PT  - JOURNAL ARTICLE
AU  - Caiwang Yan
AU  - Meng Zhu
AU  - Yanbing Ding
AU  - Ming Yang
AU  - Mengyun Wang
AU  - Gang Li
AU  - Chuanli Ren
AU  - Tongtong Huang
AU  - Wenjun Yang
AU  - Bangshun He
AU  - Meilin Wang
AU  - Fei Yu
AU  - Jinchen Wang
AU  - Ruoxin Zhang
AU  - Tianpei Wang
AU  - Jing Ni
AU  - Jiaping Chen
AU  - Yue Jiang
AU  - Juncheng Dai
AU  - Erbao Zhang
AU  - Hongxia Ma
AU  - Yanong Wang
AU  - Dazhi Xu
AU  - Shukui Wang
AU  - Yun Chen
AU  - Zekuan Xu
AU  - Jianwei Zhou
AU  - Guozhong Ji
AU  - Zhaoming Wang
AU  - Zhengdong Zhang
AU  - Zhibin Hu
AU  - Qingyi Wei
AU  - Hongbing Shen
AU  - Guangfu Jin
TI  - Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations
AID  - 10.1136/gutjnl-2019-318760
DP  - 2019 Aug 05
TA  - Gut
PG  - gutjnl-2019-318760
4099  - http://gut.bmj.com/content/early/2019/08/17/gutjnl-2019-318760.short
4100  - http://gut.bmj.com/content/early/2019/08/17/gutjnl-2019-318760.full
AB  - Objective Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development.Design We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies.Results The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10−8 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1, resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L, while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10−9) and 4q28.1 (OR=1.14, p=3.33×10−11) were associated with GC risk.Conclusion We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis.