk of SCC of the uterine cervix in north Indian women.     

Cyclin D1 G870A polymorphism is associated with an increased risk of hepatocellular carcinoma in the Turkish population: Case–control study

Background: A common G to A polymorphism (G870A) in the splice donor region of exon 4 of cyclin D1 (CCND1) gene generates two mRNAs (cyclin D1a and D1b) through an alternative splicing at the site of this polymorphism. Cyclin D1a and b proteins differ in their COOH-terminus, a region involved in protein degradation. We examined the association between this CCDN1 genotype and the susceptibility to hepatocellular carcinoma (HCC) in a Turkish population. Methods: The genotype frequency of this polymorphism was determined by using a polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) assay. Hospital-based case–control study was designed consisting of 160 diagnosis subjects with hepatocellular carcinoma and 160 cancer-free control subjects matched on age, gender, smoking and alcohol status. Results: The allele frequencies of case subjects (A, 0.55; G, 0.45) were significantly different from those of control subjects (A, 0.42; G, 0.58) (p = 0.002). The odds ratios (ORs) for the CCND1 870 GA and AA genotypes when compared with the GG genotypes were 1.39 (95% confidence interval [CI] 0.82–2.36, p = 0.22) and 2.52 (95% CI 1.38–4.62, p = 0.003) respectively. The presence of at least one CCND1 870A allele was associated with increased risk for HCC (OR, 1.73; 95% CI, 1.06–2.82, p = 0.03). When combining the GG and GA genotypes as a reference genotype, we found that the OR for the AA genotype was 2.06 (95% CI 1.24–3.44, p = 0.006). Conclusion: Our results suggest that the CCND1 G870A single nucleotide polymorphism is associated with an increased risk of HCC in our Turkish population.     

Cyclin D1 (CCND1) G870A gene polymorphism is an ethnicity-dependent risk factor for digestive tract cancers: a meta-analysis comprising 20,271 subjects

Published data on the association between Cyclin D1 (CCND1) G870A gene polymorphism and digestive tract cancers (DTC) are inconclusive. We carried out a meta-analysis of published case-control studies to derive a more precise estimation of the association. Relevant studies were identified from PubMed, EMBASE, and China National Knowledge Infrastructure up to February 1st, 2011. Crude odds ratios (OR) and 95% confidence intervals (CI) were used to investigate the strength of the association. Data were available from a total of 33 case-control studies with 8534 cases and 11,737 controls. The combined results based on all studies showed that there was a statistically significant link between CCND1 G870A polymorphism and DTC risk (GG vs. AA: OR=0.83, 95%CI=0.71-0.96). In the analysis of ethnic groups, we found the A allele carriers had a significantly increased DTC susceptibility among Caucasians, but not among Asians. When stratified for tumor location, the results based on all studies only showed the variant allele 870A might have a significantly increased risk of colorectal cancer (CRC), especially of rectal cancer (GG vs. AA: OR=0.71, 95%CI=0.58-0.89). When stratifying by the stage and histological differentiation of CRC, we only observed that patients had a significantly higher frequency of CCND1 870 AA than non-cancer patients among Caucasians. The A allele carriers (hetero- or homozygotes) were significantly more common in cases with a family history of CRC than in controls. There was no evidence of publication bias for CCND1 G870A polymorphism with DTC risk. In summary, this meta-analysis demonstrates that the CCND1 G870A polymorphism may be an ethnicity-dependent risk factor for DTC. And this genetic variant may increase the risk of rectal cancer, but not colon cancer.     

