Objective To assess the causality between 14 malignant tumors and hypertension.Methods Publicly available datasets from genome-wide association study were used,from which independent genetic variants strongly associated with hypertension and 14 malignant tumors were extracted as instrumental variables for bidirectional Mendelian randomization(MR)analysis,including random effect inverse variance weighted(IVW),simple mode,weighted median,weighted mode and MR-Egger to evaluate the causal effect.Sensitivity analysis was used to test the validity and robustness of the analytical results,and multivariate MR method was used to further control for the effects of confounding factors.Results In the MR analysis of malignant melanoma and hypertension,the study included a total of 11 single nucleotide polymorphisms(SNPs)strongly associated with malignant melanoma.After Bonferroni correction,the IVW-based results showed a causal relationship between malignant melanoma and hypertension(OR=1.67,95％CI:1.27-2.21,P＜0.001).Cochran's Q test,Mendelian randomization pleiotropy residual sum and outlier test and MR-Egger intercept test showed that there were no outliers and no horizontal pleiotropy among the instrumental variables,and the sensitivity analysis of the leave-one-out method showed that there was no single SNP that had a significant impact on the overall results.In the analysis of hypertension and leukemia,the preliminary analysis results showed that there may be a relationship between the two,but after adjusting for confounders,the effect of hypertension on the risk of leukemia was no longer significant.Conclusion Malignant melanoma may be a risk factor in the development of hypertension.

ObjectiveTo explore the effects of genetic variation of obesity-related biological pathways and gene-obesity interactions on the incidence of gastric cancer, so as to better understand the pathogenesis of gastric cancer and help identify high-risk populations for individualized prevention of gastric cancer. MethodsA case-control study based on the Shanghai Suburban Adult Cohort and Biobank study (SSACB) was conducted on the cases with gastric cancer. A total of 267 cases with gastric cancer and 267 healthy controls matched 1∶1 by age and gender using propensity score were included in the study. After genome-wide genotyping, quality control and imputation, 19 250 single nucleotide polymorphism (SNP) sites from 115 genes in 4 obesity-related biological pathways were extracted. Univariate and multivariate logistic regression analyses were used to evaluate the association between these SNP sites and the risk of gastric cancer, and false positive report probability (FPRP) was used for multiple test correction.Data from Biobank Japan (BBJ) and FinnGen public accessible databases were used to validate significant SNP sites. For validated sites, expression quantitative trait loci (eQTL) analysis and differentially expressed genes analysis were further performed. Additive and multiplicative interactions were used to evaluate the gene-obesity interactions on the incidence of gastric cancer. Additive interaction evaluation indicators included relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (SI), while multiplicative interaction evaluation indicators include OR_GxE and P_inter. ResultsA total of 41 SNP sites were significantly associated with the onset of gastric cancer (P_adj<0.05, FPRP_0.1<0.1), among which 7 groups of haplotype blocks were formed. ACACB/ rs2268401 [SSACB: P=0.005, BBJ: P=0.049], HRAS/ rs12785860 (SSACB: P<0.001, FinnGen: P=0.045), and PTPN1/ rs6095985 (SSACB: P<0.001, FinnGen: P=0.023) were significantly associated with the risk of gastric cancer after validation in different populations. Among which, the G allele of HRAS/ rs12785860 was correlated with the downregulation of HRAS mRNA expression (P<0.001), and the expression level of HRAS in gastric cancer tissues was higher than that in adjacent normal tissues (P<0.001). Additionaly, JAK1/rs11208559 showed a positive additive interaction with waist circumstance (WC) on the risk of gastric cancer [RERI=2.29(0.06~4.53), AP=0.57(0.23~0.90), SI=4.03(2.20~5.87)]. ConclusionObesity-related biological pathway SNP sites and their haplotypes are associated with the risk of gastric cancer, suggesting that genetic variations in obesity pathways may affect gastric cancer. The HRAS/ rs12785860 is significantly associated with downregulation of HRAS gene expression, which may serve as a potential genetic marker for gastric cancer. JAK1/rs11208559 interacts with obesity additively on the risk of gastric cancer. Individuals with GC+CC genotypes and pre-central or central obesity have an increased risk of gastric cancer, providing clues and evidences for individualized prevention of gastric cancer.