Apoptosis plays a key role in inhibiting tumor growth, progression and resistance to anti-tumor therapy. We hypothesized that genetic variants in apoptotic genes may affect the prognosis of lung cancer. To test this h...Apoptosis plays a key role in inhibiting tumor growth, progression and resistance to anti-tumor therapy. We hypothesized that genetic variants in apoptotic genes may affect the prognosis of lung cancer. To test this hypoth- esis, we selected 38 potentially functional single nucleotide polymorphisms （SNPs） from 12 genes （BAX, BCL2, BID, CASP3, CASP6, CASP7, CASPS, CASP9, CASPIO, FAS, FASLG and MCL1） involved in apoptosis to assess their prognostic significance in lung cancer in a Chinese case cohort with 568 non-small cell lung cancer （NSCLC） patients. Thirty-five SNPs passing quality control underwent association analyses, 11 of which were shown to be significantly associated with NSCLC survival （P 〈 0.05）. After Cox stepwise regression analyses, 3 SNPs were independently associated with the outcome of NSCLC （BID rs8190315： P = 0.003; CASP9 rs4645981： P = 0.007 and FAS rs1800682： P = 0.016）. A favorable survival of NSCLC was significantly associated with the genotypes of BID rs8190315 AG/GG （adjusted HR = 0.65, 95% CI： 0.49-0.88）, CASP9 rs4645981 AA （HR = 0.22, 95% CI： 0.07-0.69） and FAS rs1800682 GG （adjusted HR = 0.67, 95% CI： 0.46-0.97）. Time-dependent receptor operation curve （ROC） analysis revealed that the area under curve （AUC） at year 5 was significantly increased from 0.762 to 0.819 after adding the risk score of these 3 SNPs to the clinical risk score. The remaining 32 SNPs were not sig- nificantly associated with NSCLC prognosis after adjustment for these 3 SNPs. These findings indicate that BID rs8190315, CASP9 rs4645981 and FAS rs1800682 polymorphisms in the apoptotic pathway may be involved in the prognosis of NSCLC in the Chinese population.展开更多
Objective： Inflammation induced by H.pylori colonization in the stomach is related to the development of gastric cancer and the genetic variations of the genes involved in the immune responses modify the host respons...Objective： Inflammation induced by H.pylori colonization in the stomach is related to the development of gastric cancer and the genetic variations of the genes involved in the immune responses modify the host response to the infection. The aim of this study was to evaluate whether polymorphisms in the toll-like receptor 4 （TLR4） gene, a key regulator of both innate and adaptive immunity, were related to the susceptibility to展开更多
Superficial esophageal squamous cell carcinoma(SESCC)is defined as carcinoma with mucosal or submucosal invasion,regardless of regional lymph node metastasis(LNM).The lymph node status is not only a key factor to dete...Superficial esophageal squamous cell carcinoma(SESCC)is defined as carcinoma with mucosal or submucosal invasion,regardless of regional lymph node metastasis(LNM).The lymph node status is not only a key factor to determine the training strategy,but also the most important prognostic factor in esophageal cancer.In this study,we establish a clinical nomogram for predicting LNM in patients with SESCC.A predictive model was established based on the training cohort composed of 711 patients who underwent esophagectomy for SESCC from December 2009 to June 2018.A prospective cohort of 203 patients from June 2018 to January 2019 was used for validation.Favorable calibration and well-fitted decision curve analysis were conducted and good discrimination was observed(concordance index[C-index],0.860;95%confidence interval[CI],0.825-0.894)through internal validation.The external validation cohort presented good discrimination(C-index,0.916;95%CI,0.860-0.971).This model may facilitate the prediction of LNM in patients with SESCCs.展开更多
Long noncoding RNA(lncRNA) HOTAIR and MALAT1 are implicated in the development of multiple cancers. Genetic variants within HOTAIR and MALAT1 may affect the gene expression, thereby modifying genetic susceptibility to...Long noncoding RNA(lncRNA) HOTAIR and MALAT1 are implicated in the development of multiple cancers. Genetic variants within HOTAIR and MALAT1 may affect the gene expression, thereby modifying genetic susceptibility to cervical cancer. A case-control study was designed, including 1 486 cervical cancer patients and 1 536 healthy controls. Based on RegulomeDB database, 11 SNPs were selected and genotyped by using Sequenom’s Mass ARRAY. Univariate and multivariate logistic regression models were used to calculate the odds ratio(OR) and 95% confidence interval(CI). We found that the A allele of rs35643724 in HOTAIR was associated with increased risk of cervical cancer, while the C allele of rs1787666 in MALAT1 was associated with decreased risk. Compared to individuals with 0–1 unfavorable allele, those with 3–4 unfavorable alleles showed18% increased odds of having cervical cancer. Our findings suggest that HOTAIR rs35643724 and MALAT1 rs1787666 might represent potential biomarkers for cervical cancer susceptibility.展开更多
MET tyrosine kinase and its ligand,hepatocyte growth factor（HGF）,play a pivotal role in the activties of tumor cells.A germline missense variant in exon 2 of the MET gene,N375S（rs33917957 A〉G）,may alter the bindi...MET tyrosine kinase and its ligand,hepatocyte growth factor（HGF）,play a pivotal role in the activties of tumor cells.A germline missense variant in exon 2 of the MET gene,N375S（rs33917957 A〉G）,may alter the binding affinity of MET for HGF and thus modify the risk of tumorigenesis.In this study,we performed a case-control study to assess the association between N375S and gastric cancer risk in 1,681 gastric cancer cases and 1,858 cancer-free controls.Logistic regression analysis was applied to estimate crude and adjusted odds ratios（ORs） and 95% confidence intervals（CIs） for the associations between genotypes and gastric cancer risk.We found that MET N375S variant genotypes（NS/SS） were associated with a significantly decreased risk of gastric cancer（OR = 0.78,95% CI = 0.63-0.96,P = 0.021） compared with the wildtype homozygote（NN）.The finding indicates that this germline variant in MET may decrease gastric cancer susceptibility in Han Chinese.展开更多
With recent advances in biotechnology, genome-wide association study （GWAS） has been widely used to identify genetic variants that underlie human complex diseases and traits. In case-control GWAS, typical statistica...With recent advances in biotechnology, genome-wide association study （GWAS） has been widely used to identify genetic variants that underlie human complex diseases and traits. In case-control GWAS, typical statistical strategy is traditional logistical regression （LR） based on single-locus analysis. However, such a single-locus analysis leads to the well-known multiplicity problem, with a risk of inflating type I error and reducing power. Dimension reduction-based techniques, such as principal component-based logistic regression （PC-LR）, partial least squares-based logistic regression （PLS-LR）, have recently gained much attention in the analysis of high dimensional genomic data. However, the perfor- mance of these methods is still not clear, especially in GWAS. We conducted simulations and real data application to compare the type I error and power of PC-LR, PLS-LR and LR applicable to GWAS within a defined single nucleotide polymorphism （SNP） set region. We found that PC-LR and PLS can reasonably control type I error under null hypothesis. On contrast, LR, which is corrected by Bonferroni method, was more conserved in all simulation settings. In particular, we found that PC-LR and PLS-LR had comparable power and they both outperformed LR, especially when the causal SNP was in high linkage disequilibrium with genotyped ones and with a small effective size in simulation. Based on SNP set analysis, we applied all three methods to analyze non-small cell lung cancer GWAS data.展开更多