Potential role of CCND1 G870A genotype as a predictor for urothelial carcinoma susceptibility and muscle-invasiveness in Taiwan

The cell cycle regulator cyclin D1 (CCND1) is thought to play a major role in the transition of cell cycle from G1 to S phase. It is known that a common CCND1 G870A genotype is associated with bladder cancer in Japan and China, but not in the Western World. There is neither a report about its role in Taiwan's population, nor its genetic role of CCND1 G870A in another worldwide urothelial cancer, upper tract urothelial cancer (UTUC). Therefore, we aimed at investigating the role of CCND1 G870A in both bladder cancer and UTUC in Taiwanese cohorts. The CCND1 G870A genotypes of 171 (101 bladder cancer and 70 UTUC) patients and 243 control subjects were determined by PCR-RFLP and their correlation with clinical and histopathological data was evaluated. The genotype analysis results showed that CCND1 GG genotype was associated with a lower risk overall in urothelial (P = 0.008, OR = 0.44, 95% CI = 0.24-0.81) and bladder cancer patients (P = 0.008, OR = 0.34, 95% CI = 0.15-0.76) than those of the AA genotype. In addition, patients carrying the AG genotype had a 0.29-fold lower odds ratio of muscle-invasive cancer procession (95% CI = 0.12-0.70) compared with those carrying the AA genotype in bladder cancer patients. Surprisingly, the GG genotype had a 5.88-fold higher odds ratio of muscle-invasive cancer procession (95% CI = 1.08-32.01) compared with those carrying the AA genotype in UTUC. No association between any CCND1 G870A genotype and higher-grade risk was found. Our results suggest that the G allele of the CCND1 G870A polymorphism may be a potential predictive and prognostic biomarker to distinguish between bladder cancer and UTUC in Taiwan.     

Myeloperoxidase gene-463G > A polymorphism and premature coronary artery disease

We investigated the association between myeloperoxidase gene -463G > A polymorphism and premature coronary artery disease (CAD) in two Chinese population samples: 229 patients and 230 controls. Genotypes were determined by ligase detection reaction-polymerase chain reaction sequencing and the grouping technique. We found lower frequencies of both the A/A genotype and the A allele in patients (p < 0.05). Multivariate logistic regression showed that the risk of premature CAD in subjects carrying the AA genotype was reduced by 83% in relation to individuals carrying the G/G genotype (OR = 0.172, 95% CI: 0.057-0.526, p = 0.002). Our results indicate that -463G > A polymorphism of the myeloperoxidase gene is associated with premature CAD in Chinese individuals, suggesting that the AA genotype is a protective factor against premature CAD.     

Transforming growth factor-beta3 gene SfaN1 polymorphism in Korean nonsyndromic cleft lip and palate patients

The nonsyndromic cleft lip and palate (NSCL/P) is a congenital deformity of multifactorial origin with a relatively high incidence in the oriental population. Various etiologic candidate genes have been reported with conflicting results, according to race and analysis methods. Recently, the ablation of the TGF-beta3 gene function induced cleft palates in experimental animals. Also, polymorphisms in the TGF-beta3 gene have been studied in different races; however, they have not been studied in Koreans. A novel A --> G single nucleotide polymorphism (defined by the endonuclease SfaN1) was identified in intron 5 of TGF-beta3 (IVS5+104 A > G). It resulted in different genotypes, AA, AG, and GG. The objective of this study was to investigate the relationship between the SfaN1 polymorphism in TGF-beta3 and the risk of NSCL/P in the Korean population. The population of this study consisted of 28 NSCL/P patients and 41 healthy controls. The distribution of the SfaN1 genotypes was different between the cases and controls. The frequency of the G allele was significantly associated with the increased risk of NSCL/P [odds ratio (OR) = 15.92, 95% confidence interval (CI) = 6.3-41.0]. The risk for the disease increased as the G allele numbers increased (GA genotype: OR = 2.11, 95% CI = 0.38-11.68; GG genotype: OR = 110.2, 95% CI = 10.67 - 2783.29) in NSCL/P. A stratified study in patients revealed that the SfaN1 site IVS5+104A > G substitution was strongly associated with an increased risk of NSCL/P in males (p < 0.001), but not in females. In conclusion, the polymorphism of the SfaN1 site in TGF-beta3 was significantly different between the NSCL/P patients and the control. This may be a good screening marker for NSCL/P patients among Koreans.     

Fibroblast growth factor receptor 4 polymorphisms and the prognosis of non-Hodgkin lymphoma

Fibroblast growth factors and their receptors (FGFRs) play important roles in blood system. FGFR4 rs351855 (Gly388Arg) polymorphism has shown to be a risk factor for many diseases. The aim of this study was to investigate the association between FGFR4 polymorphisms and the susceptibility to non-Hodgkin lymphoma (NHL) in the Chinese population. We identified two polymorphisms in the FGFR4 gene, rs351855G/A (Gly388Arg), and rs147603016G/A, by polymerase chain reaction-restriction fragment length polymorphism in 412 NHL cases and 476 healthy controls. Results showed that frequencies of AA genotype and A allele in rs351855 (Gly388Arg) polymorphism were significantly higher in patients than in controls (odds ratio (OR) 2.12, 95 % confidence intervals (CI) 1.99–3.48, P < 0.0001; OR 1.45, 95 % CI 1.21–1.88, P < 0.0001, respectively; data were adjusted for age and sex). The rs147603016G/A polymorphism did not show any correlation with NHL. When analyzing the survival time of NHL patients with FGFR4 rs351855G/A polymorphism, cases with AA genotype had significantly shorter survival time compared to the patients with GG and GA genotypes (P = 0.002). These results suggested polymorphism in FGFR4 gene was associated with increased susceptibility to NHL and could be used as a prognostic marker for this malignancy.     

Cyclin D1 G870A polymorphism and breast cancer risk: a meta-analysis comprising 9,911 cases and 11,171 controls

Cyclin D1 represents a key molecule in the regulation of cell cycle. CCND1 G870A (rs603965) polymorphism has drawn considerable attention as the A allele may generate a variant splice product with possible oncogenic actions. A meta-analysis examining the association between CCND1 G870A polymorphism and breast cancer risk was performed. Separate analyses on Caucasian and Chinese populations were also implemented. Eligible articles were identified for the period up to July 2010. Pooled odds ratios (OR) were appropriately derived from fixed-effects or random-effects models. Sensitivity analysis excluding studies whose genotype frequencies in controls significantly deviated from Hardy–Weinberg Equilibrium (HWE) was performed. Nine case–control studies on Caucasians (7,304 cases and 8,149 controls) and four case–control studies on Chinese (2,607 cases and 3,022 controls) were eligible. At the overall analysis the A allele seemed to be associated with elevated breast cancer risk; the effect seemed to be confined to homozygous carriers (pooled OR = 1.091, 95% CI: 1.008–1.179, P = 0.030, fixed effects) as heterozygous carriers did not exhibit significantly elevated breast cancer risk. No statistically significant associations were demonstrated in Caucasians. On the other hand, Chinese AA carriers exhibited marginally elevated breast cancer risk (pooled OR = 1.144, 95% CI: 0.984–1.329, P = 0.080, fixed effects). Nevertheless, the controls in two out of the four Chinese studies deviated from HWE. In conclusion, this meta-analysis suggests that the A allele of the CCND1 G870A polymorphism may confer additional breast cancer risk when it comes to homozygosity and Chinese populations. The need for additional, methodologically sound studies on Chinese populations seems warranted.     

Is paraoxonase 192 gene polymorphism a risk factor for membranoproliferative glomerulonephritis in children?

