A genetic variant in the immune-related gene ERAP1 affects colorectal cancer prognosis / 中华医学杂志(英文版)

BACKGROUND@#Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism.@*METHODS@#We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments.@*RESULTS@#The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 ( ERAP1 ) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1 . The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes.@*CONCLUSION@#The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1 .@*TRIAL REGISTRATION@#No. NCT00454519 ( https://clinicaltrials.gov/ ).

Association between genetic variants in p53 binding sites and risks of breast cancer in Chinese population / 中华流行病学杂志

Objective To investigate the association between breast tissue specified variants in p53 binding sites and the risk of BC in Chinese women.Methods ChIP-seq database on p53 binding sites in MCF-7 cell lines was extracted to identify the possible variants in p53 target genes.A hospital-based case-control study was then performed to investigate the association between variants in p53 binding sites and the risk of BC in a Chinese women population.Results Three variants were identified from the bioinformatics analysis.A total of 1 274 BC cases and 1 255 frequency-matched cancer-free controls were included in this case-control study.The average age was comparable between the case and the control groups,with the P value as 0.318.Meanwhile,distributions on menopausal status,smoking and alcohol intake between cases and controls were similar with the P values as 0.539,0.258 and 0.131,respectively.The genotype distribution of rs1295925 was significantly different between the case and the control groups.Individuals that carrying rs1295925-CT and rs1295925-TT genotypes were significantly associated with an increased BC risk when compared with rs1295925-CC genotype after adjustment of age,menopausal status,smoking and alcohol intake (0R=1.32,95％ CI:1.07-1.62 and OR=1.41,95％CI:1.13-1.78,respectively).Positive associations were also observed under the allelic,dominant and additive models.Conclusion rs1295925 which located in VMP1 gene was associated with increased BC risk in the Chinese women population.

Association between genetic variants in p53 binding sites and risks of breast cancer in Chinese population / 中华流行病学杂志

Objective To investigate the association between breast tissue specified variants in p53 binding sites and the risk of BC in Chinese women.Methods ChIP-seq database on p53 binding sites in MCF-7 cell lines was extracted to identify the possible variants in p53 target genes.A hospital-based case-control study was then performed to investigate the association between variants in p53 binding sites and the risk of BC in a Chinese women population.Results Three variants were identified from the bioinformatics analysis.A total of 1 274 BC cases and 1 255 frequency-matched cancer-free controls were included in this case-control study.The average age was comparable between the case and the control groups,with the P value as 0.318.Meanwhile,distributions on menopausal status,smoking and alcohol intake between cases and controls were similar with the P values as 0.539,0.258 and 0.131,respectively.The genotype distribution of rs1295925 was significantly different between the case and the control groups.Individuals that carrying rs1295925-CT and rs1295925-TT genotypes were significantly associated with an increased BC risk when compared with rs1295925-CC genotype after adjustment of age,menopausal status,smoking and alcohol intake (0R=1.32,95％ CI:1.07-1.62 and OR=1.41,95％CI:1.13-1.78,respectively).Positive associations were also observed under the allelic,dominant and additive models.Conclusion rs1295925 which located in VMP1 gene was associated with increased BC risk in the Chinese women population.

Risk prediction of colorectal cancer with common genetic variants and conventional non-genetic factors in a Chinese Han population / 中华流行病学杂志

<p><b>OBJECTIVE</b>To understand the association between multiple genetic loci identified by genome-wide association studies (GWASs) and colorectal cancer (CRC) risk, and whether these genetic factors, along with traditional risk factors, could contribute to the colorectal cancer risk prediction in a Chinese Han population.</p><p><b>METHODS</b>A case-control study (1 066 CRC cases and 3 880 controls) was initially conducted to assess the association between 21 recently discovered single-nucleotide polymorphisms (SNPs) and CRC risk. Genetic risk score (GRS) and weighted genetic risk score (wGRS) were calculated to evaluate the joint effects of selected loci. Multiple models combining genetic and non-genetic factors were established and receiver operating characteristic curve analysis was used to compare the discriminatory power of different predictive models.</p><p><b>RESULTS</b>There were 7 SNPs significantly associated with CRC susceptibility. As the GRS or wGRS increased, the risk of CRC also increased (trend P=0.002 6 for GRS, trend P<0.000 1 for wGRS). The ORs for highest versus lowest quartile of GRS and wGRS were 1.33 (95% CI: 1.12-1.58, P=0.001 0) and 1.76 (95% CI: 1.45-2.14, P<0.000 1) , respectively. The model incorporating wGRS and traditional risk factors, including sex, age, smoking and drinking, was the best one to predict CRC risk in this population, with an area under curve of 0.593 (95% CI: 0.573-0.613).</p><p><b>CONCLUSION</b>Multiple genetic loci identified by GWASs jointly influenced the CRC risk. The combination of genetic factors and conventional non-genetic factors improved the performance of risk predictive model for colorectal cancer.</p>

Research on the association between U2-dependent spliceosome gene and hepatocellular cancer / 中华流行病学杂志

Objective To determine the association between U2-dependent spliceosome related 8 key genes and hepatocellular cancer (HCC).Methods A two-stage case-control study was conducted.Twenty-two candidate tag single nucleotide polymorphisms (taggNPs) were genotyped by TaqMan Openarray assay in a screened population that living in Central China (378 HCC incident cases and 461 controls).Frequencies of 4 SNPs (rs2074733,rs9608886,rs7288947 and rs5994293) showed significant difference between cases and controls in the screened population and then genotyped by TaqMan real-time polymerase chain reaction in the validation Chinese Han population from Beijing (428 cases and 647 controls).Results The rs5994293 in SF3A1 gene showed a significant association with HCC in both screened population and combined population.Subjects with G allele had a lower risk of HCC,compared to those with the TT genotype.OR appeared to be 0.70 (95％ CI:0.58-0.84,false discovery rate adjusted P=0.000 5) for the combined population.An additive interaction between smoking,drinking alcohol and rs5994293 TT was observed in HBsAg negative subjects of the combined populations.Conclusion Our results showed an association existing between SF3A1 rs5994293 and HCC.These findings should be confirmed by further independently large-scale population studies and functional analysis.

Association between pancreatic cancer risk and the interaction of U2AF65 gene polymorphisms and smoking / 中华流行病学杂志

Objective To determine the association between U2 small nuclear ribonucleoprotein auxiliary factor 35/65(U2AF35 and U2AF65)and pancreatic cancer(PC). Methods A two-stage analysis case-control study was conducted. Four candidate tag single nucleotide polymorphisms (tagSNPs)were genotyped by Taqman Openarray assay in a screening population living in Central China(298 PC cases and 525 controls). Thereafter,rs310445 in U2AF65 was genotyped by TaqMan real-time polymerase chain reaction(RT-PCR)in a validation Chinese Han population from Beijing (413 cases and 557 controls). Results rs310445 in U2AF65 gene was significantly associated with PC in both screened population and combined population. Subjects with C allele had a higher risk of PC compared to those with the TT genotype,with OR of 1.31(95%CI:1.07-1.60,P=0.010)for the combined population. A synergic effect of smoking and C allele of rs310445 was also observed in the combined population,with Synergic Index of 2.08(95%CI:1.37-2.78) in the combined population. Conclusion Our findings suggested the interaction between smoking and U2AF65 might play a role in PC. These findings should be confirmed by further independently large-scale population studies.

Association between pancreatic cancer risk and the interaction of U2AF65 gene polymorphisms and smoking / 中华流行病学杂志

Objective To determine the association between U2 small nuclear ribonucleoprotein auxiliary factor 35/65(U2AF35 and U2AF65)and pancreatic cancer(PC). Methods A two-stage analysis case-control study was conducted. Four candidate tag single nucleotide polymorphisms (tagSNPs)were genotyped by Taqman Openarray assay in a screening population living in Central China(298 PC cases and 525 controls). Thereafter,rs310445 in U2AF65 was genotyped by TaqMan real-time polymerase chain reaction(RT-PCR)in a validation Chinese Han population from Beijing (413 cases and 557 controls). Results rs310445 in U2AF65 gene was significantly associated with PC in both screened population and combined population. Subjects with C allele had a higher risk of PC compared to those with the TT genotype,with OR of 1.31(95%CI:1.07-1.60,P=0.010)for the combined population. A synergic effect of smoking and C allele of rs310445 was also observed in the combined population,with Synergic Index of 2.08(95%CI:1.37-2.78) in the combined population. Conclusion Our findings suggested the interaction between smoking and U2AF65 might play a role in PC. These findings should be confirmed by further independently large-scale population studies.

