Predicting hepatocellular carcinoma development for cirrhosis patients via methylation detection of heparocarcinogenesis-related genes.

Background: Most hepatocellular carcinoma (HCC) patients have undergone a progression from chronic hepatitis, then liver cirrhosis (LC), and finally to carcinoma. The objective of this study was to elucidate risk factors to predict HCC development for cirrhosis patients. Methods: Multiple methylated specific PCR (MSP) was applied to determine methylation status of heparocarcinogenesis-related genes in 396 tissue and plasma specimens and multivariate cox model was used to analyze the relationship between risk variables and HCC development among cirrhosis patients, followed up in a median period of 30 months. Results: Among 105 LC cases, HCC incidence rate at 30 months was 30.48% (32/105), which were statistically associated with patients' age and aberrant methylation of p16, SFRP, and LINE1 (p<0.05). Receiver operating characteristic (ROC) curve showed the overall predictive accuracy reached the highest (90.7%) if the four risk variables were concurrent to predict HCC development. Moreover, along with the growth of age from 0-40, 40-55, to 55-70 years or the increased number of aberrantly-methylated gene from 0-1 to 2-3, the HCC incidence rate of cirrhosis patients rised from 10.00%, 12.28% to 82.14% and 17.44% to 89.47%, separately. Thus, based on combined analysis with diverse age and number of aberrantly-methylated gene, 105 cases were divided into five groups and computed their respective HCC incidecne rate to categorize them into different risk groups. Of note, A significant lifting of HCC incidence rate in the high-risk group (40-55 years coupled with 2-3 aberrantly-methylated genes, 55-70 years coupled with 0-1 aberrantly-methylated gene, 55-70 years coupled with 2-3 aberrantly-methylated genes; n=33) was observed compared with the low-risk group (0-40 years coupled with 0-1 aberrantly-methylated gene, 40-55 years coupled with 0-1 aberrantly-methylated gene; (n=72) (p<0.01). Conclusions: Ultimately, high-risk cirrhosis patients with 55-over years or 2-3 aberrantly-methylated genes should be paid more attention to be regularly screened with HCC development.

Application of multiplex methylated-specific PCR with capillary electrophoresis to explore prognostic value of TSGs hypermethylation for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor that severely threatens human health. To date, early detection for HCC patients is particularly significant due to their poor survival rates even after liver resection. METHODS: Therefore, an efficient and sensitive detection method for monitoring liver cancer, multiplex methylation-specific PCR (MSP) coupled with capillary electrophoresis, is developed. RESULTS: Simulations demonstrated that the methylation status of RASSF1A, p16, SFRP1, and ELF could be detected even when DNA equaled or exceeded 12.5 ng simultaneously. Also, its accuracy for methylation detection outweighed polyacrylamide gel electrophoresis (87.5%) and agarose electrophoresis (84.3%), reaching 92.1%. Subsequently, we implemented multiplex MSP with capillary electrophoresis to investigate methylation status of the four tumor suppressor genes in tissue specimens and explore the prognostic value for HCC patients. As the data suggested, multivariate cox regression analysis revealed that the recurrence-free survival of 46 patients was greatly associated with portal vein tumor thrombus (PVTT) and p16 methylation and receiver operating characteristic (ROC) curves demonstrated that the predictive range of portal vein tumor thrombus (PVTT) combined with p16 hypermethylation was more sensitive than that of either PVTT or p16 hypermethylation alone with regard to disease recurrence in patients with HCC, which could be testified as a valuable biomarker in Clinical application. CONCLUSION: Multiplex MSP coupled with capillary electrophoresis has an excellent prospect of clinical application for monitoring early liver cancer and screening valuable biomarkers for prognosis of HCC patients.

No association between single nucleotide polymorphisms in pre-mirnas and the risk of gastric cancer in Chinese population.

