Abstract 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.
Abstract
Background
CDKN2A
hypermethylation is among the major events associated with carcinogenesis and is also observed in non-neoplastic colonic mucosa in patients with ulcerative colitis (UC). ...Macrophage migration inhibitory factor (MIF) plays a crucial role in promoting gastrointestinal inflammation characteristic of UC. The aim of this study is to explore associations between
CDKN2A
methylation status and
MIF
polymorphisms (rs755622 and rs5844572).
Methods
One hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status of
p14
ARF
and
p16
INK4a
was determined by MSP;
MIF
genotypes were identified by PCR-SSCP.
Results
We found no differences with respect to mean age, gender, clinical type (chronic continuous or relapse/remitting), or extent of disease among the patients with methylated and unmethylated
p14
ARF
or
p16
INK4a
. Carrying the rs755622 C allele indicated a significantly higher risk for
p14
ARF
methylation (odds ratio (OR), 2.16; 95% confidence interval (CI), 1.08–4.32;
p
= 0.030); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk for
p16
INK4a
methylation (OR, 2.57; 95% CI, 1.26–5.24;
p
= 0.0094) after an adjusted regression analysis. The carriers of the rs755662 C allele or the rs5844572 7-repeat allele were both at a significantly higher risk for methylation of both
p14
ARF
and
p16
INK4a
when compared to the cohort in which neither of the genes were methylated (OR, 2.70; 95% CI, 1.22–6.01;
p
= 0.015 and OR, 2.87; 95% CI, 1.25–6.62;
p
= 0.013, respectively). Additionally, carrying rs755622 C allele was significantly associated with CIHM in chronic continuous of clinical type and total colitis (OR, 25.9; 95% CI, 2.55–262.6;
p
= 0.0059 and OR, 4.38; 95% CI, 1.12–17.2;
p
= 0.034, respectively), and carrying 7-repeat allele of rs5844572 was significantly associated in chronic continuous type (OR, 14.5; 95%CI, 1.46–144.3;
p
= 0.022).
Conclusions
Taken together, our findings suggest that
MIF
genotypes associated with inflammation may also be involved in promoting carcinogenesis via
CDKN2A
hypermethylation in patients diagnosed with UC.
This study investigated the trends in idiopathic peptic ulcers, examined the characteristics of refractory idiopathic peptic ulcer, and identified the optimal treatment. The characteristics of 309 ...patients with idiopathic peptic ulcer were examined. We allocated idiopathic peptic ulcers that did not heal after 8 weeks’ treatment (6 weeks for duodenal ulcers) to the refractory group and those that healed within this period to the healed group. The typical risk factors for idiopathic peptic ulcer (atherosclerosis-related underlying disease or liver cirrhosis complications) were absent in 46.6% of patients. Absence of gastric mucosal atrophy (refractory group: 51.4%, healed group: 28.4%; p = 0.016), and gastric fundic gland polyps (refractory group: 17.6%, healed group: 5.9%; p = 0.045) were significantly more common in the refractory group compared to the healed group. A history of H. pylori eradication (refractory group: 85.3%, healed group: 66.0%; p = 0.016), previous H. pylori infection (i.e., gastric mucosal atrophy or history of H. pylori eradication) (refractory group: 48.5%, healed group: 80.0%; p = 0.001), and potassium-competitive acid blocker treatment (refractory group: 28.6%, healed group, 64.1%; p = 0.001) were significantly more frequent in the healed group compared to the refractory group. Thus, acid hypersecretion may be a major factor underlying the refractoriness of idiopathic peptic ulcer.
CpG methylation of tumor suppressor genes occurs in the early stage of carcinogenesis. Detecting risk factors for aberrant CpG methylation is clinically important for predicting cancer development. ...DNA methyltransferase (DNMT) 3a is considered to play critical roles in the DNA methylation process during pathogenesis. In this study, we evaluated the association between DNMT3A polymorphisms (rs6733868 and rs13428812) and CpG methylation status in non-cancerous gastric mucosa. We determined the DNMT3A genotype and CpG methylation status of 4 genes (p14.sup.ARF, p16.sup.INK4a, DAPK, and CDH1) in 510 subjects without gastric cancer. Helicobacter pylori (HP) infection status was determined by the rapid urease test, urea breath test, speculum examination, or serum antibody test. We determined the DNMT3A genotype using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). CpG methylation status was determined by methylation-specific polymerase chain reaction (MSP). When the methylated band was stronger than 10 ng/muL according to the DNA marker, we judged CpG island hypermethylation (CIHM) to be present. Associations between genotypes and susceptibilities were assessed by logistic regression analysis. The minor allele frequencies of both polymorphisms (rs6733868 and rs13428812) were lower in the CpG methylated groups of each of the 4 genes (p14.sup.ARF, p16.sup.INK4a, DAPK, and CDH1). Using a dominant genetic model, rs6733868 was significantly associated with the hypermethylation of each gene, whereas rs13428812 was associated with the methylation of 3 genes (all except p14.sup.ARF). When low-CIHM was defined as 1 or 2 CpG islands methylated and high-CIHM was defined as 3 or more CpG islands methylated, carrying the minor allele of rs6733868 was associated with both decreased low- and high-CIHM, and that of rs13428812 also was associated with a decrease. Comparing low-CIHM with high-CIHM, carrying the minor alleles of rs6733868 or rs13428812 was related to decreased susceptibility to high-CIHM. In HP-infected subjects, carrying the minor alleles of rs6733868 or rs13428812 had a significantly greater association with decreased susceptibility to high-CIHM. Our study indicates that polymorphisms of DNMT3A are associated with the accumulation of gene methylation in gastric mucosa. Carrying the minor alleles of rs6733868 or rs13428812 inhibits aberrant gene methylations, which are typically enhanced by HP infection.