Objective:Although our previous genome-wide association study(GWAS)has identified chromosome 2q33.1 as a susceptibility locus for non-small cell lung cancer(NSCLC),the causal variants remain unclear.The aims of this s...Objective:Although our previous genome-wide association study(GWAS)has identified chromosome 2q33.1 as a susceptibility locus for non-small cell lung cancer(NSCLC),the causal variants remain unclear.The aims of this study were to identify the causal variants in 2q33.1 and to explore their biological functions in NSCLC.Methods:CCK-8,colony formation,EdU incorporation,Transwell,and quantitative real-time polymerase chain reaction assays were applied to examine variant function.The tumor xenograft model was used to examine variant function in vivo.Caspase-8 activity assays,flow cytometry analysis,and co-immunoprecipitation assays were used to explore the molecular mechanism.Results:The missense variant rs3769823(A>G),which caused the substitution of lysine with arginine at amino acid 14 in caspase-8(caspase-8K14R),was identified as a potential causal candidate in 2q33.1.Compared with the wild type caspase-8(caspase8WT)group,the caspase-8K14R group had higher expression of caspase-8 and cleaved caspase-8.Caspase-8K14R inhibited the proliferation and metastasis of human lung cancer cell lines in vitro.Moreover,caspase-8K14R repressed lung cancer cell growth in vivo.Mechanistically,caspase-8K14R was more sensitive than caspase-8WT to tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-mediated apoptosis and showed higher binding of caspase-8 and FADD.Conclusions:These results suggested that rs3769823 is the causal variant in chromosome 2q33.1 and is involved in an apoptosis pathway,leading to a decreased risk of NSCLC.展开更多
The extent to which factors affect the probability of clinical pregnancy in the first fresh embryo transfer after assisted conception is unknown.In order to examine the predictors of clinical pregnancy,a retrospective...The extent to which factors affect the probability of clinical pregnancy in the first fresh embryo transfer after assisted conception is unknown.In order to examine the predictors of clinical pregnancy,a retrospective cohort study was launched between January 1,2013 and December 31,2016 in four infertility clinics including 19837 in vitro fertilization and intracytoplasmic sperm injection(IVF/ICSI)fresh cycles with known outcomes and relevant records.A multivariable logistic regression was used to select the most significant predictors in the final nomogram for predicting clinical pregnancy.Furthermore,the model was validated by an independent validation set and the performance of the model was evaluated by the receiver operating characteristic(ROC)curves along with the area under the ROC curve(AUC)and calibration plots.In a training set including 17854 participants,we identified that female age,tubal factor,number of embryos transferred,endometrial thickness and number of good-quality embryos were independent predictors for clinical pregnancy.We developed a nomogram using these five factors and the predictive ability was 0.66 for AUC(95%CI=0.64−0.68),which was independently validated in the validation set(AUC=0.66,95%CI=0.65−0.68).Our results show that some specific factors can be used to provide infertile couples with an accurate assessment of clinical pregnancy following assisted conception and facilitate to guide couples and clinicians.展开更多
Plasma lipid abnormalities are implicated in the pathogenic process of type 2 diabetes. The IDE-KIFII-HHEX gene cluster on chromosome 10q23.33 has been identified as a susceptibility locus for type 2 diabetes. We hy- ...Plasma lipid abnormalities are implicated in the pathogenic process of type 2 diabetes. The IDE-KIFII-HHEX gene cluster on chromosome 10q23.33 has been identified as a susceptibility locus for type 2 diabetes. We hy- pothesized that genetic variants at 10q23.33 may be associated with plasma lipid concentrations. Seven tagging single nucleotide polymorphisms （SNPs： rs7923837, rs2488075, rs947591, rs11187146, rs5015480, rs4646957 and rs1111875） at 10q23.33 were genotyped in 3,281 subjects from a Han Chinese population, using the Taq- Man OpenArray and Sequenom MassARRAY platforms. Multiple linear regression analyses showed that SNP rs7923837 in the 3＂-flanking region of HHEX was significantly associated with triglyceride levels （P = 0.019, 0.031 mmol/L average decrease per minor G allele） and that rs2488075 and rs947591 in the downstream region of HHEX were significantly associated with total cholesterol levels （P = 0.041, 0.058 mmol/L average decrease per minor C allele and P = 0.018, 0.063 mmol/L average decrease per minor A allele, respectively）. However, the other four SNPs （rs11187146, rs5015480, rs4646957 and rs1111875） were not significantly associated with any plasma lipid concentrations in this Chinese population. Our data suggest that genetic variants in the IDE-KIF11- HHEX gene cluster at 10q23.33 may partially explain the variation of plasma lipid levels in the Hart Chinese pop- ulation. Further studies are required to confirm these findings in other populations.展开更多
There were few studies of cumulative live birth rates(CLBRs) based on multicenter reproductive clinical data from the general Chinese population.Here we report a retrospective cohort study,including 14 311 women with1...There were few studies of cumulative live birth rates(CLBRs) based on multicenter reproductive clinical data from the general Chinese population.Here we report a retrospective cohort study,including 14 311 women with17 315 cycles,in three reproductive centers to evaluate two estimated parameters of CLBRs with multiple transfer cycles of in vitro fertilization(IVF)/intracytoplasmic sperm injection(ICSI) in a Chinese population.We found that CLBRs were related to female age and endometrial thickness.By the fourth transfer cycle,the conservative and optimal estimates of CLBRs were 52.95% and 77.30% in women under 30 years of age,and 18.17% and26.51% in those 37 years of age or older,respectively.The two estimates were 44.70% and 63.15% in women with endometrial thickness more than 7 mm,and 32.05% and 46.18% in those with less than 7 mm,respectively.In addition,body mass index(BMI),duration of infertility,and infertility diagnoses may also be related to CLBRs on certain conditions.The findings from this study on CLBRs after multiple transfer cycles of IVF/ICSI treatment on different conditions in the Chinese population should be beneficial to both infertile couples and clinicians.展开更多
