Dongyan Zhong

A Functional Polymorphism in miRNA-196a2 Is Associated with Colorectal Cancer Risk in a Chinese Population

Single-nucleotide polymorphisms in microRNAs (miRNAs) may alter miRNA expression levels or processing and, thus, may contribute to cancer development. We hypothesized that miRNA-196a2 polymorphism is associated with risk of colorectal cancer (CRC). In a case-control study of 573 patients with CRC and 588 cancer-free controls frequency matched by age and sex, we genotyped the functional polymorphism rs11614913 (T>C) and assessed its association with the risk of CRC in a Chinese population. We found that the CT/CC genotypes were associated with a significantly increased risk of CRC (odds ratio [OR]=1.44, 95% confidence interval [CI]=1.10-1.88), compared with the TT genotype. Further, the polymorphism was significantly associated with the risk of patients with advanced stage tumor (Dukes C and D) (OR=1.65, 95% CI=1.11-2.46). Our results suggest that the functional polymorphism rs11614913 in miRNA-196a2 is involved in the etiology of CRC and, thus, may be a marker for genetic susceptibility to CRC.

Genetic Variants in miRNAs Predict Bladder Cancer Risk and Recurrence

miRNAs play important roles in numerous cellular processes, including development, proliferation, apoptosis, and carcinogenesis. Because altered expression and function of miRNAs has been observed in bladder cancer, we investigated whether genetic variations in miRNAs are associated with bladder cancer risk and prognosis. Using bioinformatics tools, we selected five single-nucleotide polymorphisms located in miRNAs and used these to evaluate miRNA-disease associations in a two-stage model, consisting of 1,019 bladder cancer cases and 1,182 controls (683 cases and 728 controls in the training set and 336 cases and 454 controls in the test set). We found that miR-146a rs2910164 C allele was associated with significantly decreased risk of bladder cancer in both the training and test sets, as well as the combined set [OR = 0.80, 95% confidence interval (CI) = 0.71-0.90, P = 2.92 × 10(-4)]. Furthermore, the rs2910164 GC/CC genotypes conferred a significantly reduced risk of recurrence, compared with the GG genotype (P = 0.016). Functional analysis revealed that miR-146a rs2910164 C allele inhibited cell proliferation and significantly downregulated expression of IRAK1 and TRAF6 in bladder cancer cells. Additional examination of 64 bladder cancer tissues showed that individuals carrying the C allele had increased expression levels of miR-146a compared with those carrying the G allele (P = 0.010). Taken together, our findings show that miR-146a rs2910164 plays an important role in the risk and recurrence of bladder cancer, suggesting it may represent a biomarker for risk prevention and therapeutic intervention. Further larger and prospective cohorts are needed to validate our findings.

A Genetic Variant in pre-miR-27a Is Associated with a Reduced Renal Cell Cancer Risk in a Chinese Population

Background MicroRNAs (miRNAs) are a class of small non-coding RNAs to regulate cell differentiation, proliferation, development, and apoptosis. The single nucleotide polymorphism (SNP) rs895819 is located at the terminal loop of pre-miR-27a. Here, we aimed to investigate whether SNP rs895819 was associated with the development of renal cell cancer (RCC) in a Chinese population. Methods In this case-control study, we recruited 594 RCC patients and 600 cancer-free controls with frequency matched by age and sex. We genotyped this polymorphism using the TaqMan assay and assessed the effect of this polymorphism on RCC survival. Logistic regression model was used to assess the genetic effects on the development of RCC and interactions between rs895819 polymorphism and risk factors. Results Compared with AA homozygote, individuals carrying AG/GG genotypes had a statistically significant reduced susceptibility to RCC (adjusted OR = 0.71, 95% CI = 0.56–0.90). Furthermore, AG/GG genotypes were associated with reduced RCC susceptibility in localized clinical stage (adjusted OR = 0.71, 95% CI = 0.55–0.91), and similar effects were observed in well differentiated and poorly differentiated RCC (adjusted OR = 0.71, 95% CI = 0.55–0.93 for well differentiated, adjusted OR = 0.51, 95% CI = 0.28–0.93 for poorly differentiated). We also observed that rs895819 had multiplicative interactions with age and hypertension. However, the polymorphism did not influence the survival of RCC. Conclusion Our results suggest that the pre-miR-27a rs895819 polymorphism can predict RCC risk in a Chinese population. Larger population-based prospective studies should be used to validate our findings.