Background
Visceral sensory impulses are transmitted via C-fibers from the gastrointestinal tract to the central nervous system. The tetrodotoxinresistant (TTX-r) sodium channel, Na(V) 1.8/SNS ...(sensory-neuron specific), encoded by
SCN10A
, has been identified on C-fibers. We attempted to clarify the association between functional dyspepsia (FD) and
SCN10A
non-synonymous polymorphisms (2884 A>G, 3218 C>T and 3275 T>C).
Methods
The study was performed in 642 subjects (345 with no symptoms and 297 with FD). We employed a multiplex polymerase chain reaction single-strand confirmation polymorphism (PCR-SSCP) method to detect the gene polymorphisms.
Results
The 3218 CC homozygotes had a reduced risk for the development of FD odds ratio (OR) 0.589; 95 % confidence interval (CI) 0.402–0.864;
p
= 0.0067. In addition, both 2884 A>G and 3275 T>C, which were in linkage disequilibrium, were also associated with the development of FD (
p
= 0.039 and 0.028, respectively). Each 2884 G carrier, 3218 CC homozygote, and 3275 C carrier had a reduced risk for the development of both epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). The subjects with the 2884 G allele, 3275 C allele, and no 3218 T allele had a reduced risk for FD (OR 0.618; 95 % CI 0.448–0.853;
p
= 0.0034). This haplotype was associated with a reduced risk for both EPS and PDS (
p
= 0.0011 and 0.0056, respectively). In addition, there was a significant association between FD and this haplotype in
Helicobacter pylori
-negative subjects (OR 0.463; 95 % CI 0279–0.9768;
p
= 0.0029).
Conclusion
We conclude that genetic polymorphisms of
SCN10A
are closely associated with FD (both EPS and PDS), especially in
H. pylori
-negative subjects, in Japanese.
AIM To investigate whether single nucleotide polymorphisms in maf protein K(MAFK), which encodes the MAFK, lead to increased susceptibility to ulcerative colitis in the Japanese population. METHODS ...This case control study examined the associations between MAFK single nucleotide polymorphisms(rs4268033 G>A, rs3735656 T>C and rs10226620 C>T) and ulcerative colitis susceptibility in 174 patients with ulcerative colitis(UC) cases, and 748 subjects without no lower abdominal symptoms, diarrhea or hematochezia(controls). In addition, as the second controls, we set 360 subjects, who have an irregular bowel movement without abnormal lower endoscopic findings(IBM controls).RESULTS The genotype frequency of rs4268033 AA and allelic frequency of the rs4268033 A allele were significantly higher in the UC cases than in both controls(P = 0.0005 and < 0.0001, P = 0.015 and 0.0027 vs controls and IBM controls, respectively). Logistic regression analysis after adjustment for age and gender showed that the rs4268033 AA and rs3735656 CC genotypes were significantly associated with susceptibility to UC development(OR = 2.63, 95%CI: 1.61-4.30, P = 0.0001 and OR = 1.81; 95%CI: 1.12-2.94, P = 0.015, respectively). Similar findings were observed by the comparison with IBM controls. In addition, the rs4268033 AA genotype was significantly associated with all phenotypes of UC except early onset. There was no significant association between rs10226620 and ulcerative colitis. CONCLUSION Our results provide the first evidence that MAFK genetic polymorphisms are significantly associated with susceptibility to UC development. In particular, rs4268033 is closely associated with an increased risk for the development of UC.
Background
The role of genetics in the susceptibility to functional dyspepsia (FD) remains unclear. We attempted to clarify the association between FD and polymorphisms in
SLC6A4
. In addition, ...rs5981521 (C>T) in the pri-microRNA 325 (pri-miR-325) coding region was also investigated.
Methods
The study was performed in 395 subjects (172 with no upper abdominal symptoms and 223 with FD, including medication-resistant FD). We employed a polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method to detect gene polymorphisms.