Runs of homozygosity （ROHs） are a class of important but poorly studied genomic variations and may be in- volved in individual susceptibility to diseases. To better understand ROH and its relationship with lung canc...Runs of homozygosity （ROHs） are a class of important but poorly studied genomic variations and may be in- volved in individual susceptibility to diseases. To better understand ROH and its relationship with lung cancer, we performed a genome-wide ROH analysis of a subset of a previous genome-wide case-control study （1,473 cases and 1,962 controls） in a Han Chinese population. ROHs were classified into two classes, based on lengths, intermedi- ate and long ROils, to evaluate their association with lung cancer risk using existing genome-wide single nucleofide polymorphism （SNP） data. We found that the overall level of intermediate ROHs was significantly associated with a decreased risk of lung cancer （odds ratio = 0.63; 95% confidence interval： 0.51-0.77; P = 4.78 × 10-6 ）, while the long ROHs seemed to be a risk factor of lung cancer. We also identified one ROH region at 14q23A that was con- sistently associated with lung cancer risk in the study. These results indicated that ROHs may be a new class of variation which may be associated with lung cancer risk, and genetic variants at 14q23.1 may be involved in the development of lung cancer.展开更多
Objective： To evaluate the effects of polymorphisms in TLR7 and TLRS（as potential candidate genes） on asthma risk and asthma-related phenotypes. Methods： We consecutively recruited 318 unrelated adult asthmatic pa...Objective： To evaluate the effects of polymorphisms in TLR7 and TLRS（as potential candidate genes） on asthma risk and asthma-related phenotypes. Methods： We consecutively recruited 318 unrelated adult asthmatic patients and 352 healthy volunteers from the same area of southeast China. Genotyping of each selected SNP was performed using multiplex PCR in conjunction with tagged array single base extension technology. We conducted case-control and case-only association studies between the selected SNPs in TLR7 and TLR8 and asthma or asthma-related phenotypes. Results： The T allele of rs5935436 SNP in TLR7 was protective from developing asthma in males （adjusted ORs = 0.126, 95% CIs = 0.016-0.995）. The CT/TT genotype of rs5935436 was less frequent in female asthmatics with allergic rhinitis （adjusted ORs = 0.18, 95% CIs = 0.04-0.90）. The homozygote AA of rs3761623 and GG of rs3764880 were positively associated with lower FEV1% and asthma severity in female asthmatics. These results were confirmed by haplotype analysis. Conclusion：TLR7 and TLR8 polymorphisms may play an important role in the pathogenesis of asthma that is gender-dependent. This could be clinically useful, both for identifying patients at risk of asthma and for preventing its occurrence.展开更多
Human genome epidemiology （HUGE） uses sys- tematic applications of epidemiologic methods to as- sess the impact of human genetic variation on health and disease. In the past ten years, human genome epi- demiology ha...Human genome epidemiology （HUGE） uses sys- tematic applications of epidemiologic methods to as- sess the impact of human genetic variation on health and disease. In the past ten years, human genome epi- demiology has made great progresses along with ad- vances in genomics technologies, which make it pos- sible for the examination of genetic variants in a large sample size at a sufficiently low cost. Genetic associa- tion study in population provides a powerful approach to identify variants or genes associated with disease of interest by comparing distributions of genetic variants between affected and unaffected individuals.展开更多
To investigate whether genetic variants may provide additional prognostic value to improve the existing clinical staging system for gastric cancer(GC),we performed two genome-wide association studies(GWASs)of GC survi...To investigate whether genetic variants may provide additional prognostic value to improve the existing clinical staging system for gastric cancer(GC),we performed two genome-wide association studies(GWASs)of GC survival in the Jiangsu(N=1049)and Shanghai(N=1405)cohorts.By using a TCGA dataset,we validated genetic markers identified from a meta-analysis of these two Chinese cohorts to determine GC survival-associated loci.Then,we constructed a weighted polygenic hazard score(PHS)and developed a nomogram in combination with clinical variables.We also evaluated prognostic accuracy with the time-dependent receiver operating characteristic(ROC)curve,net reclassification improvement(NRI)and integrated discrimination improvement(IDI).We identified a single nucleotide polymorphism(SNP)of rs1618332 at 15q15.1 that was associated with the survival of GC patients with a P value of 4.12×10^(-8),and we also found additional 25 SNPs having consistent associations among these two Chinese cohort and TCGA cohort.The PHS derived from these 26 SNPs(PHS-26)was an independent prognostic factor for GC survival(all P<0.001).The 5-year AUC of PHS-26 was 0.68,0.66 and 0.67 for Jiangsu,Shanghai and their pooled cohorts,respectively,which increased to 0.80,0.82 and 0.81,correspondingly,after being integrated into a nomogram together with variables of the clinical model.The PHS-26 could improve the NRIs by 16.20%,4.90%and 8.70%,respectively,and the IDIs by 11.90%,8.00%and 9.70%,respectively.The 26-SNP based PHS could substantially improve the accuracy of prognostic assessment and might facilitate precision medicine for GC patients.展开更多
Patients with advanced gastric cancer typically face a grim prognosis.This phase 1a(dose escalation)and phase 1b(dose expansion)study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemo...Patients with advanced gastric cancer typically face a grim prognosis.This phase 1a(dose escalation)and phase 1b(dose expansion)study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapyfor advanced gastric or gastroesophageal junction adenocarcinoma.The primary endpoints included maximum tolerated dose(MTD)in phase 1a and objective response rate(ORR)across phase 1a and 1b.Phase 1a tested three dose regimens of camrelizumab,apatinib,oxaliplatin,and S-1.Dose regimen 1:camrelizumab 200 mg on day 1,apatinib 250 mg every other day,oxaliplatin 100 mg/m^(2) on day 1,and S-140 mg twice a day on days 1-14.Dose regimen 2:same as dose regimen 1,but oxaliplatin 130mg/m.Dose regimen3:same as dose regimen 2,but apatinib 250 mg daily.Thirty-four patients were included(9 in phase 1a,25 in phase 1b).No dose-limiting toxicities occurred so no MTD was identified.Dose 3 was set for the recommended phase 2 doses and administered in phase 1b.The confrmed ORR was 76.5%(95%CI 58.8-89.3).The median progression-free survival was 8.4 months(95%CI 5.9-not evaluable[NE]),and the median overall survival(OS)was not mature(11.6-NE).Ten patients underwent surgery after treatment and the multidisciplinary team evaluation.Among 24 patients without surgery,the median OS was 19.6 months(7.8-NE).Eighteen patients(52.9%)developed grade≥3 treatment-emergent adverse events.Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer(ChiCTR2000034109).展开更多
