Shan Kang

Association of polymorphisms −1154G/A and −2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women

BACKGROUND Vascular endothelial growth factor (VEGF) plays an important role in the development of endometriosis. The aim of this study was to investigate the association of polymorphisms in the VEGF gene with the susceptibility to endometriosis. METHODS This study comprised 344 North Chinese women with endometriosis and 360 healthy women without endometriosis recruited as control. Genotyping of the VEGF gene polymorphisms at -460C/T, -1154G/A, -2578C/A and +936C/T were performed by PCR and restriction fragment length polymorphism analysis. RESULTS No significant difference was found in allele and genotype distributions of the -460C/T, +936C/T polymorphisms between patients and controls. However, the frequencies of -1154G/A, -2578C/A genotype and allele were significantly different between the two groups (all P-value <0.013). The -2578A/A, -1154A/A genotypes were found less frequently in patients with endometriosis compared with controls. The haplotype distributions derived from three polymorphisms (-2578C/A, -1154G/A, -460C/T) differed between the two groups (P = 0.000). CONCLUSIONS The VEGF-460/-1154/-2578 TGC, CAA, TAA and TAC haplotypes were associated with endometriosis. The -1154A and -2578A alleles may be protective against the development of endometriosis in North Chinese women.

Association between genetic polymorphisms in fibroblast growth factor (FGF)1 and FGF2 and risk of endometriosis and adenomyosis in Chinese women

BACKGROUND Angiogenesis appears to be an important event in the pathophysiology of endometriosis (EM) and adenomyosis. Two angiogenic factors, fibroblast growth factor (FGF) 1 and 2, play a central role in the initiation of angiogenesis. We investigated whether FGF1 -1385A/G and FGF2 754C/G polymorphisms are associated with a risk of developing EM and adenomyosis. METHODS Genotypes were analyzed by the PCR-restriction fragment length polymorphism method in two groups of women, of Han ethnicity in north China, aged 16-55 years: (1) 421 EM patients and 421 controls; (2) 269 adenomyosis patients and 269 controls. RESULTS There was no difference in genotype distribution of the FGF1 -1385A/G polymorphism between adenomyosis cases and controls (P > 0.05), but the frequency of the A allele in EM patients was lower than that in controls (P = 0.013). Genotype and allele frequencies of the FGF2 754C/C polymorphism were significantly different in both EM and adenomyosis cases versus control groups. Compared with C/C homozygotes, the G allele (C/G + G/G) was associated with a decreased susceptibility to developing EM [odds ratio (OR) = 0.575, 95% confidence interval (CI) = 0.387-0.854] and adenomyosis (OR = 0.577, 95% CI = 0.367-0.906). Combined genotype analysis of both polymorphisms also showed differences between cases versus controls (all P < 0.001). CONCLUSIONS Our study shows for the first time that the FGF2 754C/G polymorphism may be associated with a risk of developing EM and adenomyosis in north Chinese women. Carriers of the G allele in the FGF2 gene appear to be protected from these gynecological diseases. Further studies in other populations, and of other candidate genes, are now warranted.

Association of p73 and MDM2 polymorphisms with the risk of epithelial ovarian cancer in Chinese women.

Objective: This study was to investigate the association of p73 G4C14-to-A4T14 and Murine Double Minute2 (MDM2) 309T/G, Del1518+/− single nucleotide polymorphisms with the risk of epithelial ovarian cancer (EOC) in Chinese. Materials and Methods: This hospital-based case-control study included 257 ovarian cancer patients and 257 healthy women who were matched for age. p73 and MDM2 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. Results: There were no significant differences in allele frequencies and genotype distributions of the p73 G4C14-to-A4T14 polymorphism between cases and control women (P = 0.55 and 0.20, respectively). The frequencies of the G allele of the MDM2 309T/G polymorphism were significantly lower in ovarian cancer cases (46.7%) than those in healthy controls (54.7%), there was a statistical difference between the 2 groups (P = 0.01). Compared with the T/T genotype, the G allelotype (T/G+G/G genotype) significantly decreased the risk of developing EOC (odds ratio, 0.65; 95% confidence interval, 0.44-0.97). Although MDM2 Del1518+/− genotypes and allele frequencies did not differ between the case and the control groups (P = 0.68 and P = 0.45), Del1518 +/+ genotype tended to increase the risk of mucinous ovarian cancer or earlier ovarian cancer by stratification analysis according to histological subtypes or clinical stage. Besides, there was a significant interaction between p73 G4C14-to-A4T14 and MDM2 309T/G polymorphisms by the likelihood ratio test (P = 0.03; odds ratio, 0.89; 95% confidence interval, 0.80-0.99). Conclusion: The MDM2 SNP309G allele significantly decreased the risk of EOC and might be a potentially protective factor for EOC development in Chinese women.