OBJECTIVE(S): Accumulating evidence has demonstrated that miRNAs contribute to various genetic and epigenetic modifications in the pathogenesis of gastric cancer (GC). Recent studies focused on the four single nucleotide polymorphisms (SNPs) of pre-miRNAs including rs11614913, rs3746444, rs2910164, and rs2292832. It was suggested that these four SNPs were significantly associated with the risk of GC and were described as candidate susceptibility factors. However, the previous results show conflicting findings. The aim of this study was to investigate whether these four SNPs are associated with GC in Chinese Han population. MATERIALS AND METHODS: Genotype frequencies of these four SNPs of pre-miRNAs in 220 GC patients and 530 control subjects were performed using a PCR-RFLP assay. RESULTS: No significant differences in genotype and allelic distribution were found in these four SNPs between GC and control subjects in the Chinese Han population. However, we found that the allelic frequency distributions of control subjects in these four SNPs were significantly different from those of the Japanese and the Koreans (All the P<0.05). CONCLUSION: The four SNPs did not show any significant correlation with the development of GC in the Chinese Han population, based on the current study.

Engrailed-2 is down-regulated but also ectopically expressed in clear cell renal cell carcinoma.

Engrailed-2 (EN2), a member of the homeobox family of genes, encodes a homeodomain-containing transcription factor that is thought to be a potential oncogene in a number of cancers. Because the role of EN2 in clear cell renal cell carcinoma (CCRCC) has not been determined, we investigated its expression in CCRCC tissues and cell lines. Using immunohistochemical (IHC) staining, we found that EN2 protein was expressed in normal renal cells and tubules, but was frequently down-regulated in tissues from patients with CCRCC and in CCRCC cell lines. In addition, we found that EN2, which functions in the nucleus, was completely localized to the cytoplasm of CCRCC cells as detected by IHC and immunofluorescence staining. Furthermore, expression of EN2 protein was negatively correlated with increasing histological grade of CCRCC tumors (P = 0.003). The exact role of EN2 expression in renal carcinoma carcinogenesis requires further investigation.

Genetic polymorphisms in Matrix Metalloproteinases -1 and -7 and susceptibility to gastric cancer: an association study and meta-analysis.

Matrix Metalloproteinases (MMPs) play an important role in gastric cancer (GC). Accumulated evidence suggests that functional MMP-1 and MMP-7 gene polymorphisms are associated with several tumors. The aim of this study was to investigate two single nucleotide polymorphisms, MMP-1 -1607 1G/2G and MMP-7 -181 A/G, and their potential relationship with GC. We examined 246 GC patients and 252 age-and sex-matched controls from Sichuan province in China. Genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism strategy and DNA sequencing. We also performed a meta-analysis of relevant studies, involving 1084 cases and 1721 controls, to place our findings in a broader context. No significant relationship was observed between the MMP-1 -1607 1G/2G alleles and genotypes and the risk of GC. There were significant differences in the genotypes and allele distributions of the -181 A/G polymorphism of the MMP-7 gene between cases and controls. The -181 A allele carriers had a significantly increased risk of GC compared with -181 G allele carriers (OR=3.051, 95% CI, 1.475-6.310, P=0.002), and the AA genotype of -181 A/G was associated with an increased risk of GC compared with the AG genotype (OR=3.189, 95% CI, 1.523-6.676, P=0.001). A meta-analysis of six studies also showed a significant risk of GC associated with MMP-7 polymorphism.

A genetic variant in the promoter region of miR-34b/c is associated with a reduced risk of colorectal cancer.