Previous studies have showed clinical characteristics of patients with the 2019 novel coronavirus disease(COVID-19)and the evidence of person-to-person transmission.Limited data are available for asymptomatic infectio...Previous studies have showed clinical characteristics of patients with the 2019 novel coronavirus disease(COVID-19)and the evidence of person-to-person transmission.Limited data are available for asymptomatic infections.This study aims to present the clinical characteristics of 24 cases with asymptomatic infection screened from close contacts and to show the transmission potential of asymptomatic COVID-19 virus carriers.Epidemiological investigations were conducted among all close contacts of COVID-19 patients(or suspected patients)in Nanjing,Jiangsu Province,China,from Jan 28 to Feb 9,2020,both in clinic and in community.Asymptomatic carriers were laboratory-confirmed positive for the COVID-19 virus by testing the nucleic acid of the pharyngeal swab samples.Their clinical records,laboratory assessments,and chest CT scans were reviewed.As a result,none of the 24 asymptomatic cases presented any obvious symptoms while nucleic acid screening.Five cases(20.8%)developed symptoms(fever,cough,fatigue,etc.)during hospitalization.Twelve(50.0%)cases showed typical CT images of ground-glass chest and 5(20.8%)presented stripe shadowing in the lungs.The remaining 7(29.2%)cases showed normal CT image and had no symptoms during hospitalization.These 7 cases were younger(median age:14.0 years;P=0.012)than the rest.None of the 24 cases developed severe COVID-19 pneumonia or died.The median communicable period,defined as the interval from the first day of positive nucleic acid tests to the first day of continuous negative tests,was 9.5 days(up to 21 days among the 24 asymptomatic cases).Through epidemiological investigation,we observed a typical asymptomatic transmission to the cohabiting family members,which even caused severe COVID-19 pneumonia.Overall,the asymptomatic carriers identified from close contacts were prone to be mildly ill during hospitalization.However,the communicable period could be up to three weeks and the communicated patients could develop severe illness.These results highlighted the importance of close contact tracing and longitudinally surveillance via virus nucleic acid tests.Further isolation recommendation and continuous nucleic acid tests may also be recommended to the patients discharged.展开更多
Background:Most lung cancer risk prediction models were developed in European and North-American cohorts of smokers aged≥55 years,while less is known about risk profiles in Asia,especially for never smokers or indivi...Background:Most lung cancer risk prediction models were developed in European and North-American cohorts of smokers aged≥55 years,while less is known about risk profiles in Asia,especially for never smokers or individuals aged<50 years.Hence,we aimed to develop and validate a lung cancer risk estimate tool for ever and never smokers across a wide age range.Methods:Based on the China Kadoorie Biobank cohort,we first systematically selected the predictors and explored the nonlinear association of predictors with lung cancer risk using restricted cubic splines.Then,we separately developed risk prediction models to construct a lung cancer risk score(LCRS)in 159,715 ever smokers and 336,526 never smokers.The LCRS was further validated in an independent cohort over a median follow-up of 13.6 years,consisting of 14,153 never smokers and 5,890 ever smokers.Results:A total of 13 and 9 routinely available predictors were identified for ever and never smokers,respectively.Of these predictors,cigarettes per day and quit years showed nonlinear associations with lung cancer risk(Pnon-linear<0.001).The curve of lung cancer incidence increased rapidly above 20 cigarettes per day and then was relatively flat until approximately 30 cigarettes per day.We also observed that lung cancer risk declined sharplywithin the first 5 years of quitting,and then continued to decrease but at a slower rate in the subsequent years.The 6-year area under the receiver operating curve for the ever and never smokers’models were respectively 0.778 and 0.733 in the derivation cohort,and 0.774 and 0.759 in the validation cohort.In the validation cohort,the 10-year cumulative incidence of lung cancerwas 0.39%and 2.57%for ever smokers with low(<166.2)and intermediate-high LCRS(≥166.2),respectively.Never smokers with a high LCRS(≥21.2)had a higher 10-year cumulative incidence rate than those with a low LCRS(<21.2;1.05%vs.0.22%).An online risk evaluation tool(LCKEY;http://ccra.njmu.edu.cn/lckey/web)was developed to facilitate the use of LCRS.Conclusions:The LCRS can be an effective risk assessment tool designed for ever and never smokers aged 30 to 80 years.展开更多
Background:A polygenic risk score(PRS)derived from 112 single-nucleotide polymorphisms(SNPs)for gastric cancer has been reported in Chinese populations(PRS-112).However,its performance in other populations is unknown....Background:A polygenic risk score(PRS)derived from 112 single-nucleotide polymorphisms(SNPs)for gastric cancer has been reported in Chinese populations(PRS-112).However,its performance in other populations is unknown.A functional PRS(fPRS)using functional SNPs(fSNPs)may improve the generalizability of the PRS across populations with distinct ethnicities.Methods:We performed functional annotations on SNPs in strong linkage disequilibrium(LD)with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation.Subsequently,we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort.Finally,the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer.Results:During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases,we found no significant association between the PRS-112 and gastric cancer risk in the European population(hazard ratio[HR]=1.00[95%confidence interval(CI)0.93–1.09],P=0.846).We identified 125 fSNPs,including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs,and used them to construct the fPRS-125.Our result showed that the fPRS-125 was significantly associated with gastric cancer risk(HR=1.11[95%CI,1.03–1.20],P=0.009).Compared to participants with a low fPRS-125(bottom quintile),those with a high fPRS-125(top quintile)had a higher risk of incident gastric cancer(HR=1.43[95%CI,1.12–1.84],P=0.005).Moreover,we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer(HR=4.99[95%CI,1.55–16.10],P=0.007)compared to those with both a favorable lifestyle and a low genetic risk.Conclusion:These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.展开更多
基金supported in part by the National Natural Science Foundation of China (81270044,30972541,30901233)the Doctoral Fund of Ministry of Education of China (20093234110001)A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institution
文摘Apoptosis plays a key role in inhibiting tumor growth, progression and resistance to anti-tumor therapy. We hypothesized that genetic variants in apoptotic genes may affect the prognosis of lung cancer. To test this hypoth- esis, we selected 38 potentially functional single nucleotide polymorphisms （SNPs） from 12 genes （BAX, BCL2, BID, CASP3, CASP6, CASP7, CASPS, CASP9, CASPIO, FAS, FASLG and MCL1） involved in apoptosis to assess their prognostic significance in lung cancer in a Chinese case cohort with 568 non-small cell lung cancer （NSCLC） patients. Thirty-five SNPs passing quality control underwent association analyses, 11 of which were shown to be significantly associated with NSCLC survival （P 〈 0.05）. After Cox stepwise regression analyses, 3 SNPs were independently associated with the outcome of NSCLC （BID rs8190315： P = 0.003; CASP9 rs4645981： P = 0.007 and FAS rs1800682： P = 0.016）. A favorable survival of NSCLC was significantly associated with the genotypes of BID rs8190315 AG/GG （adjusted HR = 0.65, 95% CI： 0.49-0.88）, CASP9 rs4645981 AA （HR = 0.22, 95% CI： 0.07-0.69） and FAS rs1800682 GG （adjusted HR = 0.67, 95% CI： 0.46-0.97）. Time-dependent receptor operation curve （ROC） analysis revealed that the area under curve （AUC） at year 5 was significantly increased from 0.762 to 0.819 after adding the risk score of these 3 SNPs to the clinical risk score. The remaining 32 SNPs were not sig- nificantly associated with NSCLC prognosis after adjustment for these 3 SNPs. These findings indicate that BID rs8190315, CASP9 rs4645981 and FAS rs1800682 polymorphisms in the apoptotic pathway may be involved in the prognosis of NSCLC in the Chinese population.
