CpG 岛基因变异与胃腺癌易感性相关。

A genetic variation in the CpG island of pseudogene GBAP1 promoter is associated with gastric cancer susceptibility.

机构信息

Department of Environmental Genomics, Center for Global Health, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.

Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.

出版信息

Cancer. 2019 Jul 15;125(14):2465-2473. doi: 10.1002/cncr.32081. Epub 2019 Apr 5.

DOI:10.1002/cncr.32081

PMID:30951202

Abstract

BACKGROUND

Previous genome-wide association studies (GWASs) have identified that several single nucleotide polymorphisms (SNPs) are implicated in gastric cancer (GC) risk. However, the multiple statistical comparisons of GWASs may reject some true biological positives with subthreshold P values.

METHODS

This study annotated the genomic locations of all CpG islands in the genome using the Encyclopedia of DNA Elements (ENCODE). The SNPs in the regions were then genotyped using the Illumina 660W Quad chip. The effects of the prominent variations on GC risk were further confirmed in the other independent cohorts.

RESULTS

SNP rs2990245, which is located in the promoter of pseudogene GBAP1, was associated with GC risk using GWASs data. An additional cohort of 1275 GC patients and 1424 controls validated that individuals with the CC genotype had a 62% decreased risk of GC compared with those who carried the TT genotype (P = 2.01E-04) in the codominant model. The significant association was observed in the additive, dominant, and recessive models. A meta-analysis combining the results from the GWASs and replication studies revealed that rs2990245 was significantly associated with decreased GC risk (P = 5.59E-12). Importantly, rs2990245 can regulate the expression of GBAP1 by influencing the methylation status of the GBAP1 promoter. GBAP1 can act as a competing endogenous RNA by binding competitively with micro-RNA-212-3p and then promoting GBA expression.

CONCLUSION

rs2990245 is significantly associated with a decreased risk of GC. Pseudogene GBAP1 contributes to the development and progression of GC by sequestering the miR-212-3p from binding to GBA.

摘要

背景

先前的全基因组关联研究（GWAS）已经确定了几个单核苷酸多态性（SNP）与胃癌（GC）风险相关。然而，GWAS 的多次统计比较可能会以亚阈值 P 值拒绝一些真正的生物学阳性结果。

方法

本研究使用 DNA 元件百科全书（ENCODE）注释了基因组中所有 CpG 岛的基因组位置。然后使用 Illumina 660W Quad 芯片对这些区域的 SNP 进行基因分型。在其他独立队列中进一步证实了显著变异对 GC 风险的影响。

结果

位于假基因 GBAP1 启动子中的 SNP rs2990245，使用 GWASs 数据与 GC 风险相关。在加性、显性和隐性模型中均观察到显著的关联。在共显性模型中，与携带 TT 基因型的个体相比，携带 CC 基因型的个体患 GC 的风险降低了 62%（P=2.01E-04）。在加性、显性和隐性模型中均观察到显著的关联。结合 GWASs 和复制研究的结果进行荟萃分析表明，rs2990245 与降低 GC 风险显著相关（P=5.59E-12）。重要的是，rs2990245 可以通过影响 GBAP1 启动子的甲基化状态来调节 GBAP1 的表达。GBAP1 可以作为一种竞争性内源 RNA，通过与 micro-RNA-212-3p 竞争结合，从而促进 GBA 的表达。