The miR-34 family members, described as potential tumor suppressors, were downregulated in colorectal cancer (CRC). Loss of miR-34 impairs TP53-mediated cell death, while overexpression of miR-34 induces apoptosis. A potentially functional polymorphism (i.e., rs4938723T/C) in the promoter region of pri-miR-34b/c was predicted to influence the GATA-X binding sites. We aimed to investigate the association between miR-34b/c rs4938723 and TP53 Arg72Pro polymorphisms and the risk of CRC. We genotyped the two polymorphisms in 347 CRC patients and 488 healthy controls using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing assay. We found that the CC genotype and C allele of the miR-34b/c rs4938723 were associated with a significantly decreased risk of CRC compared with the TT genotype and T allele (CC vs. TT: adjusted OR=0.56; 95% CI, 0.34-0.91; C vs. T: adjusted OR=0.78; 95% CI, 0.64-0.97). In combined analysis, a borderline significance was also observed in subjects carrying the rs4938723 CT/CC and TP53 GG genotypes (adjusted OR=0.66; 95% CI, 0.43-0.99). These findings indicate that the rs4938723 in the promoter region of pri-miR-34b/c was a protective factor for the development of CRC. As the significance is marginal, further replication studies are warranted to confirm these results.

Stereological analysis of age-related changes of testicular peritubular cells in men.

This work aimed to analyze quantitative changes of peritubular cells in testes of aged men. Testicular tissues were obtained from 42 aged men with advanced prostate cancer and 16 young men with biopsy, quantitatively investigated with stereological techniques with quadrate mask grid, measured the parameters volume density (V(V)), numerical density on area (N(A)), and numerical density (N(V)) with grid test points. No significant differences were found in cell ratio, peritubular cell number per tubule, diameter of seminiferous tubules between young and old men (p>0.05). Aged men had higher pathologic assignment score than that of young men, which demonstrated more severe pathologic changes (p<0.05). Peritubular cell V(V) and pachytene germ cell V(V) increased significantly in old men compared to young men (p<0.05). Sertoli cell (SC) number per tubule in two-dimensional was significantly less in aged men than that of young men, p<0.01. Peritubular cell N(A), N(V) decreased significantly in aged men compared to young one, p<0.05. It is concluded that the stereological data of peritubular cells from three-dimensional level in testes of aged men suggest a significant decrease when compared with young men, indicating age-related changes.

Association between pri-miR-218 polymorphism and risk of hepatocellular carcinoma in a Han Chinese population.

MicroRNAs are noncoding RNA molecules of 18-25 nucleotides that regulate gene expression at the post-transcriptional level. The aim of this study was to investigate whether pri-miR-218 rs11134527 A/G polymorphism influences the risk of hepatocellular carcinoma (HCC) or not. pri-miR-218 rs11134527 A/G was genotyped in 302 HCC patients and 513 control subjects using the polymerase chain reaction-restriction fragment length polymorphism assay. The AG genotype of pri-miR-218 rs11134527 A/G was associated with family history (p=0.018, odds ratio [OR]=2.96, 95% confidence interval [CI]: 1.16-7.56) and elevated serum α-fetoprotein (serum alpha-fetoprotein [AFP]) levels (≥20 ng/mL; p=0.009, OR=1.92, 95% CI: 1.17-3.14) in HCC patients. These findings suggested that the AG genotype of pri-miR-218 rs11134527 might relate to genetic predisposition and be involved in regulating the expression of AFP in Chinese HCC patients.

Null genotypes of GSTM1 and GSTT1 contribute to risk of cervical neoplasia: an evidence-based meta-analysis.

BACKGROUND AND OBJECTIVES: Glutathione S-transferases (GSTs) are multifunctional enzymes that play a key role in the detoxification of varieties of both endogenous products of oxidative stress and exogenous carcinogens. METHODS: In this meta-analysis, twenty-five studies were identified by searching PubMed, EMBASE, ISI Web of Science and CBM databases: 23 evaluated GSTM1 and 19 evaluated GSTT1. Crude odds ratios with corresponding 95% confidence intervals were used to estimate the association between GSTM1 and GSTT1 polymorphisms and risk of cervical neoplasia. Subgroup analyses were conducted by pathological history, ethnicity, source of DNA for genotyping, quality score, and matching variable. RESULTS: The null genotypes of GSTM1 and GSTT1 polymorphisms were associated with a significantly increased risk of cervical neoplasia (for GSTM1: OR = 1.40; 95%CI, 1.19-1.65; for GSTT1: OR = 1.30; 95%CI, 1.05-1.62, respectively). Subgroup analyses showed that the null genotype of GSTM1 increased the risk of cervical neoplasia in Asians, studies with DNA isolation from white blood cells and tissue samples, both high and low quality studies, and matched studies. In GSTM1-GSTT1 interaction analysis, individuals with dual null genotype were associated with a significantly increased risk of cervical neoplasia (OR = 1.72; 95%CI, 1.18-2.51). CONCLUSION: These findings indicate that GSTM1 and GSTT1 polymorphisms, particularly GSTM1-GSTT1 interaction, may play critical roles in the development of cervical neoplasia. A conservative manner should be adopted to interpret these results because of obvious heterogeneity between-study, unadjusted data, and relatively small sample size in this meta-analysis. Well designed studies with larger sample size are of great value to confirm these results.