基金supported in part by National Natural Science Foundation of China (30700684 and 30671814)Jiangsu Natural Science Foundation (BK2008221)the Key Project of Nanjing Medical University (09NJMUZ12)
文摘Objective： Inflammation induced by H.pylori colonization in the stomach is related to the development of gastric cancer and the genetic variations of the genes involved in the immune responses modify the host response to the infection. The aim of this study was to evaluate whether polymorphisms in the toll-like receptor 4 （TLR4） gene, a key regulator of both innate and adaptive immunity, were related to the susceptibility to
基金supported by the National Natural Science Foundation of China for studies on early-stage GI neoplasms(Grant No.81072032 and No.81470830).
文摘Superficial esophageal squamous cell carcinoma(SESCC)is defined as carcinoma with mucosal or submucosal invasion,regardless of regional lymph node metastasis(LNM).The lymph node status is not only a key factor to determine the training strategy,but also the most important prognostic factor in esophageal cancer.In this study,we establish a clinical nomogram for predicting LNM in patients with SESCC.A predictive model was established based on the training cohort composed of 711 patients who underwent esophagectomy for SESCC from December 2009 to June 2018.A prospective cohort of 203 patients from June 2018 to January 2019 was used for validation.Favorable calibration and well-fitted decision curve analysis were conducted and good discrimination was observed(concordance index[C-index],0.860;95%confidence interval[CI],0.825-0.894)through internal validation.The external validation cohort presented good discrimination(C-index,0.916;95%CI,0.860-0.971).This model may facilitate the prediction of LNM in patients with SESCCs.
基金supported by National Natural Science Foundation of China(81502873)the Natural Science Foundation of Jiangsu Province(BK20150997)+3 种基金Priority Academic Program for the Development of Jiangsu Higher Education Institutions(Public Health and Preventive Medicine)Innovation Fund of State key Laboratory of Reproductive Medicine(SKLRMGC201802)Clinical Medicine Research Fund of the Chinese Medical Association(17020420711)Top-notch Academic Programs Project of Jiangsu Higher Education Institutions(PPZY2015A067)
文摘Long noncoding RNA(lncRNA) HOTAIR and MALAT1 are implicated in the development of multiple cancers. Genetic variants within HOTAIR and MALAT1 may affect the gene expression, thereby modifying genetic susceptibility to cervical cancer. A case-control study was designed, including 1 486 cervical cancer patients and 1 536 healthy controls. Based on RegulomeDB database, 11 SNPs were selected and genotyped by using Sequenom’s Mass ARRAY. Univariate and multivariate logistic regression models were used to calculate the odds ratio(OR) and 95% confidence interval(CI). We found that the A allele of rs35643724 in HOTAIR was associated with increased risk of cervical cancer, while the C allele of rs1787666 in MALAT1 was associated with decreased risk. Compared to individuals with 0–1 unfavorable allele, those with 3–4 unfavorable alleles showed18% increased odds of having cervical cancer. Our findings suggest that HOTAIR rs35643724 and MALAT1 rs1787666 might represent potential biomarkers for cervical cancer susceptibility.
基金supported by grants from National Natural Science Foundation of China(No.81001276 and No.81072380)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘MET tyrosine kinase and its ligand,hepatocyte growth factor（HGF）,play a pivotal role in the activties of tumor cells.A germline missense variant in exon 2 of the MET gene,N375S（rs33917957 A〉G）,may alter the binding affinity of MET for HGF and thus modify the risk of tumorigenesis.In this study,we performed a case-control study to assess the association between N375S and gastric cancer risk in 1,681 gastric cancer cases and 1,858 cancer-free controls.Logistic regression analysis was applied to estimate crude and adjusted odds ratios（ORs） and 95% confidence intervals（CIs） for the associations between genotypes and gastric cancer risk.We found that MET N375S variant genotypes（NS/SS） were associated with a significantly decreased risk of gastric cancer（OR = 0.78,95% CI = 0.63-0.96,P = 0.021） compared with the wildtype homozygote（NN）.The finding indicates that this germline variant in MET may decrease gastric cancer susceptibility in Han Chinese.
基金founded by the National Natural Science Foundation of China(81202283,81473070,81373102 and81202267)Key Grant of Natural Science Foundation of the Jiangsu Higher Education Institutions of China(10KJA330034 and11KJA330001)+1 种基金the Research Fund for the Doctoral Program of Higher Education of China(20113234110002)the Priority Academic Program for the Development of Jiangsu Higher Education Institutions(Public Health and Preventive Medicine)
文摘With recent advances in biotechnology, genome-wide association study （GWAS） has been widely used to identify genetic variants that underlie human complex diseases and traits. In case-control GWAS, typical statistical strategy is traditional logistical regression （LR） based on single-locus analysis. However, such a single-locus analysis leads to the well-known multiplicity problem, with a risk of inflating type I error and reducing power. Dimension reduction-based techniques, such as principal component-based logistic regression （PC-LR）, partial least squares-based logistic regression （PLS-LR）, have recently gained much attention in the analysis of high dimensional genomic data. However, the perfor- mance of these methods is still not clear, especially in GWAS. We conducted simulations and real data application to compare the type I error and power of PC-LR, PLS-LR and LR applicable to GWAS within a defined single nucleotide polymorphism （SNP） set region. We found that PC-LR and PLS can reasonably control type I error under null hypothesis. On contrast, LR, which is corrected by Bonferroni method, was more conserved in all simulation settings. In particular, we found that PC-LR and PLS-LR had comparable power and they both outperformed LR, especially when the causal SNP was in high linkage disequilibrium with genotyped ones and with a small effective size in simulation. Based on SNP set analysis, we applied all three methods to analyze non-small cell lung cancer GWAS data.
