Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma / 医学前沿

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

Genome-wide association study based risk prediction model in predicting lung cancer risk in Chinese / 中华流行病学杂志

<p><b>OBJECTIVE</b>To evaluate the predictive power of risk model by combining traditional epidemiological factors and genetic factors.</p><p><b>METHODS</b>Our previous GWAS data of lung cancer in Chinese were used in training set (Nanjing and Shanghai: 1473 cases vs. 1962 control) and testing set (Beijing and Wuhan: 858 cases vs. 1 115 control). All the single nucleotide polymorphisms (SNPs) associated with lung cancer risk were systematically selected and stepwise logistic regression analysis was used to select independent factors in the training set. The wGRS (weighted genetic score) was further used to calculate genetic risk score. To evaluate the contribution of the genetic factors, 3 risk models were established by using the training set, i.e. smoking model (based on smoking status) , genetic risk model (based on genetic risk score) and combined model (based on smoke and genetic risk score). The predictability of the models were evaluated by the areas under the receiver operating characteristic (ROC) curves, area under curve (AUC), net reclassification improvement (NRI) and integrated discrimination index (IDI). Besides, the results were further verified in the testing set.</p><p><b>RESULTS</b>In the training set, it was found that the AUC of the smoking, genetic risk and combined models were 0.65 (0.63-0.66), 0.60 (0.59-0.62) and 0.69 (0.67-0.71), respectively. Compared with combined model, the predictive power of other two models significantly declined, the difference was statistically significant (P<0.001). Furthermore, compared with the smoking model, the NRI of the combined model increased by 4.57% (2.23%-6.91%) and IDI increased by 3.11% (2.52%-3.69%) in the training set, the difference was statistically significant (P<0.001). Similarly, in the testing set NRI increased by 2.77%, the difference was not statistically significant (P=0.069) , and IDI increased by 3.16%, the difference was statistically significant (P<0.001).</p><p><b>CONCLUSION</b>This study showed that combining 14 genetic variants with traditional epidemiological factors could improve the predictive power of risk model for lung cancer. The model could be used in the screening of high-risk population of lung cancer in Chinese and provide evidence for the early diagnosis and treatment of lung cancer.</p>

Genetic risk score: principle, methods and application / 中华流行病学杂志

Genetic risk score (GRS) is used for evaluating the effects of genetic susceptible factors in risk prediction models.Five methods are commonly used for GRS:i.e.simple count genetic risk score (SC-GRS),odds ratio weighted genetic risk score (OR-GRS),direct logistic regression genetic risk score (DL-GRS),polygenic genetic risk score (PG-GRS) and explained variance weighted genetic risk score (EV-GRS).This paper summarizes the models,application conditions,advantages and limitations of the five methods.The complexity of prediction models increased along with the inclusion of more susceptible SNPs,some method have been developed to solve the problems,but the effects of new methods needs further evaluation.

Effect of heat shock protein 27 on the cardiac dysfunction induced by endotoxemia / 中华急诊医学杂志

Objective To study the effects of heat shock proetin 27(Hsp27)on the cardiac dysfunction induced by endotoxemia.Method All experiments were performed in the geriatric lab of the First Affiliated Hospital Of Nanjing Medical University,and in the Animal Model Center of Nanjing University.The genotyping of the transgenic mice with cardiac-specific overexpression of Hsp27(Hsp27 Tg)was assayed by PCR and the expression of Hsp27 was determined by western blot.Hsp27 Tg and its wild type littermates(WT)were intraperitoneally injected with LPS(10 mg/kg),and 24 hours later,cardiac function was measured by echocardiography(n=6/group).The accumulated mice mortality was recorded within 70 hous after intraperitoneal injection of LPS(20mg/kg)(n=37/WT,n=27/Hsp27Tg).The NF-kB activity for cardiac-tissue samples was analyzed by electrophoretic mobility shift assay(ENSA)and for cell culture samples by dual-reporter gene assay(n=4/group).The comparison of multiple groups was performed by one-way analysis of variance(ANOVA),and comparison of two groups was performed by Scheffe-test.Survival curves were analyzed by the log-rank test.P＜0.05 wns considered to be significant.Results The high expression of Hsp27 exhibited in myocardium of Hsp27 Tg,whereas not in myocardium of WT.LPS significantly reduced the cardiac function both in Hsp27 Tg and WT.However,compaled with LPS-treated WT,cardiac function was more significantly improved as evidenced by the increases of EF by 27.33%and FS by 37.09%(P＜0.01 or P＜0.05).Seventy hours after LPS injection,the mortality was 11.11% in Hsp27 Tg and 37.84% in WT.Compared with WT,the survival rate of Hsp27 Tg significantly increased(P＜0.05).The NF-kB activation was significantly inhibited by Hsp27(P＜0.01 or P＜0.05).Conclusions The high cardiac-specific expression of Hsp27 significantly inhibits cardiac dysfunction induced by endotoxemia,and at the same time improve the survival rate.The mechanism may be connected with Hsp27 downregulating NF-kB-activation induced by LPS.