The association between two polymorphisms in pre-miRNAs and breast cancer risk: a meta-analysis.

Emerging evidence has shown that miRNAs participate in human carcinogenesis as tumor suppressors or oncogenes. Single nucleotide polymorphism (SNP) which located in the pre-miRNA may affect the processing and then influence the expression of mature miRNA. Previous studies yielded conflicting results as to the association of two common polymorphisms in pre-miRNAs (i.e. hsa-miR-146 rs2910164 and hsa-miR-196a2 rs11614913) with breast cancer. To derive a more precise effect on the association between these polymorphisms and breast cancer risk, we conducted a meta-analysis. Through retrieving PubMed for the period up to May 2010, a total of four studies were identified with 3,007 cases and 3,718 controls for has-miR-146a rs2910164 polymorphism and with 3,287 cases and 4,298 controls for hsa-miR-196a2 rs11614913 polymorphism. We found that individuals carrying CC genotype of has-miR-196a2 rs11614913 polymorphism was associated with an increased breast cancer risk in homozygote comparison (OR = 1.30; 95% CI, 1.01-1.68), and dominant model (OR = 1.11; 95% CI, 1.01-1.23). However, no significant association between has-miR-146a rs2910164 polymorphism and breast cancer risk was observed in all comparison models tested. These findings suggest that has-miR-196a2 rs11614913 polymorphism may play crucial roles in breast cancer development.

RAD51 135G/C polymorphism and breast cancer risk: a meta-analysis from 21 studies.

Growing evidence suggests that RAD51 plays a pivotal role in the repair of DNA double-strand breaks and the maintenance of genomic stability. A single nucleotide polymorphism, 135G/C, has been identified in the 5' untranslated region of the RAD51 gene and has been shown to influence gene transcription activity. Previous studies yielded conflicting results as to the association of 135G/C polymorphism with breast cancer. We aimed to assess the effect of 135G/C of RAD51 on breast cancer susceptibility with the use of a meta-analysis. We performed a meta-analysis of 21 published case-control studies up to April 2010. We found that the CC genotype was associated with a significantly increased risk of breast cancer when compared with the GG, CG, and CG/GG genotypes. Subgroup analyses showed that individuals carrying the CC genotype were associated with an elevated tumor risk in European populations and in sporadic breast cancer. After stratified analyses according to manuscript quality, the CC genotype was associated with a significantly increased risk of breast cancer compared with the CG genotype in studies of both higher and lower quality. However, significantly elevated risk was found in studies of higher quality, but not in studies of lower quality when homozygote and a recessive comparison model were tested. This meta-analysis indicates that RAD51 135G/C polymorphism may be identified as a susceptibility locus for breast cancer.

The association between ATM D1853N polymorphism and breast cancer susceptibility: a meta-analysis.