Vascular endothelial growth factor gene polymorphisms are associated with the risk of developing adenomyosis

Vascular endothelial growth factor (VEGF), a major mediator of angiogenesis and vascular permeability, may play a key role in the development of adenomyosis. The aim of this study was to investigate whether these four VEGF polymorphisms (−2578C/A, −1154G/A, −460C/T, and +936C/T) were associated with the risk of adenomyosis development. Genotypes were determined by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) assay in 174 adenomyosis patients and 199 frequency‐matched control women. There were significant differences between patients and control group in allele frequencies and genotype distributions of the −2578C/A polymorphisms (P = 0.010 and 0.044, respectively). Compared with the C/C genotype, the A/A + C/A genotype could significantly modify the risk of developing adenomyosis [odds ratio (OR) = 0.64, 95% confidence interval (CI) = 0.42–0.97]. For the −1154G/A polymorphism, the allele frequencies and genotype distributions in patient group were significant different from those of the controls (P = 0.001 and 0.007, respectively). Compared with the G/G genotype, the A/A + G/A genotype could significantly decrease the risk of developing adenomyosis (OR = 0.51, 95% CI = 0.33–0.80). However, the genotype distributions and allele frequencies of the −460C/T and +936C/T polymorphisms did not significantly differ between controls and patients (all P value > 0.05). The haplotype analysis suggested that the TGA (VEGF −460/−1154/−2578) and CGA haplotypes exhibited a significant decrease in the risk of developing adenomyosis compared with the haplotype of TGC (OR = 0.64, 95% CI = 0.41–1.00; OR = 0.44, 95% CI = 0.21–0.93, respectively). The study indicated that the −2578A or −1154A allele of VEGF gene could significantly decrease the risk of adenomyosis and might be potentially protective factors for adenomyosis development. Environ. Mol. Mutagen., 2009.

The functional polymorphisms on promoter region of matrix metalloproteinase-12, -13 genes may alter the risk of epithelial ovarian carcinoma in Chinese.

Backgrounds and Aims: Growing evidences indicate that single nucleotide polymorphisms (SNPs) of matrix metalloproteinases (MMPs) gene promoter may alter MMPs protein expression levels to influence malignant tumors developing and progressing. Our study was to assess the effects of the SNPs in the promoter region of MMP-12 and MMP-13 on the risk of epithelial ovarian carcinoma (EOC) developing and progressing. Methods: MMP-12 A-82G and MMP-13 A-77G SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism in 256 EOC patients and 329 controls. Results: The A/G genotype frequency of MMP-12 was significantly higher in patients than in controls (7.0% vs 3.3%, P = 0.04); similarly, the frequency of MMP-12 82G allele was higher in patients too (P = 0.04). Compared with A/A genotype, A/G genotype significantly increased the risk of EOC (odds ratio, 2.19; 95% confidence interval, 1.01-4.72). Age-stratified analysis showed that individuals with A/G genotype had a higher risk in the final diagnosis aged younger than 50 years. We observed no overall association between MMP-13-77A/G polymorphism and EOC. However, an elevated positive association was observed for A/A versus G/G + A/G genotypes in mucinous ovarian cancer. Combining the analyzed 2 SNPs, the haplotype distributions in patients were not significantly different from that in controls. Conclusion: These results suggested that the G allele of the MMP-12 82A/G polymorphism might be a risk factor for the development and progression of EOC and that the A/A genotype of MMP-13-77A/G polymorphism was associated with special pathological subtype and clinical stage in EOC at least in Chinese women.

Association of polymorphisms of the MMP-2 and TIMP-2 genes with the risk of endometriosis in North Chinese women

We investigated whether three polymorphisms in the matrix metalloproteinase-2 (MMP-2; -1306C-->T and -735C-->T) and tissue inhibitor of metalloproteinase-2 (TIMP-2; -418G-->C) genes were related to the risk of endometriosis in reproductive-aged women with and without endometriosis. Our results indicate that the TIMP-2 -418C/C homozygote may be a protective factor against the development of endometriosis in North Chinese women.

Polymorphisms in the Matrix Metalloproteinase-2 and Tissue Inhibitor of Metalloproteinase-2 and the Risk of Human Adenomyosis

The matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) may contribute to the development of adenomyosis. The aim of the present study was to investigate whether three single nucleotide polymorphisms (SNPs) in the promoter regions of MMP‐2 (−1306C/T and −735C/T) and TIMP‐2 (‐418G/C) genes were related to the risk of adenomyosis development. Genotypes were determined by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) assay in 180 adenomyosis patients and 324 frequency‐matched control women in a Chinese population. There were significant differences in allele frequencies and genotype distributions of the MMP‐2 −1306C/T polymorphism between patients and control women (P = 0.01 and 0.04, respectively). The frequency of C allele in patients (92.2%) was significantly higher than in the controls (87.0%) (P = 0.01). Compared with the C/T+T/T genotypes, the C/C genotype could significantly increase the risk of adenomyosis development, with an odds ratio of 1.83 (95% CI = 1.13–2.96). However, no statistically significant difference was found in allele frequencies and genotype distributions of MMP‐2 −735C/T and TIMP‐2 −418G/C SNPs between the two groups (all P values > 0.05). Two polymorphisms of MMP‐2 displayed linkage disequilibrium (D′ = 0.74). The haplotype analysis suggested no significant association of four haplotypes with the risk of adenomyosis development. Our results indicated an association of MMP‐2 −1306C/T polymorphism with the risk of adenomyosis, suggesting a potential role in adenomyosis development in North Chinese women. Environ. Mol. Mutagen. 2008.

