Association between interleukin‑1β and tumor necrosis factor‑α polymorphisms and symptoms of dyspepsia
- Authors:
- Published online on: January 8, 2015 https://doi.org/10.3892/mmr.2015.3163
- Pages: 3888-3893
Abstract
Introduction
The most common cause underlying the development of symptoms of dyspepsia in the West, and increasingly in other parts of the world, is functional dyspepsia (FD) (1), which affects ~25% of the population worldwide (2). Symptoms of dyspepsia are defined by the presence of ‘chronic or recurrent symptoms centered in the upper abdomen in the absence of any organic, systemic or metabolic disease that is likely to explain the symptoms’ (3).
FD is a heterogeneous disorder, which lacks a well-defined pathophysiology. Gastrointestinal motor abnormalities (4,5), altered visceral sensation (6,7) and psychosocial factors (8,9) have been investigated as potential pathophysiological mechanisms underlying the development of FD, and their altered functions may be partially explained by genetic abnormalities (10–12). A study reporting familial clustering of FD suggested that genetic factors may exhibit a significant role in mediating the development of FD (13).
Infection with Helicobacter pylori (H. pylori) represents a significant pathogenic factor underlying gastric disorders. Numerous studies have revealed associations between H. pylori infection and multiple gastric diseases (14,15). H. pylori infection results in persistent colonization, chronic gastric inflammation and gastric atrophy (15). Patients infected with H. pylori, exhibiting chronic or recurrent upper abdominal symptoms, without ulceration or erosion of the gastroduodenal mucosa as identified by gastrointestinal endoscopy, are diagnosed with FD according to the Rome III criteria (3). For this reason, at least one FD subtype may be associated with the pathological state induced by H. pylori infection; however, to date, the data have remained inconclusive (16,17). A study demonstrated that post-infectious FD symptoms may persist following the elimination of gastrointestinal infection, in addition to the development of post-infectious irritable bowel syndrome accompanying the colonic inflammation (18). These observations suggested that an altered inflammatory immune response may influence the development of functional gastrointestinal diseases.
Interleukin (IL)-1β and tumor necrosis factor (TNF)-α are particularly important in the initiation and amplification of the inflammatory responses to H. pylori infection (19,20). The two cytokines have been demonstrated to be upregulated in the H. pylori-infected mucosa. Furthermore, IL-1β and TNF-α are potent inhibitors of gastric acid secretion (21,22), which is a significant factor for the mediation of dyspeptic symptoms (23,24). IL-1β is a 100-fold more potent inhibitor of gastric acid secretion than proton pump inhibitors, and a 6,000-fold more potent inhibitor than H2-receptor antagonists (H2RAs) (21).
The human IL-1β gene has multiple polymorphisms, and the C>T and T>C transitions at positions -511 and -31, respectively, have been reported to be associated with inter-individual variations in physiological IL-1β concentrations (25,26). The IL-1β -511 TT and CT genotypes are associated with increased IL-1β production compared with that of the IL-1β -511 CC genotype (25,27). The IL-1β -511 genotypes have been reported to be in linkage disequilibrium with IL-1β -31 among ethnically distinct populations (28,29).
The TNF-α gene also contains multiple polymorphisms and three of these polymorphisms, TNF-α -1031 (T>C), -863 (C>A) and -857 (C>T), which are in linkage disequilibrium, have been identified amongst Japanese individuals (30–32). These polymorphisms have been associated with increased transcriptional promoter activity (30,31).
Due to the significant role of inflammatory responses against H. pylori in the development of gastrointestinal diseases, multiple studies have evaluated the effects of IL-1β and TNF-α polymorphisms on the development of H. pylori-associated gastric diseases, including gastric cancer and peptic ulcer diseases (25,26,30). However, to the best of our knowledge, there have been no studies investigating the potential association between IL-1β and TNF-α polymorphisms, and FD. The function of IL-1β and TNF-α in the mediation of the H. pylori-associated inflammatory immune response and gastric acid secretion may represent a significant influencing factor in the induction of dyspeptic symptoms, and inter-individual functional differences caused by polymorphisms may be associated with altered susceptibility to the development of FD.
Accordingly, the present study was designed to evaluate a potential association between common polymorphisms in the IL-1β gene [-31 (T>C)], which is in linkage disequilibrium with IL-1β polymorphism -511 (C>T) (28,29), and TNF-α polymorphism -857 (C>T), which is in complete linkage disequilibrium with TNF-α polymorphisms -1031 (T>C) and -863 (C>A) (32), and dyspeptic symptoms. In addition, the association between these polymorphisms and various subtypes of symptoms, including the Rome III classification, were assessed.
