Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations

生物 遗传学 连锁不平衡 等位基因 增强子 全基因组关联研究 基因敲除 遗传关联 基因 单核苷酸多态性 单倍型 基因型 转录因子
作者
Caiwang Yan,Meng Zhu,Yanbing Ding,Ming Yang,Mengyun Wang,Gang Li,Chuanli Ren,Tongtong Huang,Wenjun Yang,Bangshun He,Meilin Wang,Fei Yu,Jinchen Wang,Ruoxin Zhang,Tianpei Wang,Jing Ni,Jiaping Chen,Yue Jiang,Juncheng Dai,Erbao Zhang
出处
期刊:Gut [BMJ]
卷期号:69 (4): 641-651 被引量:50
标识
DOI:10.1136/gutjnl-2019-318760
摘要

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.
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