We investigated the effects of paraoxonase (PON1) 192 polymorphism on serum PON1 activity and the impact of phenotypic expression on the risk and prognosis of Turkish children with membranoproliferative glomerulonephritis (MPGN). Eighteen children with biopsy-proven Type I MPGN (10 boys, 8 girls) and age-matched 53 healthy controls were included in the study. PCR (polymerase chain reaction), RFLP (restriction fragment length polymorphism) and agarose gel electrophoresis techniques were used to determine the PON1 192 genotype. PON1 activity was measured by spectrophotometric assay of p-nitrophenol production following addition of paraoxon. We found that PON1 192 genotype distribution (AA, AB, BB) in MPGN patients were 61.1%, 22.3%, 16.6% and 15.1%, 35.8%, 49.1% in controls, respectively. The frequency of AA genotypes was significantly higher in the MPGN group (0.611) compared with the healthy controls (0.151) (p < 0.001). Although the serum PON1 activity was lower in MPGN patients (103.3 +/- 55.2 U/l) than the healthy controls (130.9 +/- 71.2 U/mol), the difference was not statistically significant (p = 0.0563). In the genotypes of patients and controls classified according to PON1 A/B polymorphism; serum PON1 activities were significantly increased (p < 0.001, ANOVA) in the order of PON1 AA, AB and BB in both MPGN patients (82.4, 91.7 and 173.6 U/l) and healthy controls (85.9, 119.9 and 193.1 U/l), respectively. There was a significant relationship between the poor prognosis and having AA genotype and low PON1 activity. Of the 8 patients with poor prognosis, 7 had genotype AA and the remaining one was AB heterozygote. Our results suggest that homozygosity for the A allele might have an important role on the risk for developing MPGN and may also be associated with the poor prognosis of disease. In conclusion, we suggest that the PON1 activities are affected by PON1 genetic variability in Turkish patients with MPGN.     

Association of leptin genetic polymorphism -2548 G/A with gestational diabetes mellitus

The aim of this study was to investigate possible associations of -2548 G/A polymorphism in leptin gene promoter and pregnancy-associated diseases with abnormal fetal growth such as preeclampsia and gestational diabetes. The study was also focused on whether it is rather maternal or fetal variants that determines the pathological growth status. Peripheral or cord blood samples obtained from 49 preeclamptic women and their 39 newborns, 53 healthy controls and their 53 healthy newborns and 48 patients with gestational diabetes mellitus were evaluated for leptin gene (LEP) locus -2548 genotypes. The significantly higher risk for gestational diabetes mellitus was observed in the presence of an allele (AA and AG genotypes) against carriers of GGgenotype(OR=2.84, 95%CI1.14-7.07,p=0.02). Thereisa significant risk of diabetes mellitus associated to A allele (OR=1.79, 95%CI 1.02-3.14, p=0.03). Furthermore, evaluations of preeclamptic patients' data revealed a significant association of genotype distribution and delivery and spontaneous abortion rate, where the GG carriers performed the highest pregnancy rate while the AG carriers performed the lowest spontaneous abortion rate. Our results support the hypothesis for -2548 G/A leptin gene polymorphism involvement in ethiopathogenesis of pregnancy-associated diseases with abnormal fetal growth, especially gestational diabetes mellitus.     

Cytotoxic T-lymphocyte antigen-4 +49G/A polymorphism and susceptibility to pancreatic cancer

Although pancreatic cancer has been extensively studied, few risk factors have been identified. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays important roles in downregulating T-cell activation, thereby attenuating antitumor responses and increasing cancer susceptibility. The CTLA-4 gene +49G/A polymorphism (rs231775) has been reported to be associated with various cancers. The current study evaluated the association of the CTLA-4 gene +49G/A polymorphism with pancreatic cancer in the Chinese population. Six hundred and two pancreatic cancer patients and 651 healthy controls were investigated for CTLA-4 +49G/A polymorphism by polymerase chain reaction-restriction fragment length polymorphism analysis. Data showed that prevalence of CTLA-4 gene +49 AA genotype and +49 A allele was significantly higher in pancreatic patients compared to controls (odds ratio [OR]=2.20, 95% confidence interval [CI]: 1.23-2.95, p=0.007; OR=1.32, 95% CI: 1.03-1.69, p=0.029; and OR=1.47, 95% CI: 1.03-2.09, p=0.033). These results indicate that the CTLA-4 +49G/A polymorphism is associated with increased risk of pancreatic cancer.     