BACKGROUND: Emerging evidence suggests that ataxia telangiectasia-mutated (ATM) is involved in numerous damage repair signaling pathways and cell-cycle checkpoints. Heterozygous carriers of ATM-mutations have an increased risk for the development of breast cancer. The purpose of this study is to evaluate the association between ATM exon39 5557G > A (D1853N, rs1801516) polymorphism and breast cancer susceptibility with the use of a meta-analysis. METHODS: By searching PubMed and Embase databases, a total of 9 epidemiological studies with 4,191 cases and 3,780 controls were identified. Crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) for ATM D1853N polymorphism and breast cancer risk were calculated using fixed- or random-effects model based on the degree of heterogeneity among studies. RESULTS: No significant association between the ATM D1853N polymorphism and breast cancer risk was observed in overall analysis (GA versus GG: OR = 1.18; 95% CI, 0.90-1.53; AA versus GG: OR = 0.77; 95% CI, 0.58-1.03; dominant model: OR = 1.16; 95% CI, 0.89-1.51; and recessive model: OR = 0.78; 95% CI, 0.59-1.04, respectively). CONCLUSION: Our results indicate that ATM D1853N polymorphism is not a risk factor for developing breast cancer.

CTLA4 and CD86 gene polymorphisms and susceptibility to chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) may be related to chronic inflammation and immune-mediated conditions, and its pathogenesis involves T-cell activation and proliferation. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and costimulatory molecules (CD80/CD86) genes are important mediators of T-cell activation in the immune response. The aim of this study was to investigate whether +2379G/C (rs17281995) and +1057G/A (rs1129055) in CD86 and -318C/T (rs5742909) and +49A/G (rs231775) in CTLA-4 genes single nucleotide polymorphisms (SNPs) are associated with COPD in a Chinese population. The four polymorphisms were identified in 396 COPD patients and 400 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The frequency of the T allele of the -318C/T in CTLA-4 and the A allele of the +1057G/A in CD86 polymorphisms showed significant association with COPD when compared with controls (T allele: p < 0.0001; A allele: p = 0.009). Comparison of genotype frequencies showed that -318CT, +1057GA, and +1057AA genotype was overrepresented in the COPD group, respectively (-318CT: 50.8% vs 28.5%, p < 0.0001; +1057GA: 58.6% vs 54.2%, p = 0.002; +1057AA: 30.1% vs 25.8%, p = 0.002). However, we failed to find any association between the four SNPs and COPD when cases were classified by smoking status or clinical stages (p > 0.05). The results indicate that the polymorphisms of CTLA-4 (-318C/T) and CD86 (+1057G/A) may be important genetic factor associated with risk or protection for COPD in Chinese population.

Association of matrix metalloproteinases 1, 7, and 9 gene polymorphisms with genetic susceptibility to colorectal carcinoma in a Han Chinese population.

Matrix metalloproteinases (MMPs) play an important role in colorectal cancer (CRC). Accumulated evidence suggests an association between MMP-1, MMP-7, and MMP-9 functional gene polymorphisms with several tumors. The aim of this study was to investigate the association of single-nucleotide polymorphism (SNP) at MMP-1 16071G/2G, MMP-7 181A/G, and MMP-9 279R/Q genes with CRC in the southwest Chinese Han population. The study used 237 CRC patients and 252 normal control matched by age and sex from Sichuan province in China. Samples were genotyped using both polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. We found significant differences in the genotype and allele frequency of MMP-9 279 R/Q between the case and control group. Individuals who carried MMP-9 279 R allele were more susceptible to CRC (odds ratio = 1.737, 95% confidence interval = 1.323-2.281, p < 0.001). Moreover, the RR genotype of MMP-9 279 R/Q was associated with an increased risk of CRC compared with the QQ genotype (odds ratio = 2.213, 95% confidence interval = 1.248-3.926, p = 0.006). However, there were no significant differences in the genotype and allele frequency of the MMP-1 16071G/2G and MMP-7 181 A/G between the case and control group, and the latter may be due to lower minor allele frequency. The MMP-9 279R/Q alleles and genotypes may be associated with the risk of CRC in Han Chinese.

Association of tumor necrosis factor gene polymorphisms with susceptibility to dilated cardiomyopathy in a Han Chinese population.