Association between pancreatic cancer risk and the interaction of U2AF65 gene polymorphisms and smoking / 中华流行病学杂志

<p><b>OBJECTIVE</b>To determine the association between U2 small nuclear ribonucleoprotein auxiliary factor 35/65 (U2AF35 and U2AF65) and pancreatic cancer (PC).</p><p><b>METHODS</b>A two-stage analysis case-control study was conducted. Four candidate tag single nucleotide polymorphisms (tagSNPs) were genotyped by Taqman Openarray assay in a screening population living in Central China (298 PC cases and 525 controls). Thereafter, rs310445 in U2AF65 was genotyped by TaqMan real-time polymerase chain reaction (RT-PCR) in a validation Chinese Han population from Beijing (413 cases and 557 controls).</p><p><b>RESULTS</b>rs310445 in U2AF65 gene was significantly associated with PC in both screened population and combined population. Subjects with C allele had a higher risk of PC compared to those with the TT genotype, with OR of 1.31 (95%CI:1.07-1.60, P = 0.010) for the combined population. A synergic effect of smoking and C allele of rs310445 was also observed in the combined population, with Synergic Index of 2.08 (95% CI:1.37-2.78) in the combined population.</p><p><b>CONCLUSION</b>Our findings suggested the interaction between smoking and U2AF65 might play a role in PC. These findings should be confirmed by further independently large-scale population studies.</p>

Lung cancer risk associated with genetic polymorphism in myeloperoxidase (-463 G/A) in a Chinese population / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To examine the relationship between susceptibility to lung cancer among Chinese and genetic polymorphism at nucleotide -463 (G/A) in myeloperoxidase (MPO), an enzyme found in lysosomes of phagocytes and involved in the formation of hydroxyl radicals and activation of various smoking-related carcinogens.</p><p><b>METHODS</b>The association of this polymorphism with lung cancer in a hospital-based case-control study of 314 patients and 320 age- and sex-matched controls was tested. The MPO genotypes were determined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP).</p><p><b>RESULTS</b>The allele frequency for MPO-463A was found to be 11.0% for controls, compared with 15.0% for patients. Multivariate analysis showed an increased risk for overall lung cancer in subjects having GG genotype (OR, 1.7; 95% CI, 1.2 - 2.5), however, the elevated risk was limited to squamous cell carcinoma (OR, 2.4; 95% CI, 1.4 - 3.9; n = 177) but not to adenocarcinoma (OR, 1.3; 95% CI, 0.8 - 2.1; n = 137). In addition, the risky effect of the GG genotype on squamous cell carcinoma of the lung was evident only in the smokers and those who smoked >/= 26 pack-years (OR, 20.5; 95% CI, 5.6 - 75.3) as compared with GA and AA genotypes (OR, 6.2; 95% CI, 1.7 - 22.5) but not in the nonsmokers or those who smoked < 26 pack-years.</p><p><b>CONCLUSION</b>Our data support the hypothesis that -463A polymorphism in the MPO gene may reduce the susceptibility to lung cancer in the Chinese.</p>

Study on the association between smoking behavior and dopamine receptor D2 gene polymorphisms among lung cancer cases / 中华流行病学杂志

<p><b>OBJECTIVE</b>To investigate the possible association between dopamine D2 receptor (DRD2) TaqI A and TaqI B genotypes as well as smoking behavior and the risk of lung cancer among Chinese Han people.</p><p><b>METHODS</b>PCR was used to perform genotyping on peripheral WBC DNA from 326 lung cancer patients and 326 age, sex and ethnicity-matched healthy controls. Subjects were interviewed to obtain relevant information and lifetime history of tobacco use.</p><p><b>RESULTS</b>There were no statistically significant differences in the distribution of DRD2 genotypes between lung cancer cases and controls. The DRD2 genotypes and smoking status showed no correlation among cases and among controls as well. However, among controls, the frequency of the DRD2 * A2/A2 genotype in smokers who smoked > or = 25 cigarettes/day appeared to be higher than that in those who smoked < 25 cigarettes/day (42.5% versus 26.1%, P = 0.047). A similar trend was also found for the DRD2 * B2/B2 genotype, which was linked to the DRD2 * A2/A2 genotype, although the difference was not significant (40.0% versus 26.1%, P = 0.091). In contrast to controls, no association was found between the DRD2 genotypes and smoking among lung cancer cases.</p><p><b>CONCLUSION</b>Our results suggested that DRD2 * A2/A2 genotype might be associated with a greater smoking intensity in Chinese. Further studies are needed to confirm this preliminary finding.</p>