Investigation of CTLA‐4 and CD86 gene polymorphisms in Iranian patients with brucellosis infection

The protective immune response against Brucella involves T‐cell‐mediated immunity. T‐lymphocyte receptors, CD28 and cytotoxic T‐lymphocyte‐associated protein‐4 (CTLA‐4), bind the same ligands, CD80 (B7‐1) and CD86 (B7‐2) on antigen‐presenting cells and regulate T cell activation. CD28 delivers stimulatory signals whereas CTLA‐4 provides inhibitory signals for T cell activation. Here, we investigated the association of four polymorphisms in CTLA4 (+49A/G [rs231775] and ?318 C/T [rs5742909]) and its ligand CD86 (+1057 G/A [rs1129055] and +2379G/C [rs17281995]) with brucellosis infection. The study included 153 Iranian patients with active brucellosis and 128 healthy individuals as the control group. Genotyping of the CTLA4 and CD86 variants was performed using tetra amplification refractory mutation system‐polymerase chain reaction (T‐ARMS‐PCR) and PCR–restriction fragment length polymorphism analysis, respectively. It was found that the CTLA4 ?318 CT genotype and T allele were present more frequently in cases than in controls and are therefore associated with an increased risk for brucellosis (?318 TT genotype; OR = 2.544, P = 0.002). Likewise, the CD86 +1057 GA and AA genotypes and A allele were associated with an increased risk of brucellosis (+1057 AA genotype; OR = 3.81, P = 0.001). However, no statistically significant difference between brucellosis patients and controls in the allele and genotype distributions of CTLA4, +49A/G (P = 0.859) and CD86, +2379G/C (P = 0.476) was found. In conclusion, CTLA4 ?318 CT genotype and T allele and the CD86 +057 GA and AA genotypes and A allele play roles as risk factors for developing brucellosis infection in Iran.

     

CD86 +1057G/A polymorphism and susceptibility to Ewing's sarcoma: a case-control study

The development of Ewing's sarcoma (ES) is a complex process resulting from interplay between mutations in oncogenes and tumor suppressors, host susceptibility factors, and cellular context. CD86 (B7-2) may affect cancer susceptibility by modulating T cell response. CD86 +1057G/A polymorphism (rs1129055) has been reported to be associated with various diseases. Here, we investigated the association between CD86 +1057G/A polymorphism and the risk of ES in a Chinese population. The CD86 +1057G/A polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in 158 ES cases and 212 age-matched healthy controls. Frequencies of CD86 +1057 AA genotype and +1057 A allele were significantly increased in patients with ES compared to healthy controls (odds ratio [OR]=2.12, 95% confidence interval [CI], 1.11-3.79, p=0.021; and OR=1.41, 95% CI, 1.10-1.91, p=0.018). Our data suggest that the +1057G/A polymorphism of the CD86 gene is associated with increased susceptibility to ES.     

Glutathione S-transferase M1, T1, and P1 genotypes and breast cancer risk: a study in a Portuguese population

Glutathione S-transferases are a superfamily of multifunctional enzymes that play a key role in Phase II metabolism, detoxifying therapeutic drugs, and various carcinogens by conjugation with glutathione. We undertook a case-control study in Central-Eastern Portuguese population to evaluate the association of null genotype in GSTM1 and GSTT1 along with the polymorphism in GSTP1 (A/G) and susceptibility to breast cancer. The population sample consisted of 85 patients with histological diagnosis of breast cancer and 102 healthy women. Genomic DNA was extracted from blood samples, and genotyping analyses were performed by PCR-based methods. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by unconditional logistic regression. We found a increased breast cancer risk associated with GSTM1 null genotype (OR = 3.597; 95% CI = 1.849-6.999; P = 0.0001) and GSTT1 (OR = 2.592; 95% CI = 1.432-4.690; P = 0.002), but the presence of valine alleles compared to isoleucine alleles in codon 105 in GSTP1 did not increase the risk of breast cancer development. The two-way combination of GSTM1 and GTTT1 null genotypes resulted in 8-fold increase for breast cancer risk (OR = 8.287; 95% CI = 3.124-21.980; P = 0.0001) and the three-way combination of GSTP1 105AA/AG and null genotypes for both GSTM1 and GSTT1 resulted in 5-fold increase for breast cancer risk (OR = 5.040; 95% CI = 1.392-18.248; P = 0.016). Our results suggest that GSTM1 and GSTT1 null genotype alone, both combined or combined with GSTP1 valine alleles, are associated with higher susceptibility to breast cancer development.     