Tumor necrosis factor (TNF) is an immunomodulatory cytokine that plays an important role in many inflammatory and autoimmune diseases. We investigated the correlation between single-nucleotide polymorphisms of the TNF gene [i.e., TNF-α (308), TNF-α (857), TNF-α (863), TNF-α (1031), and TNF-ß (+252)] and dilated cardiomyopathy (DCM). A total of 110 DCM patients and 110 control subjects were genotyped using polymerase chain reaction-restriction fragment length polymorphism and DNA-sequencing assay. GA=AA genotypes of TNF-α (308) were significantly associated with increased risk of DCM compared with GG genotype (odds ratio[OR]=1.92; 95% confidence intervals [CI], 1.05-3.52). Similarly, GA=AA of TNF-ß (+252) was significantly associated with increased risk of DCM compared with GG genotype (OR=1.97; 95% CI, 1.14-3.38). Additionally, A allele of TNF-α (-308) and TNF-ß (+252) was associated with a 1.76-fold increased risk of DCM compared with G allele (OR=1.76; 95% CI, 1.05-2.95 and OR=1.79; 95% CI, 1.22-2.63, respectively). However,no association between DCM and TNF-α (857), TNF-α (1031), and TNF-α (863) was observed. TNF gene polymorphisms may be associated with risk of DCM.

IL-8 -251A/T polymorphism is associated with decreased cancer risk among population-based studies: evidence from a meta-analysis.

Growing evidence suggests that interleukin-8 (IL-8) play pivotal roles in the pathogenesis of cancer through the modulation of tumour immune response or enhanced angiogenesis. A single nucleotide polymorphism, -251A/T, has been identified in the promoter region of the IL-8 gene and has been shown to influence its production. Results from previous studies on the association of -251A/T polymorphism with different cancer types remained contradictory. To assess the effect of -251A/T of IL-8 on cancer susceptibility, we conducted a meta-analysis, up to May 2009, of 14,876 cases with different cancer types and 18,465 controls from 45 published case-control studies. Summary odds ratios and corresponding 95% confidence intervals (CIs) for IL-8 polymorphism and cancer were estimated using fixed- and random-effects models when appropriate. The AA/AT genotypes were associated with a significantly increased risk of nasopharyngeal carcinoma when compared with TT genotype (OR=1.48; 95% CI, 1.16-1.89). Moreover, significantly elevated risks were observed in 'other cancers', and also in African population when population is concerned. Interestingly, when stratified separately by population-based studies and hospital-based studies, significantly elevated risk was found among hospital-based studies (OR=1.21, 95% CI, 1.07-1.37), whereas significantly decreased risk was found among population-based studies (OR=0.90, 95% CI, 0.83-0.97). This meta-analysis shows that IL-8 -251A/T polymorphism may play a complex role in cancer development.

CD86 +1057 G/A polymorphism and the risk of colorectal cancer.

CD86 (B7-2), one of the costimulatory molecules on antigen-presenting cells, plays essential roles not only in autoimmunity and transplantation but also in tumor immunity. The purpose of this study was to investigate whether CD86 gene polymorphism was involved in predisposing an individual to colorectal cancer (CRC). The CD86 +1057 G/A polymorphism was genotyped by performing polymerase chain reaction-restriction fragment length polymorphism in 273 patients with CRC and 292 healthy controls. There were significant differences in the genotype and allele distribution of +1057 G/A polymorphism of the CD86 gene between cases and controls. The +1057 AA genotype was associated with a significantly increased risk of CRC when compared with the GG genotype (odds ratio [OR] = 2.16; 95% confidence interval [CI], 1.31-3.58). Using the G allele as a reference, a significant correlation was detected between the presence of the A allele and a risk of developing CRC (OR = 1.42; 95% CI, 1.12-1.80). Interestingly, the A allele in female patients with CRC was significantly higher than that in male patients after stratified analysis (OR = 1.49; 95% CI, 1.04-2.14). These data suggest that CD86 +1057G/A polymorphism may contribute to genetic susceptibility to CRC in a Chinese population.

