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• <i>ATG16L1</i> and <i>ATG12</i> Gene Polymorphisms Are Involved in the Progression of Atrophic Gastritis

  Yamaguchi, N; Sakaguchi, T; Isomoto, H; Inamine, T; Ueda, H; Fukuda, D; Ohnita, K; Kanda, T; Kurumi, H; Matsushima, K; Hirayama, T; Yashima, K; Tsukamoto, K

  JOURNAL OF CLINICAL MEDICINE ( Journal of Clinical Medicine )  12 ( 16 )   2023.08 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Helicobacter pylori (H. pylori) infection causes a progression to atrophic gastritis and results in gastric cancer. Cytotoxin-associated gene A (CagA), a major virulence factor of H. pylori, is injected into gastric epithelial cells using the type IV secretion system. On the other hand, gastric epithelial cells degrade CagA using an autophagy system, which is strictly regulated by the autophagy-related (ATG) genes. This study aimed to identify SNPs in ATG5, ATG10, ATG12, and ATG16L1 associated with gastric mucosal atrophy (GMA). Here, two-hundred H. pylori-positive participants without gastric cancer were included. The degree of GMA was evaluated via the pepsinogen method. Twenty-five SNPs located in the four candidate genes were selected as tag SNPs. The frequency of each SNP between the GMA and the non-GMA group was evaluated. The rs6431655, rs6431659, and rs4663136 in ATG16L1 and rs26537 in ATG12 were independently associated with GMA. Of these four SNPs, the G/G genotype of rs6431659 in ATG16L1 has the highest odd ratio (Odds ratio = 3.835, 95% confidence intervals = 1.337-1.005, p = 0.008). Further functional analyses and prospective analyses with a larger sample size are required.

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• Polymorphism in autophagy-related genes <i>LRP1</i> and <i>CAPZA1</i> may promote gastric mucosal atrophy

  Yamaguchi, N; Sakaguchi, T; Isomoto, H; Inamine, T; Tsukamoto, R; Fukuda, D; Ohnita, K; Kanda, T; Matsushima, K; Hirayama, T; Yashima, K; Tsukamoto, K

  GENES AND ENVIRONMENT ( Genes and Environment )  45 ( 1 ) 18 - 18   2023.05 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  BACKGROUND: Helicobacter pylori secretes cytotoxin-associated gene A (CagA) into the gastric epithelium, causing gastric mucosal atrophy (GMA) and gastric cancer. In contrast, host cells degrade CagA via autophagy. However, the association between polymorphisms in autophagy-related genes and GMA must be fully elucidated. RESULTS: We evaluated the association between single nucleotide polymorphisms (SNPs) in autophagy-related genes (low-density lipoprotein receptor-related protein 1, LRP1; capping actin protein of muscle Z-line alpha subunit 1, CAPAZ1; and lysosomal-associated membrane protein 1, LAMP1) and GMA in 200 H. pylori-positive individuals. The frequency of the T/T genotype at rs1800137 in LRP1 was significantly lower in the GMA group than in the non-GMA group (p = 0.018, odds ratio [OR] = 0.188). The frequencies of the G/A or A/A genotype at rs4423118 and T/A or A/A genotype at rs58618380 of CAPAZ1 in the GMA group were significantly higher than those in the non-GMA group (p = 0.029 and p = 0.027, respectively). Multivariate analysis revealed that C/C or C/T genotype at rs1800137, T/A or A/A genotype at rs58618380, and age were independent risk factors for GMA (p = 0.038, p = 0.023, and p = 0.006, respectively). Furthermore, individuals with the rs1800137 C/C or C/T genotype of LRP1 had a 5.3-fold higher susceptibility to GMA. These genetic tests may provide future directions for precision medicine for individuals more likely to develop GMA. CONCLUSION: LRP1 and CAPZA1 polymorphisms may be associated with the development of GMA.

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• Letrozole ameliorates liver fibrosis through the inhibition of the CTGF pathway and 17β-hydroxysteroid dehydrogenase 13 expression.

  Sakai N, Kamimura K, Miyamoto H, Ko M, Nagoya T, Setsu T, Sakamaki A, Yokoo T, Kamimura H, Soki H, Tokunaga A, Inamine T, Nakashima M, Enomoto H, Kousaka K, Tachiki H, Ohyama K, Terai S

  Journal of gastroenterology ( Journal of Gastroenterology )  58 ( 1 ) 53 - 68   2022.10 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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• SNP rs2920280 in PSCA Is Associated with Susceptibility to Gastric Mucosal Atrophy and Is a Promising Biomarker in Japanese Individuals with <i>Helicobacter pylori</i> Infection

  Isomoto, H; Sakaguchi, T; Inamine, T; Takeshita, S; Fukuda, D; Ohnita, K; Kanda, T; Matsushima, K; Honda, T; Sugihara, T; Hirayama, T; Nakao, K; Tsukamoto, K