Genetic polymorphisms in the Fas and FasL genes are associated with epithelial ovarian cancer risk and clinical outcomes.

AIM In this study, we evaluated whether functional polymorphisms within the Fas and FasL genes were associated with the risk of developing epithelial ovarian cancer (EOC) and survival of patients with EOC. METHODS A case-control study was performed in 342 EOC patients and 344 control women. The genotypes of three promoter region polymorphisms (Fas -1377G/A, -670A/G and FasL -844T/C) were determined using ligase detection reaction-polymerase chain reaction (LDR-PCR). The clinical outcomes in 202 EOC patients were compared across genotypes. RESULTS The genotype frequencies of the FasL -844 T/C polymorphism were significantly different between the case and control groups (P=0.034). Compared to the T/T and T/C genotypes, the C/C genotype significantly increased the risk of developing EOC (OR=1.46, 95% CI=1.08-1.99). The survival analysis showed that the Fas -1377G/A and -670A/G polymorphisms were related to prognosis in EOC patients. Compared with patients with the G/G genotype of the -1377G/A polymorphism, patients carrying the A allele had a shorter PFS and OS, as determined by univariate and multivariate analysis (HR=1.81, 95% CI=1.26-2.62 and HR=1.86, 95% CI=1.15-3.00, respectively). Similarly, Kaplan-Meier and Cox proportional hazard model analyses indicated that patients carrying the G allele of Fas -670A/G polymorphisms had shorter PFS and OS than those carrying the AA genotype (HR=1.67, 95% CI=1.15-2.42 and HR=1.80, 95% CI=1.10-2.94, respectively). CONCLUSIONS Functional polymorphisms in the Fas and FasL genes may be involved in epithelial ovarian cancer development and progression in northern Chinese women.

DNA Repair Gene Associated with Clinical Outcome of Epithelial Ovarian Cancer Treated with Platinum-based Chemotherapy

OBJECTIVE The nucleotide excision repair (NER) and base excision repair (BER) pathways, two DNA repair pathways, are related to platinum resistance in cancer treatment. In this paper, we studied the association between single nucleotide polymorphisms (SNPs) of involved genes and response to platinum-based chemotherapy in epithelial ovarian cancer. METHOD Eight SNPs in XRCC1 (BER), XPC and XPD (NER) were assessed in 213 patients with epithelial ovarian cancer using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) techniques. RESULTS The median progression-free survival (PFS) of patients carrying the Lys/Lys and Lys/Gln+Gln/Gln genotype of the XPC Lys/Gln polymorphism were 25 and 12 months, respectively (P=0.039); and the mean overall survival (OS) of patients was 31.1 and 27.8 months, respectively (P=0.048). Coxs multivariate analysis suggested that patients with epithelial ovarian cancer with the Gln allele had an increased risk of death (HR=1.75; 95% CI=1.06-2.91) compared to those with the Lys/Lys genotype. There are no associations between the XPC PAT+/-, XRCC1 Arg194Trp, Arg280His, Arg399Gln, and XPD Asp312Asn, Lys751Gln polymorphisms and the survival of patients with epithelial ovarian cancer when treated with platinum-based chemotherapy. CONCLUSION Our results indicated that the XPC Lys939Gln polymorphism may correlate with clinical outcome of patients with epithelial ovarian cancer when treated with platinum-based chemotherapy in Northern China.

Association between Genetic Variants of the VEGFR-2 Gene and the Risk of Developing Endometriosis in Northern Chinese Women

Aim: To investigate the association of tag single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor receptor 2 (VEGFR-2) gene with susceptibility to endometriosis. Methods: This study comprised 571 patients with endometriosis and 580 women in the control group. Five tag SNPs in the VEGFR-2 gene were selected using a Haploview program, and those SNPs were genotyped by a method of polymerase chain reaction and ligase detection reaction. Results: Statistical results show that there was a significant difference in the genotype and allele distribution of the 1192C/T polymorphism between the disease group and the control group (p = 0.041 and 0.017). The women carrying the T allele (C/T+T/T genotype) had a lower risk of developing endometriosis compared with the women with the C/C genotype (OR 0.75, 95% CI 0.57-0.99). There was no significant difference in the allele and genotype distribution of four other tag SNPs (1719T/A, +31C/T, IVS25-92A/G and IVS6+54C/T) between the disease group and the control group (all p > 0.05). Conclusions: Our results suggested that the 1192C/T polymorphisms on the VEGFR-2 gene might affect the risk of developing endometriosis in Northern Chinese women of Han ethnicity.