Genetic Variation in DROSHA 3’UTR Regulated by hsa-miR-27b Is Associated with Bladder Cancer Risk

Purpose miRNAs can regulate the biological processes, including differentiation, proliferation and apoptosis. DICER and DROSHA are two members of RNase III family, playing pivotal roles in the pathway of miRNAs biogenesis. In this study, we hypothesized that genetic variations of the DICER and DROSHA genes were associated with the bladder cancer risk. Experimental Design We performed a case-control study of 685 bladder cancer cases and 730 controls to investigate the association between the seven functional SNPs of DICER and DROSHA genes and bladder cancer risk. We then evaluated the functionality of the important SNPs. Results We found that rs10719T>C polymorphism located in 3’ untranslated region (UTR) of DROSHA gene was associated with the increased risk of bladder cancer. Stratified analysis suggested that rs10719TC/CC genotype can increase risk of bladder cancer among male patients (Adjusted OR = 1.34, 95% CI = 1.05-1.70, P = 0.018), and ever smokers (1.56, 1.14-2.14, 0.006), compared with TT genotype. Furthermore, DROSHA rs10719T>C polymorphism was predicted to regulate the binding activity of hsa-miR-27a/b. Luciferase reported gene assay confirmed that rs10719 T to G substitution disrupted the binding site for hsa-miR-27b, resulting the increased levels of DROSHA protein. Conclusions Taken together, these findings suggested that DROSHA rs10719T>C polymorphism may be associated with bladder cancer risk in a Chinese population, and hsa-miR-27b can influence the expression of DROSHA protein by binding with 3’UTR.

AdipoQ polymorphisms are associated with type 2 diabetes mellitus: a meta-analysis study.

Adiponectin (AdipoQ) plays an important role in the pathogenesis of diabetes mellitus and is considered as an important candidate gene for type 2 diabetes mellitus (T2DM). So far, there have been many studies to investigate the association between the adiponectin polymorphisms and T2DM risk. However, the results are conflicting. To derive a more precise estimation, we performed a meta‐analysis to assess the association between five AdipoQ polymorphisms [−11426A > G (rs16861194), −11391G > A (rs17300539), −11377C > G (rs266729), +45T > G (rs2241766) and +276G > T (rs1501299)], and T2DM risk.

hOGG1 Ser326Cys polymorphism is associated with risk of bladder cancer in a Chinese population: A case‐control study

Human oxoguanine glycosylase 1 (hOGG1) is a DNA repair enzyme, which plays important roles in the base excision repair (BER) pathway. Several studies reported a common polymorphism Ser326Cys (rs1052133) in hOGG1, which conferred the susceptibility of bladder cancer. We hypothesized that the polymorphism is associated with risk of bladder cancer in a Chinese population. In a case‐control study of 1050 histologically confirmed bladder cancer patients and 1404 age and sex matched healthy controls, we genotyped the hOGG1 Ser326Cys polymorphism using TaqMan technology and assessed its association with bladder cancer risk. We found that the hOGG1 Ser/Cys + Ser/Ser genotypes were associated with a significantly increased risk of bladder cancer (adjusted odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.01–1.41), compared with the Cys/Cys genotype. Furthermore, the increased risk was more pronounced among subjects over age 65 years (OR = 1.31, 95% CI = 1.04–1.66), male subjects (OR = 1.21, 95% CI = 1.00–1.47), ever smokers (OR = 1.29, 95% CI = 1.00–1.68) and heavy smokers (>20 pack‐years) (OR = 1.45, 95% CI = 1.03–2.04). No significant association was observed in the stratification of tumor grade and tumor stage for bladder cancer. In conclusion, our results suggest that hOGG1 Ser326Cys polymorphism may contribute to the susceptibility to bladder cancer in a Chinese population. (Cancer Sci 2012; 103: 1215–1220)