  DIAGNOSTICS ( MDPI AG )  12 ( 8 ) 1988 - 1988   2022.08 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Helicobacter pylori infection results in gastric cancer (GC) with gastric mucosal atrophy (GMA). Some single-nucleotide polymorphisms (SNPs) in the prostate stem cell antigen gene (PSCA) are associated with GC and duodenal ulcers. However, the relationship of other identified SNPs in PSCA with these diseases remains unclear. Herein, the association between PSCA SNPs and GMA among 195 Japanese individuals with H. pylori infection was evaluated. The definition of GMA or non-GMA was based on serum pepsinogen levels or endoscopic findings. Five tag PSCA SNPs were analyzed using PCR high-resolution melting curve analysis with nonlabelled probes. The frequencies of alleles and the genotypes of each tag SNP were compared between the GMA and non-GMA groups. Subsequently, a genetic test was performed using associated SNPs as biomarkers to detect patients developing GMA. Two tag PSCA SNPs (rs2920280 and rs2294008) were related to GMA susceptibility. Individuals with the rs2920280 G/G genotype or the rs2294008 T/T genotype in PSCA had 3.5- and 2.1-fold susceptibility to GMA, respectively. In conclusion, SNP rs2920280 is a possible biomarker for detecting individuals developing GMA. PSCA polymorphisms may be useful biomarkers for predicting GMA linked to GC risk and a screening endoscopy strategy to detect GC related to early stage H. pylori associated GMA.

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• The SNP rs6508974 in AXL is a functional polymorphism and a promising biomarker for gefitinib treatment

  Megumi Kamikatahira, Tatsuo Inamine, Sara Kawano, Haruna Ohba, Kyohei Obata, Risako Iwanaga, Minoru Fukuda, Masaaki Fukuda, Hiroyuki Yamaguchi, Tatsuro Hirayama, Hiroshi Mukae, Kazuhiro Tsukamoto

  Acta Medica Nagasakiensia ( 長崎大学医学部 )  65 ( 3 ) 111 - 121   2022 [ Peer Review Accepted ]

  Type of publication: Research paper (bulletin of university, research institution)

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  Somatic mutations in epidermal growth factor receptor (<i>EGFR</i>) found in lung adenocarcinomas are used as biomarkers for the treatment with EGFR-tyrosine kinase inhibitors, including gefitinib. The bypass tracks with amplification of AXL is one of the mechanisms underlying the resistance to gefitinib. We, therefore, carried out a candidate gene approach method to identify <i>AXL</i> polymorphisms associated with the effectiveness of gefitinib. <i>EGFR</i> mutations were first identified by mutant-enriched PCR-restriction fragment length polymorphism (RFLP), and then 2 tag single nucleotide polymorphisms (SNPs) of <i>AXL</i> were examined by PCR-RFLP in 62 Japanese patients with advanced lung adenocarcinoma and treated with gefitinib in two general hospitals in Nagasaki. Subsequently, the association of <i>EFGR</i> mutations and the <i>AXL</i> polymorphism with the effectiveness of gefitinib was examined in these patients. We next examined the effect of the <i>AXL</i> polymorphism on the expression and function of this gene. It is worthy of note that <i>EGFR</i> mutations and the <i>AXL</i> polymorphism rs6508974 independently contributed to the effectiveness of gefitinib, and the polymorphism was proved to be a possible biomarker for selecting non-responders and responders to gefitinib treatment even in the absence of <i>EGFR</i> mutations. Furthermore, this SNP increased the transcriptional activity of the <i>AXL</i> transcript variant 3, one of the three <i>AXL</i> transcript variants, which to some extent increased the epithelial-mesenchymal transition in cancer cells. Taken together, <i>AXL</i> is one of the genes that determine the effectiveness of gefitinib and a biomarker for selecting non-responders and responders among lung adenocarcinoma patients with no <i>EGFR</i> mutations, suggesting that rs6508974 in <i>AXL</i> might be a functional SNP in lung adenocarcinoma.

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Other Papers 【 display / non-display 】

Other Papers 【 display / non-display 】

• Intestinal Fungi Contribute to Development of Alcoholic Liver Disease

  Yang, AM; Inamine, T; Chen, P; Wang, LR; Llorente-Izquierdo, AC; Xu, J; Koyama, Y; Kisseleva, T; Torralba, M; Moncera, K; Beeri, K; Chen, CS; Hoffman, HM; Garcia-Tsao, G; Mutlu, EA; Keshavarzian, A; Brown, GD; Ho, SB; Bataller, R; Starkel, P; Fouts, DE; Schnabl, B

  HEPATOLOGY   64   24A - 24A   2016.10  [Refereed]

   

Grant-in-Aid for Scientific Research 【 display / non-display 】

Grant-in-Aid for Scientific Research 【 display / non-display 】

• Grant-in-Aid for Young Scientists(B)

  Project Year: 2017.04  -  2019.03 

  Direct: 0 (YEN)  Overheads: 0 (YEN)  Total: 0 (YEN)

• Grant-in-Aid for Young Scientists(B)

  Project Year: 2014.04  -  2017.03 

  Direct: 0 (YEN)  Overheads: 0 (YEN)  Total: 0 (YEN)