基金supported by Grants from the National Natural Science Foundation of China(Grant Nos.82103926 and 81702266)Science Fund for Creative Research Groups of the National Natural Science Foundation of China(Grant No.81521004)+3 种基金Natural Science Foundation of Jiangsu Province(Grant No.BK20210534)Postdoctoral Science Foundation of China(Grant No.2021M691636)CAMS Innovation Fund for Medical Sciences(Grant No.2019RU038)Graduate Research and Innovation Program of Jiangsu Province(Grant Nos.KYCX20_1442 and KYCX20_1412).
文摘Objective:Although our previous genome-wide association study(GWAS)has identified chromosome 2q33.1 as a susceptibility locus for non-small cell lung cancer(NSCLC),the causal variants remain unclear.The aims of this study were to identify the causal variants in 2q33.1 and to explore their biological functions in NSCLC.Methods:CCK-8,colony formation,EdU incorporation,Transwell,and quantitative real-time polymerase chain reaction assays were applied to examine variant function.The tumor xenograft model was used to examine variant function in vivo.Caspase-8 activity assays,flow cytometry analysis,and co-immunoprecipitation assays were used to explore the molecular mechanism.Results:The missense variant rs3769823(A>G),which caused the substitution of lysine with arginine at amino acid 14 in caspase-8(caspase-8K14R),was identified as a potential causal candidate in 2q33.1.Compared with the wild type caspase-8(caspase8WT)group,the caspase-8K14R group had higher expression of caspase-8 and cleaved caspase-8.Caspase-8K14R inhibited the proliferation and metastasis of human lung cancer cell lines in vitro.Moreover,caspase-8K14R repressed lung cancer cell growth in vivo.Mechanistically,caspase-8K14R was more sensitive than caspase-8WT to tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-mediated apoptosis and showed higher binding of caspase-8 and FADD.Conclusions:These results suggested that rs3769823 is the causal variant in chromosome 2q33.1 and is involved in an apoptosis pathway,leading to a decreased risk of NSCLC.
文摘The extent to which factors affect the probability of clinical pregnancy in the first fresh embryo transfer after assisted conception is unknown.In order to examine the predictors of clinical pregnancy,a retrospective cohort study was launched between January 1,2013 and December 31,2016 in four infertility clinics including 19837 in vitro fertilization and intracytoplasmic sperm injection(IVF/ICSI)fresh cycles with known outcomes and relevant records.A multivariable logistic regression was used to select the most significant predictors in the final nomogram for predicting clinical pregnancy.Furthermore,the model was validated by an independent validation set and the performance of the model was evaluated by the receiver operating characteristic(ROC)curves along with the area under the ROC curve(AUC)and calibration plots.In a training set including 17854 participants,we identified that female age,tubal factor,number of embryos transferred,endometrial thickness and number of good-quality embryos were independent predictors for clinical pregnancy.We developed a nomogram using these five factors and the predictive ability was 0.66 for AUC(95%CI=0.64−0.68),which was independently validated in the validation set(AUC=0.66,95%CI=0.65−0.68).Our results show that some specific factors can be used to provide infertile couples with an accurate assessment of clinical pregnancy following assisted conception and facilitate to guide couples and clinicians.
基金supported by grants from the Project of National Natural Science Foundation of China (No.81102180,No.81072379)Ministry of Health Research Program (No.WKJ2010-2-032)+1 种基金Wuxi Science & Technology Research Program (No.CSE01016)the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine)
文摘Plasma lipid abnormalities are implicated in the pathogenic process of type 2 diabetes. The IDE-KIFII-HHEX gene cluster on chromosome 10q23.33 has been identified as a susceptibility locus for type 2 diabetes. We hy- pothesized that genetic variants at 10q23.33 may be associated with plasma lipid concentrations. Seven tagging single nucleotide polymorphisms （SNPs： rs7923837, rs2488075, rs947591, rs11187146, rs5015480, rs4646957 and rs1111875） at 10q23.33 were genotyped in 3,281 subjects from a Han Chinese population, using the Taq- Man OpenArray and Sequenom MassARRAY platforms. Multiple linear regression analyses showed that SNP rs7923837 in the 3＂-flanking region of HHEX was significantly associated with triglyceride levels （P = 0.019, 0.031 mmol/L average decrease per minor G allele） and that rs2488075 and rs947591 in the downstream region of HHEX were significantly associated with total cholesterol levels （P = 0.041, 0.058 mmol/L average decrease per minor C allele and P = 0.018, 0.063 mmol/L average decrease per minor A allele, respectively）. However, the other four SNPs （rs11187146, rs5015480, rs4646957 and rs1111875） were not significantly associated with any plasma lipid concentrations in this Chinese population. Our data suggest that genetic variants in the IDE-KIF11- HHEX gene cluster at 10q23.33 may partially explain the variation of plasma lipid levels in the Hart Chinese pop- ulation. Further studies are required to confirm these findings in other populations.
基金supported by National Key Research&Development Program(Grant No.2016YFC1000200,No.2016YFC1000204,and No.2018YFC1004200)the State Key Program of National Natural Science of China(Grant No.31530047)+2 种基金National Natural Science Foundation of China(Grant No.81602927)Innovation Fund of State Key Laboratory of Reproductive Medicine(Grant No.SKLRMGC201802)Top-notch Academic Programs Project of Jiangsu Higher Education Institutions(Grant No.PPZY2015A067)。
文摘There were few studies of cumulative live birth rates(CLBRs) based on multicenter reproductive clinical data from the general Chinese population.Here we report a retrospective cohort study,including 14 311 women with17 315 cycles,in three reproductive centers to evaluate two estimated parameters of CLBRs with multiple transfer cycles of in vitro fertilization(IVF)/intracytoplasmic sperm injection(ICSI) in a Chinese population.We found that CLBRs were related to female age and endometrial thickness.By the fourth transfer cycle,the conservative and optimal estimates of CLBRs were 52.95% and 77.30% in women under 30 years of age,and 18.17% and26.51% in those 37 years of age or older,respectively.The two estimates were 44.70% and 63.15% in women with endometrial thickness more than 7 mm,and 32.05% and 46.18% in those with less than 7 mm,respectively.In addition,body mass index(BMI),duration of infertility,and infertility diagnoses may also be related to CLBRs on certain conditions.The findings from this study on CLBRs after multiple transfer cycles of IVF/ICSI treatment on different conditions in the Chinese population should be beneficial to both infertile couples and clinicians.