Association of polymorphisms in MCP-1, CCR2, and CCR5 genes with the risk and clinicopathological characteristics of prostate cancer

The aim of our study was to determine the effect of monocyte chemotactic protein-1 (MCP-1), CC chemokine receptor 2 (CCR2), and CC chemokine receptor 5 (CCR5) gene polymorphisms on the susceptibility and clinicopathological characteristics of prostate cancer. Genotyping was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method in 156 histopathologically confirmed prostate cancer patients and 152 healthy subjects. Individuals with AA genotype or at least one A allele of CCR2 V64I gene polymorphism had a higher risk for prostate cancer as compared with those with GG genotype (p=0.010 and p=0.028, respectively). CCR5 Δ32/wt genotype and CCR5 Δ32 allele were also found to be involved in the susceptibility to prostate cancer (p=0.028 and p=0.030, respectively). However, there was no significant association between MCP-1-2518 A/G gene polymorphism and prostate cancer risk. Prostate cancer patients carrying AA genotype or at least one A allele of CCR2 V64I had significantly increased risk for high stage disease (p=0.002 and p=0.039, respectively) and metastasis (p=0.004 and p=0.022, respectively). The CCR2 A allele (64I allele) was significantly associated with high T stage (p=0.001) and metastasis (p=0.005) as compared with CCR2 G allele (64V allele). Our data indicate that gene polymorphism of CCR2 V64I may influence the susceptibility and clinicopathological characteristics of prostate cancer and CCR5 Δ32 allele may also be an important risk factor for prostate cancer in Turkish men population.     

The association of monocyte chemotactic protein-1 and CC chemokine receptor 2 gene variants with chronic obstructive pulmonary disease

Chemokines are potent proinflammatory cytokines that are implicated in numerous inflammatory diseases. Monocyte chemoattractant protein-1 (MCP-1) and its receptor CC chemokine receptor-2 (CCR2) play a major role in the recruitment of inflammatory cells to the lungs of patients with chronic obstructive pulmonary disease (COPD). We investigated a possible association between polymorphisms in MCP-1 and CCR2 genes (MCP-1 -2518 A/G and CCR2 190G/A or V64I) and the development of COPD. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism in 386 COPD cases and 398 age-matched healthy controls. Frequency of MCP-1 2518GG genotype for cases and controls was 0.396 and 0.324, respectively; individuals who had the GG genotype had a 1.59-fold increased risk of COPD (p=0.036). Frequency of CCR2 190AA (64I/64I) genotype for cases and controls was 0.285 and 0.21, respectively; subjects carrying the 64I/64I genotype had a 2.04-fold increased risk of COPD compared with the wild-type genotype (p=0.001). When analyzing the allele combination of these two polymorphisms, the combinations MCP-1-A/CCR2-A and MCP-1-G/CCR2-A were detected in significantly higher numbers in COPD cases than in healthy controls (odds ratio [OR]=1.50, 95% confidence interval [CI]: 1.04-2.17, p=0.032; and OR=1.89, 95% CI: 1.38-2.60, p=7.38×10(-5)). These data suggest that MCP-1 -2518 A/G and CCR2 190G/A polymorphisms are new risk factors for COPD.