Additive interactions between <i>PRKAA1</i> polymorphisms and <i>Helicobacter pylori</i> CagA infection associated with gastric cancer risk in Koreans

Eom, Sang‐Yong; Hong, Seonmi; Yim, Dong‐Hyuk; Kwon, Hyojin; Kim, Dae‐Hoon; Yun, Hyo-Yung; Song, Young‐Jin; Youn, Sei-jin; Hyun, Taisun; Park, Joo-Seung; Kim, Byung Sik; Kim, Yong‐Dae; Kim, Heon

doi:10.1002/cam4.926

Cited by 15 publications

(15 citation statements)

References 54 publications

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“…Eom et al. found an additive interaction between H. pylori CagA infection and PRKAA1 polymorphism, and our results are also consistent with their findings (data not shown). We further identified that in subjects with Types I and II H. pylori infection, there were significant associations between PRKAA1 polymorphisms and GC risk.…”

Section: Discussionsupporting

confidence: 93%

Environmental factors, seven GWAS‐identified susceptibility loci, and risk of gastric cancer and its precursors in a Chinese population

et al. 2017

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Gene–environment interactions may increase gastric cancer (GC) risk. Seven susceptibility loci identified by genome‐wide association studies (GWASs) suggest that genetic factors play a role in gastric carcinogenesis. Meanwhile, Helicobacter pylori (H. pylori) infection, smoking, and alcohol drinking are also important environmental factors for gastric cancer. However, studies to explore the role of gene–environment interactions in gastric carcinogenesis, and particularly the relationship between the seven susceptibility loci and their potential interactions with H. pylori infection, smoking, and alcohol drinking in risk of GC, and severe intestinal metaplasia (IM)/dysplasia, have been inconclusive. A total of 1273 subjects in a Chinese population were recruited, and genotyping was carried out using the competitive allele‐specific PCR (KASP) method. Unconditional logistic regression was applied to model the associations between genetic polymorphisms and the disease risk. Effect modifications by H. pylori infection, smoking and alcohol drinking were evaluated. PSCA rs2294008/rs2976392 showed a significant, multiplicative interaction with H. pylori infection in risk of GC. Meanwhile, PRKAA1 rs13361707 had an additive interaction with H. pylori infection. SLC52A3 rs13042395 showed an interaction with alcohol drinking in risk of GC. Moreover, three SNPs, MUC1 rs4072037, ZBTB20 rs9841504 and PRKAA1 rs13361707, were associated with precancerous gastric lesions (severe IM/dysplasia). Our data suggest that genetic predisposition factors identified by GWAS may interact with environmental risk factors, Particularly for H. pylori infection and alcohol consumption, to increase the risk of GC.

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Section: Discussionsupporting

confidence: 93%

Environmental factors, seven GWAS‐identified susceptibility loci, and risk of gastric cancer and its precursors in a Chinese population

et al. 2017

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“…On chromosome 5p13 all GC associated variants were in high LD ( r 2 > 0.8) to the most associated marker (rs6872282) and in high LD ( r 2 > 0.8) to all risk SNPs previously reported at this locus in Asians and Europeans . Thus, together with previous findings, our data provide evidence that one or more of these SNPs represent(s) the true GC conferring variant(s) in both the Asian and European population.…”

Section: Discussionsupporting

confidence: 82%

“…It has already been shown that the COX‐2/PGE2 pathway plays a key role in generation of the inflammatory microenvironment in GC and represents a downstream effector of Toll‐like receptor (TLR) activation that is—among others—triggered through H. pylori infection, the most prominent environmental GC risk factor. Interestingly, one study with H. pylori positive and negative GC cases and controls found a gene‐environment interaction between 5p13 risk SNPs and H. pylori infection that showed association with GC …”

Section: Discussionmentioning

confidence: 99%

Evidence for PTGER4,PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level

et al. 2018

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Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine‐mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10−04) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10−09). On chromosome 5p13 we found cis‐eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10−11). On chromosome 8q24 we observed cis‐eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10−47). In addition, we found trans‐eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10−09). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk‐conferring GC pathomechanisms.

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“…Helicobacter pylori infection was also verified to be positive interaction with PRKAA1 polymorphisms in GC [31]. In the present study, H. pylori infection in GC cells significantly increased the p-NF-jBp50, NF-jBp50 and PRKAA1 expression.…”

Section: Discussionsupporting

confidence: 73%

Involvement of NF-κB signaling pathway in the regulation of PRKAA1-mediated tumorigenesis in gastric cancer

Zhang

Zhou

Zhang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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AMP-activated alpha 1 catalytic subunit (PRKAA1) is one of the subunits of the mammalian 5 0-AMPactivated protein kinase (AMPK) playing an important role in maintaining intracellular energy metabolism and associating with the risk of gastric cancer (GC). This paper aims to uncover the influences of PRKAA1 on the tumorigenesis of GC, as well as the underlying mechanisms. We found that Helicobacter pylori (H. pylori) infection markedly increased p-NF-jBp50 and NF-jBp50 expression, along with the PRKAA1 expression, which was inhibited by NF-jBp50 knockdown. NF-jBp50 and PRKAA1 expression were lower in non-tumor gastric tissues compared with that in GC tumor tissues. Up-regulation of PRKAA1 expression was correlated with poor survival in GC patients. MKN-45 and BGC-823 cells stably knockdown of PRKAA1 were transplanted into nude mice and observed the decreased cell metastasis in the lungs. PRKAA1 knockdown in GC cells showed significant decreases in the cell invasion and migration and inhibited MMP-2 expression and NF-jB activation, whereas PRKAA1 involved in NF-jBp50 mediated GC cell invasion and migration. In conclusion, our findings suggest the involvement of NF-jBp50 in the regulation of PRKAA1 in GC tumorigenesis.

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Additive interactions between PRKAA1 polymorphisms and Helicobacter pylori CagA infection associated with gastric cancer risk in Koreans

Cited by 15 publications

References 54 publications

Environmental factors, seven GWAS‐identified susceptibility loci, and risk of gastric cancer and its precursors in a Chinese population

Environmental factors, seven GWAS‐identified susceptibility loci, and risk of gastric cancer and its precursors in a Chinese population

Evidence for PTGER4,PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level

Involvement of NF-κB signaling pathway in the regulation of PRKAA1-mediated tumorigenesis in gastric cancer

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