基金supported in part the by National Natural Science Foundation of China(81230067,81270044 and 30901233)Doctoral Fund of Ministry of Education of China(20093234110001)+1 种基金New Century Excellent Talents in University(NCET-10-0178)a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘Runs of homozygosity （ROHs） are a class of important but poorly studied genomic variations and may be in- volved in individual susceptibility to diseases. To better understand ROH and its relationship with lung cancer, we performed a genome-wide ROH analysis of a subset of a previous genome-wide case-control study （1,473 cases and 1,962 controls） in a Han Chinese population. ROHs were classified into two classes, based on lengths, intermedi- ate and long ROils, to evaluate their association with lung cancer risk using existing genome-wide single nucleofide polymorphism （SNP） data. We found that the overall level of intermediate ROHs was significantly associated with a decreased risk of lung cancer （odds ratio = 0.63; 95% confidence interval： 0.51-0.77; P = 4.78 × 10-6 ）, while the long ROHs seemed to be a risk factor of lung cancer. We also identified one ROH region at 14q23A that was con- sistently associated with lung cancer risk in the study. These results indicated that ROHs may be a new class of variation which may be associated with lung cancer risk, and genetic variants at 14q23.1 may be involved in the development of lung cancer.
基金supported by grants from the National Natural Science Foundation of China 30400191 and 30570797
文摘Objective： To evaluate the effects of polymorphisms in TLR7 and TLRS（as potential candidate genes） on asthma risk and asthma-related phenotypes. Methods： We consecutively recruited 318 unrelated adult asthmatic patients and 352 healthy volunteers from the same area of southeast China. Genotyping of each selected SNP was performed using multiplex PCR in conjunction with tagged array single base extension technology. We conducted case-control and case-only association studies between the selected SNPs in TLR7 and TLR8 and asthma or asthma-related phenotypes. Results： The T allele of rs5935436 SNP in TLR7 was protective from developing asthma in males （adjusted ORs = 0.126, 95% CIs = 0.016-0.995）. The CT/TT genotype of rs5935436 was less frequent in female asthmatics with allergic rhinitis （adjusted ORs = 0.18, 95% CIs = 0.04-0.90）. The homozygote AA of rs3761623 and GG of rs3764880 were positively associated with lower FEV1% and asthma severity in female asthmatics. These results were confirmed by haplotype analysis. Conclusion：TLR7 and TLR8 polymorphisms may play an important role in the pathogenesis of asthma that is gender-dependent. This could be clinically useful, both for identifying patients at risk of asthma and for preventing its occurrence.
基金supported by National Natural Science Foundation of China(81230067, 81071715, and 81001276)the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘Human genome epidemiology （HUGE） uses sys- tematic applications of epidemiologic methods to as- sess the impact of human genetic variation on health and disease. In the past ten years, human genome epi- demiology has made great progresses along with ad- vances in genomics technologies, which make it pos- sible for the examination of genetic variants in a large sample size at a sufficiently low cost. Genetic associa- tion study in population provides a powerful approach to identify variants or genes associated with disease of interest by comparing distributions of genetic variants between affected and unaffected individuals.
基金supported by National Natural Science Foundation of China(82125033,81872702,82103932,82003534)Natural Science Foundation of Jiangsu Province(BK20200674).
文摘To investigate whether genetic variants may provide additional prognostic value to improve the existing clinical staging system for gastric cancer(GC),we performed two genome-wide association studies(GWASs)of GC survival in the Jiangsu(N=1049)and Shanghai(N=1405)cohorts.By using a TCGA dataset,we validated genetic markers identified from a meta-analysis of these two Chinese cohorts to determine GC survival-associated loci.Then,we constructed a weighted polygenic hazard score(PHS)and developed a nomogram in combination with clinical variables.We also evaluated prognostic accuracy with the time-dependent receiver operating characteristic(ROC)curve,net reclassification improvement(NRI)and integrated discrimination improvement(IDI).We identified a single nucleotide polymorphism(SNP)of rs1618332 at 15q15.1 that was associated with the survival of GC patients with a P value of 4.12×10^(-8),and we also found additional 25 SNPs having consistent associations among these two Chinese cohort and TCGA cohort.The PHS derived from these 26 SNPs(PHS-26)was an independent prognostic factor for GC survival(all P<0.001).The 5-year AUC of PHS-26 was 0.68,0.66 and 0.67 for Jiangsu,Shanghai and their pooled cohorts,respectively,which increased to 0.80,0.82 and 0.81,correspondingly,after being integrated into a nomogram together with variables of the clinical model.The PHS-26 could improve the NRIs by 16.20%,4.90%and 8.70%,respectively,and the IDIs by 11.90%,8.00%and 9.70%,respectively.The 26-SNP based PHS could substantially improve the accuracy of prognostic assessment and might facilitate precision medicine for GC patients.
基金funded by the Jiangsu Province 333 High Level Talents Project,the Beijing Xisike Clinical Oncology Research Foundation (Y-HR2019-0367)the National Natural Science Foundation of China (82102981)+3 种基金the Pukou District Social Cause Science and Technology Development Project in 2020 (S2020-21)the Pukou Branch Hospital of Jiangsu Province Hospital (Nanjing Pukou Central Hospital)General Project of Science and Technology Development Fund in 2021 (KJ2021-22)the Pukou Branch Hospital of Jiangsu Province Hospital (Nanjing Pukou Central Hospital)Major Project of Science and Technology Development Fund in 2021 (KJ2021-1)Jiangsu Hengrui Pharmaceuticals.
文摘Patients with advanced gastric cancer typically face a grim prognosis.This phase 1a(dose escalation)and phase 1b(dose expansion)study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapyfor advanced gastric or gastroesophageal junction adenocarcinoma.The primary endpoints included maximum tolerated dose(MTD)in phase 1a and objective response rate(ORR)across phase 1a and 1b.Phase 1a tested three dose regimens of camrelizumab,apatinib,oxaliplatin,and S-1.Dose regimen 1:camrelizumab 200 mg on day 1,apatinib 250 mg every other day,oxaliplatin 100 mg/m^(2) on day 1,and S-140 mg twice a day on days 1-14.Dose regimen 2:same as dose regimen 1,but oxaliplatin 130mg/m.Dose regimen3:same as dose regimen 2,but apatinib 250 mg daily.Thirty-four patients were included(9 in phase 1a,25 in phase 1b).No dose-limiting toxicities occurred so no MTD was identified.Dose 3 was set for the recommended phase 2 doses and administered in phase 1b.The confrmed ORR was 76.5%(95%CI 58.8-89.3).The median progression-free survival was 8.4 months(95%CI 5.9-not evaluable[NE]),and the median overall survival(OS)was not mature(11.6-NE).Ten patients underwent surgery after treatment and the multidisciplinary team evaluation.Among 24 patients without surgery,the median OS was 19.6 months(7.8-NE).Eighteen patients(52.9%)developed grade≥3 treatment-emergent adverse events.Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer(ChiCTR2000034109).
基金supported by the project of Jiangsu province medical youth talent(QNRC2016059)Nanjing medical science and technique development foundation(ZKX17040 and YKK18153)+1 种基金the National Natural Science Foundation of China(81903382)Cheung Kong Scholars Program of China。
文摘Previous studies have showed clinical characteristics of patients with the 2019 novel coronavirus disease(COVID-19)and the evidence of person-to-person transmission.Limited data are available for asymptomatic infections.This study aims to present the clinical characteristics of 24 cases with asymptomatic infection screened from close contacts and to show the transmission potential of asymptomatic COVID-19 virus carriers.Epidemiological investigations were conducted among all close contacts of COVID-19 patients(or suspected patients)in Nanjing,Jiangsu Province,China,from Jan 28 to Feb 9,2020,both in clinic and in community.Asymptomatic carriers were laboratory-confirmed positive for the COVID-19 virus by testing the nucleic acid of the pharyngeal swab samples.Their clinical records,laboratory assessments,and chest CT scans were reviewed.As a result,none of the 24 asymptomatic cases presented any obvious symptoms while nucleic acid screening.Five cases(20.8%)developed symptoms(fever,cough,fatigue,etc.)during hospitalization.Twelve(50.0%)cases showed typical CT images of ground-glass chest and 5(20.8%)presented stripe shadowing in the lungs.The remaining 7(29.2%)cases showed normal CT image and had no symptoms during hospitalization.These 7 cases were younger(median age:14.0 years;P=0.012)than the rest.None of the 24 cases developed severe COVID-19 pneumonia or died.The median communicable period,defined as the interval from the first day of positive nucleic acid tests to the first day of continuous negative tests,was 9.5 days(up to 21 days among the 24 asymptomatic cases).Through epidemiological investigation,we observed a typical asymptomatic transmission to the cohabiting family members,which even caused severe COVID-19 pneumonia.Overall,the asymptomatic carriers identified from close contacts were prone to be mildly ill during hospitalization.However,the communicable period could be up to three weeks and the communicated patients could develop severe illness.These results highlighted the importance of close contact tracing and longitudinally surveillance via virus nucleic acid tests.Further isolation recommendation and continuous nucleic acid tests may also be recommended to the patients discharged.
基金National Natural Science Foundation of China,Grant/Award Numbers:81820108028,81922061,81973123,82273714,82192901,82192904,82192900Excellent Youth Foundation of Jiangsu Province,Grant/Award Number:BK20220100+3 种基金Research Unit of Prospective Cohort of Cardiovascular Diseases and CancerChinese Academy of Medical Sciences,Grant/Award Number:2019RU038Science and Technology Service Network Initiative of Chinese Academy of Sciences,Grant/Award Number:No.KFJ-STS-QYZD-2021-08-001the National Key Research and Development Program of China,Grant/Award Number:2016YFC0900500。
文摘Background:Most lung cancer risk prediction models were developed in European and North-American cohorts of smokers aged≥55 years,while less is known about risk profiles in Asia,especially for never smokers or individuals aged<50 years.Hence,we aimed to develop and validate a lung cancer risk estimate tool for ever and never smokers across a wide age range.Methods:Based on the China Kadoorie Biobank cohort,we first systematically selected the predictors and explored the nonlinear association of predictors with lung cancer risk using restricted cubic splines.Then,we separately developed risk prediction models to construct a lung cancer risk score(LCRS)in 159,715 ever smokers and 336,526 never smokers.The LCRS was further validated in an independent cohort over a median follow-up of 13.6 years,consisting of 14,153 never smokers and 5,890 ever smokers.Results:A total of 13 and 9 routinely available predictors were identified for ever and never smokers,respectively.Of these predictors,cigarettes per day and quit years showed nonlinear associations with lung cancer risk(Pnon-linear<0.001).The curve of lung cancer incidence increased rapidly above 20 cigarettes per day and then was relatively flat until approximately 30 cigarettes per day.We also observed that lung cancer risk declined sharplywithin the first 5 years of quitting,and then continued to decrease but at a slower rate in the subsequent years.The 6-year area under the receiver operating curve for the ever and never smokers’models were respectively 0.778 and 0.733 in the derivation cohort,and 0.774 and 0.759 in the validation cohort.In the validation cohort,the 10-year cumulative incidence of lung cancerwas 0.39%and 2.57%for ever smokers with low(<166.2)and intermediate-high LCRS(≥166.2),respectively.Never smokers with a high LCRS(≥21.2)had a higher 10-year cumulative incidence rate than those with a low LCRS(<21.2;1.05%vs.0.22%).An online risk evaluation tool(LCKEY;http://ccra.njmu.edu.cn/lckey/web)was developed to facilitate the use of LCRS.Conclusions:The LCRS can be an effective risk assessment tool designed for ever and never smokers aged 30 to 80 years.
基金supported by grants from the National Natural Science Foundation of China(Nos.82125033,82230110,81872702,82003534,and 82273714)the Natural Science Foundation of Jiangsu Province(No.BK20200674)CAMS Innovation Fund for Medical Sciences(No.2019RU038).
文摘Background:A polygenic risk score(PRS)derived from 112 single-nucleotide polymorphisms(SNPs)for gastric cancer has been reported in Chinese populations(PRS-112).However,its performance in other populations is unknown.A functional PRS(fPRS)using functional SNPs(fSNPs)may improve the generalizability of the PRS across populations with distinct ethnicities.Methods:We performed functional annotations on SNPs in strong linkage disequilibrium(LD)with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation.Subsequently,we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort.Finally,the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer.Results:During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases,we found no significant association between the PRS-112 and gastric cancer risk in the European population(hazard ratio[HR]=1.00[95%confidence interval(CI)0.93–1.09],P=0.846).We identified 125 fSNPs,including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs,and used them to construct the fPRS-125.Our result showed that the fPRS-125 was significantly associated with gastric cancer risk(HR=1.11[95%CI,1.03–1.20],P=0.009).Compared to participants with a low fPRS-125(bottom quintile),those with a high fPRS-125(top quintile)had a higher risk of incident gastric cancer(HR=1.43[95%CI,1.12–1.84],P=0.005).Moreover,we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer(HR=4.99[95%CI,1.55–16.10],P=0.007)compared to those with both a favorable lifestyle and a low genetic risk.Conclusion:These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.