Genetic polymorphism of interleukin-16 and risk of nasopharyngeal carcinoma.

BACKGROUND: Common genetic variants in inflammatory cytokine genes can affect the risk of developing nasopharyngeal carcinoma (NPC). Interleukin-16 (IL-16), a pro-inflammatory cytokine, plays a pivotal role in inflammatory diseases as well as in the pathogenesis of tumors. METHODS: We analyzed rs4778889 T/C, rs11556218 T/G, and rs4072111 C/T polymorphisms of IL-16 in 206 patients with NPC and 373 healthy controls in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy and DNA sequencing methods. RESULTS: The rs11556218 T/G polymorphism of IL-16 gene was significantly associated with the susceptibility to NPC. The TG genotype was associated with a significantly higher risk of NPC as compared with the TT genotype (OR=1.67; 95% CI, 1.18-2.36). Patients carrying the G allele had a significantly higher risk for developing NPC compared to individuals carrying the T allele (OR=1.36; 95% CI, 1.03-1.78). CONCLUSIONS: This study shows an association between IL-16 gene polymorphisms and the risk of NPC, and our data suggests that IL-16 gene polymorphisms may be useful as genetic susceptibility markers for NPC.

Association of CD40 -1C/T polymorphism in the 5'-untranslated region and chronic obstructive pulmonary disease.

BACKGROUND: Chronic inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD). It is influenced by both environmental and genetic factors. CD40 signaling has been linked to pathogenic processes of chronic inflammatory diseases. After interaction with its ligand CD154 (CD40L), CD40 induces a broad variety of chronic inflammatory responses, inducing the release of inflammatory mediators. We investigated whether a CD40 gene (-1C/T) single nucleotide polymorphism (SNP) is associated with COPD in a Chinese population. METHODS: We analyzed -1C/T SNP of the CD40 gene in 234 patients with COPD, and also in 312 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing methods. RESULTS: The frequency of CT and CT+CC of CD40 gene was significantly different from TT in the COPD group compared with the control group (for CT: OR=1.777, 95% CI: 1.117-2.826, p=0.015; for CT+CC: OR=1.614, 95% CI: 1.032-2.526, p=0.035). However, neither the allele frequency of CD40 nor the smoking and clinical stages in CD40 -1C/T genotypes frequency had significant differences between the COPD patients and control. CONCLUSION: These findings suggest that the CD40 -1C/T polymorphism may contribute to the susceptibility to COPD in a Chinese population.

The association of interleukin-16 polymorphisms with IL-16 serum levels and risk of colorectal and gastric cancer.

Interleukin (IL)-16, a multifunctional cytokine, plays a fundamental role in inflammatory diseases, as well as in the development and progression of tumors. Genetic variation in the DNA sequence of the IL-16 gene may lead to altered cytokine production and/or activity, and this variation may modulate an individual's susceptibility to both colorectal cancer (CRC) and gastric cancer (GC). To test this hypothesis, we investigated the association of IL-16 gene polymorphisms with serum levels of IL-16 and the risk of CRC and GC in a Chinese population. We analyzed single-nucleotide polymorphisms of the IL-16 gene in 596 cancer patients (376 patients with CRC and 220 patients with GC), and also in 480 age- and sex-matched controls using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. Serum IL-16 levels were measured by enzyme-linked immunosorbent assay. The rs11556218 T/G polymorphism of the IL-16 gene was significantly associated with the susceptibility to CRC and GC patients. Both male and female patients carrying the G allele had a significantly higher risk for developing CRC and GC compared with individuals carrying the T allele. Alternatively, women carrying the T allele (rs4072111 C/T) showed a decreased risk for CRC and GC compared with individuals carrying the C allele. In patients with CRC or GC, IL-16 serum levels were significantly higher than those in the healthy controls, although no significant association between IL-16 polymorphisms and serum levels of IL-16 was observed. Our data indicate that IL-16 polymorphisms may contribute to CRC and GC susceptibility.