Tomoki Fukuyama

Genetic polymorphisms of IL17A and pri-microRNA-938, targeting IL17A 3'-UTR, influence susceptibility to gastric cancer.

We report an association between gastric cancer (GC) and polymorphisms in IL17A, rs2275913 (-197 G > A), rs3748067 (*1249 C > T), and pri-miR-938, rs2505901 (T > C). We employed the multiplex PCR-SSCP method to detect gene polymorphisms in 337 GC cases and 587 controls. The minor allele frequency of rs2275913 was significantly higher, and those of rs3748067 and rs2505901 significantly lower, in GC cases than controls. The rs2275913 AA homozygote was associated with an increased risk (OR, 2.38; 95%CI, 1.63-3.46; p < 0.0001) for the development of both intestinal and diffuse types of GC. The rs3748067 T polymorphism was associated with a decreased risk for intestinal GC (OR, 0.511; 95%CI, 0.272-0.962; p = 0.037), whereas rs2505901 C locus carried a decreased risk overall for GC (OR, 0.733; 95%CI, 0.545-0.985; p = 0.039). In addition, rs3748067 T allele was inversely correlated with lymph node metastasis. Our results suggest that polymorphisms in both IL17A and pri-miR-938 contribute to cancer risk susceptibility and therefore can affect the development of gastric cancer.

Association between functional promoter polymorphisms of macrophage migration inhibitory factor (MIF) gene and ulcerative colitis in Japan.

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator. Two functional polymorphisms were identified in the promoter region of MIF gene. We attempted to clarify the associations between these polymorphisms and ulcerative colitis (UC). The study was performed in 111 patients with UC and 209 subjects without UC. We employed the PCR-SSCP method to detect gene polymorphisms. Overall, 5/5-CATT genotype was a decreased risk for the development of UC (OR, 0.51; 95% CI, 0.26-0.99). In addition, 7/7-CATT genotype was significantly associated with chronic continuous phenotype and distal colitis phenotype (OR, 5.49; 95% CI, 1.19-25.3, and OR, 6.10; 95% CI, 1.32-28.2, respectively), whereas 5/5-CATT genotype had an inhibitory effect on the development of UC after 20years of age (OR, 0.33; 95% CI, 0.14-0.82). On the other hand, G-173C polymorphism did not affect the susceptibility to and the phenotypes of UC. Our results suggested that tetranucleotide CATT repeat of MIF gene promoter may be associated with the development of UC and the severity of inflammation in patients with UC.

NFKB1 polymorphism is associated with age-related gene methylation in Helicobacter pylori-infected subjects

CpG island aberrant methylation is shown to be an important mechanism in gene silencing. The important role of NF-κB in the inflammatory response to H. pylori colonization has been indicated. We investigated the influence of NFKB1 polymorphisms, -94 ins/del (rs28362491) and -449 C>G (rs72696119), on the aberrant gene methylation under H. pylori infection. Gastric mucosal samples were obtained from sub-subjects without malignancies. Methylation status of genes (p14ARF, p16INK4a, DAPK and CDH1) was determined by methylation-specific PCR (MSP). The genotyping of NFKB1 was performed by PCR-SSCP. There was a strong allelic association between rs28362491 and rs72696119, and all H. pylori-infected -94 del/del homozygotes had a -449 GG genotype. The -94 del/del homozygosity was significantly associated with risk for development of CpG island high methylation (CIHM) (two or more gene methylations), especially DAPK and CDH1 methylations, and the number of methylated genes was significantly higher in -94 del/del homozygotes than in ins/del and ins/ins (ins carrier) H. pylori-infected elder subjects. In addition, this methylated gene number was significantly increased with age in H. pylori-infected del/del homozygotes, but not in infected ins carriers. Furthermore, the inflammation score was significantly higher in H. pylori-infected del/del homozygotes compared to ins carriers. NFKB1 -94 ins/del ATTG polymorphism (rs28362491) was significantly associated with the increased risk for the development of age-related gene methylation in non-cancerous gastric mucosa under H. pylori-induced inflammation.

Su1848 The −449c>G Polymorphism of NFKB1 Gene, Coding Nuclear Factor-Kappa-B, is Associated With the Susceptibility to Ulcerative Colitis

[Background] A polymorphism rs7521584 is located between MIR200B and MIR 429. Recently, it has been reported that both miR200 and miR429 target c-myb gene and affect the breast cancer cell growth (Cesi V, et al.: Cell cycle 2011). One of both the miR200s and miR429 targeting genes is RIPK2, coding RICK. RICK is an important molecule for inflammation by transmitting NOD signal. Then, we attempted to clarify the association between chronic gastritis and genomic variation rs7521584G>T in Japanese population. [Materials and Methods] Gastric mucosa samples were obtained from 429 subjects with no malignancies. The rs7521584 genotype was determined by PCR-SSCP method using DNA extracted from obtained gastric mucosa. The degree of gastritis was assessed in 393 cases according to the updated Sydney system, serum pepsinogen (PG) I/II levels were measured in 117 cases. [Results] The mean age of the subjects was 59.7 years old, male/female ratio was 253/176, and H. pylori (HP) positive ratio was 63.6%. The distribution of rs7521584G>T genotype in all subjects was 153GG, 215GT and 61TT (HWE, p=0.31). The atrophic gastritis group (GA group) was defined as atrophy score >0 and metaplasia score >0. Then, the distribution of rs7521584G>T genotype in GA group (n=142) was 51GG, 66GT and 22TT. The rs7521584 minor allele frequencies in GA and non-GA groups were 39.6% and 38.2%, respectively. By logistic regression analysis after adjustment for gender, age and H. pylori (HP) infection status, rs7521584 TT homozygote has a significantly high risk for gastric mucosal atrophy (OR: 2.41, 95%CI: 1.10-5.25, p=0.027). In HP positive subjects, TT homozygote was a more significant risk factor for gastric mucosal atrophy (OR: 3.31, 95%CI: 1.35-8.12, p=0.0089). In addition, in the subjects younger than 60 years old, TT homozygote has also significant risk for gastric mucosal atrophy (OR: 3.15, 95%CI: 1.03-9.61, p=0.044). The serum PG I/II ratio was reversely correlated to the age in TT homozygote (p=0.0084 by ANOVA), whereas there was no correlation between age and PG I/II ratio in G carrier (p=0.092). [Conclusions] Our results suggest that rs7521584, in pre-miR429 and premiR200s gene, TT homozygote is a risk factor for the progression of gastric mucosal atrophy under the influence of HP infection.