Results
Neither
SLC6A4
−185 A>C nor *463 G>T was associated with susceptibility to FD. The number of rs5981521 T alleles was significantly correlated with an increased risk for FD (odds ratio OR 1.45, 95 % confidence interval CI 1.05–1.98;
p
= 0.022) and the TT homozygote was more closely associated with the risk for FD (OR 3.01, 95 % CI 1.41–6.42;
p
= 0.0043). The TT homozygote also had significantly increased risks for both the epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS) subtypes of FD (OR 3.04, 95 % CI 1.25–7.42;
p
= 0.014 and OR 3.05, 95 % CI 1.14–8.13;
p
= 0.026, respectively). In addition,
Helicobacter pylori
-negative TT homozygotes had a greater risk for FD (OR 8.37, 95 % CI 1.78–39.5;
p
= 0.0072). In subjects with the
SLC6A4
5′-untranslated region (UTR) wild homozygote, the number of rs5981521 T alleles was significantly correlated to an increased risk for FD (OR 1.45, 95 % CI 1.03–2.04,
p
= 0.033). Of note, in subjects who were
SLC6A4
3′-UTR mutant carriers, the number of rs5981521 T alleles was also significantly correlated with an increased risk for FD (OR 2.07, 95 % CI 1.08–3.98;
p
= 0.029).
Conclusions
Our results suggest that the genetic polymorphism pri-miR-325 is associated with FD and interacts with
SLC6A4
polymorphisms in increasing susceptibility to FD in Japanese.
Interleukin-17A plays a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. We investigated the association between ulcerative colitis (UC) and ...polymorphisms of
IL17A
, rs2275913 (−197 G > A), and rs3748067 (*1249 C > T). The study was performed in 475 healthy subjects (controls) and 202 with UC (UC cases), including 113 controls and 64 UC cases from previous study. We employed the multiplex PCR-SSCP method to detect gene polymorphisms. The minor allele frequency of rs2275913 was significantly higher but that of rs3748067 was significantly lower in UC cases than controls. The rs2275913 minor homozygote (AA) had an increased risk of the development of UC, whereas rs3748067 minor carrier (CT + TT) had decreased risks for the development of UC. When compared with LR group (rs2275913 GG + GA with rs3748067 CT + TT), HR group (rs2275913 AA with rs3748067 CC) had a more increased risk of the development of UC (OR, 3.38;
p
= 0.0007). The polymorphisms of
IL17A
were associated with the noncontinuous and pancolitis phenotypes of UC. Our results suggest that
IL17A
polymorphisms (both rs2275913 and rs3748067) influence the susceptibility to and pathophysiological features of UC, coordinately.
There have been reports showing a protective role of nonsteroidal anti‐inflammatory drugs (NSAIDs) against gastrointestinal cancers. CpG island hyper methylation (CIHM) of tumor suppressor genes is a ...major event in carcinogenesis. We investigated the CIHM status of non‐cancerous gastric mucosa in chronic NSAID users and non‐users and assessed the effect of NSAIDs on CIHM. Gastric mucosa samples were obtained from 51 chronic NSAID users and 180 non‐users. CIHM of p14(ARF), p16(INK4a), death‐associated protein kinase (DAP‐kinase), and E‐cadherin (CDH1) genes were determined by methylation‐specific PCR. CIHM high was defined as two or more CpG islands methylated. CIHM of p14, p16, CDH1, and CIHM high were lower in chronic NSAID users than in non‐users (p14: non‐users vs users = 32.2%vs 9.8%, P = 0.003; p16: non‐users vs users = 35.0%vs 15.7%, P = 0.02; CDH1: non‐users vs users = 36.1%vs 9.8%, P = 0.0009; CIHM high: non‐users vs users = 44.4%vs 17.6%, P = 0.0009). NSAID use was also associated with decreased number of CIHM by anova (R = –0.32, P < 0.0001). Multivariate logistic regression analysis with adjustment for sex, age, Helicobacter pylori infection, and NSAID use revealed that NSAID use was inversely correlated with all four CIHM and CIHM high as an independent factor (p14: odds ratio OR = 0.17, 95% confidence interval CI = 0.06–0.48; p16: OR = 0.32, 95% CI = 0.14–0.75; DAP‐kinase: OR = 0.45, 95% CI = 0.22–0.92; CDH1: OR = 0.18, 95% CI = 0.06–0.48; CIHM high: OR = 0.21, 95% CI = 0.09–0.49). No association was found between CIHM status and the duration or dose of NSAIDs. Chronic NSAID use suppresses CIHM in human gastric mucosa. NSAIDs may have a suppressive role against methylation‐related gastric carcinogenesis. (Cancer Sci 2009; 100: 1192–1197)
We encountered three cases with incidental penetration of a straight Amsterdam-type bile duct plastic stent into the duodenal papilla. All patients had undergone insertion of a biliary plastic stent ...due to common bile duct stones. However, in all three cases, we observed penetration of the biliary plastic stent into the duodenal papilla just before the elective surgery or at the time of plastic stent replacement. We, therefore, performed stent dissection using a bipolar snare and were able to safely remove the plastic stents in all three cases. We believe that this is the first report of plastic stent dissection using a bipolar snare.
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