Polymorphisms in the IL-13 and IL-4R genes are associated with the development of renal cell carcinoma

BACKGROUND Cytokines are the important modulators that bind to their relevant receptors in response to some stimuli to mediate the homeostasis. It has been suggested that the imbalance of immune system of the host might affect the generation of diseases, including cancers. PATIENTS AND METHODS We investigated the association between six functional polymorphisms of IL-4, IL-13, and IL-4R genes and susceptibility to renal cell cancer in a hospital-based study, including 620 renal cell carcinoma (RCC) patients and 623 controls. Logistic regression model was used to assess the genetic effects on the development of RCC. RESULTS Overall, individuals with IL-4R Ile50Val CT/TT genotypes had a 0.34-fold significantly decreased RCC risk (CT/TT versus CC), and the T variant allele was associated with a decreased risk of RCC in a dose-response manner (Ptrend=0.009). In addition, we also observed that IL-13 C-1055T and Arg130Gln polymorphisms could decrease the risk of RCC [TT versus CC/CT odds ratio=0.36, 95% confidence interval (CI)=0.16-0.78; AA versus GG/GA: 0.66, 0.44-0.97, respectively]. Furthermore, a multiplicative interaction association between the combined IL-4R Ile50Val and IL-13 C-1055T genotypes was observed to decrease the risk of RCC (P=0.036). CONCLUSION IL-13 and IL-4R may play an important role in the etiology of RCC.

ADH1C Ile350Val polymorphism and cancer risk: evidence from 35 case-control studies.

Background Alcohol dehydrogenase 1C (ADH1C) is the key enzyme catalyze oxidation of alcohol to acetaldehyde, which plays vital roles in the etiology of various cancer. To date, studies investigated the association between a functional polymorphism in ADH1C, Ile350Val (rs698), and risk of cancer have shown inclusive results. Methods A meta-analysis based on 35 case-control studies was performed to address this issue. Odds ratios (OR) with 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with χ2-based Q-test. Results Overall, no significant associations between ADH1C Ile350Val polymorphism and cancer risk were observed in any genetic models (P>0.05). In the stratified analyses, there was a significantly increased cancer risk among African (Val/Val vs. Ile/Ile OR  = 2.19, 95% CI  = 1.29−3.73, P heterogeneity  = 0.989; Ile/Val + Val/Val vs. Ile/Ile: OR  = 1.79, 95%CI  = 1.18−2.71, P heterogeneity  = 0.761; Val/Val vs. Ile/Val + Ile/Ile: OR  = 1.92, 95% CI  = 1.16−3.17, P heterogeneity  = 0.981) and Asian (Ile/Val vs. Ile/Ile: OR  = 1.58, 95% CI  = 1.32−1.90, P heterogeneity  = 0.375; Val/Val vs. Ile/Ile: OR  = 3.84, 95% CI  = 1.74−8.49, P heterogeneity  = 0.160; Ile/Val + Val/Val vs. Ile/Ile: OR  = 1.65, 95% CI  = 1.38−1.96, P heterogeneity  = 0.330; Val/Val vs. Ile/Val + Ile/Ile: OR  = 3.54, 95% CI  = 1.62−7.75, P heterogeneity  = 0.154) studies. Conclusions The results indicate that ADH1C Ile350Val polymorphism may contribute to cancer risk among Africans and Asians. Additional comprehensive system analyses are required to validate this association combined with other related polymorphisms.