Materials and methods
Study populations
Study populations were recruited from patients attending the Endoscopy Center of Fujita Health University Hospital (Tayoake, Japan) between January 2007 and December 2009. All patients recruited underwent upper gastroscopy for various reasons, including for a health check or a secondary complete check up of stomach cancer following a barium radiograph or complaints of abdominal discomfort. Patients diagnosed with significant upper gastrointestinal results, including peptic ulcer disease, reflex esophagitis and malignancies, identified following gastroscopy were excluded from the study. Patients with malignancies in other organs, or who had received nonsteroidal anti-inflammatory drugs, antibiotics or H. pylori-eradication treatment were also excluded. Patients with other diseases were also excluded via a face-to-face medical history and physical examination, including blood tests, abdominal ultrasound and electrocardiogram. Patients were required to complete a questionnaire prior to gastroscopy, and patients with dyspepsia were identified as those individuals exhibiting a primary compliant of either continuous or intermittent dyspepsia for three months, predominantly located in the upper abdomen and irrespective of the use of H2RAs or proton-pump inhibitors. Control participants were recruited from those individuals who were negative for dyspeptic symptoms within the preceding 12 months. Those who had received treatment with proton-pump inhibitory drugs or H2-receptor antagonists during the previous 12 weeks were excluded from the control group. According to the criteria outlined, 261 subjects, comprising 126 control subjects and 135 subjects exhibiting symptoms of dyspepsia, were included in the present study. The 135 subjects with dyspeptic symptoms, were divided into the following seven categories based on their symptomatic subtypes: Upper abdominal pain (n=48), heavy feeling in stomach (n=24), upper abdominal discomfort (n=23), nausea (n=22), burning sensation (n=26), anorexia (n=6), belching (n=6) and other symptoms (n=19). Amongst the symptomatic group, 102 patients were diagnosed as having only one symptom, while the remaining 33 patients were diagnosed with 2–4 symptoms. Furthermore, dyspeptic symptoms were classified as epigastric pain syndrome (EPS)-like symptoms or postprandial distress syndrome (PDS)-like symptoms, according to the Rome III criteria (3). EPS-like symptoms were defined as epigastric pain and burning, whereas PDS-like symptoms were defined by postprandial fullness and early satiation. Dyspeptic symptoms, which met neither EPS- nor PDS-like symptoms were classified as other. According to these criteria, 71, 45 and 31 patients were diagnosed with EPS-like, PDS-like and other symptoms, respectively. Amongst these groups, 13 patients were diagnosed as having EPS- and PDS-like symptoms. H. pylori infection status was assessed by serological or histological analysis or a urea breath test. Patients were diagnosed with H. pylori infection following a positive result in at least one of these diagnostic tests. The experimental protocol was approved by the Ethics Committee of Fujita Health University School of Medicine (Toyoake, Japan) and written informed consent was obtained from all participants.
Genotyping for IL-1β and TNF-α polymorphisms
Genomic DNA was extracted from uninvolved mucosa of the gastric antrum or peripheral blood using the standard phenol/chloroform method in all patients (32,33). Subsequently, polymorphisms at position -31 (T>C) and of the IL-1β gene and -857 (C>T) of the TNF-α gene were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method (32,33).
Statistical analysis
Variations in genotype frequencies between two groups were determined using one- or two-sided Fisher’s exact test. Furthermore, the strength of association between genotype frequencies and the disease was assessed by calculating the odds ratio (OR) and 95% confidence intervals (CIs). P<0.05 was considered to indicate a statistically significant difference.
Results
Characteristics of the study population
The characteristics of the study population are summarized in Table I. In the comparison between subjects without symptoms and subjects with dyspeptic symptoms, the mean age was not significantly different between the two groups; however, symptoms of dyspepsia were observed to be significantly greater in female subjects and subjects positive for H. pylori-infection.
IL-1β polymorphisms are associated with the risk of developing dyspeptic symptoms
The prevalence of IL-1β and TNF-α polymorphisms amongst all subjects, and in subjects with or without dyspeptic symptoms are exhibited in Table II. All polymorphisms were successfully genotyped and the prevalence of the polymorphisms detected was similar to that reported by previous Japanese studies (32,33).
 | Table IIPrevalence of IL-1β and TNF-α polymorphisms, in subjects with or without dyspeptic symptoms. |
A comparison of genotype frequencies revealed that the frequency of the IL-1β -31 CC genotype was significantly lower among subjects with dyspeptic symptoms when compared with subjects without symptoms (38.1 vs. 25.9%, P=0.046). The ORs and 95% CIs of the CC genotype were, 0.57 and 0.34–0.96. Conversely, the other genotypes investigated (TT and TC) were associated with a significantly higher risk of dyspeptic symptoms (OR, 1.76; 95% CI, 1.04–2.98).
No significant associations were identified between the TNF-α -857 polymorphisms and dyspeptic symptoms.
IL-1β polymorphisms are associated with various subtypes of symptoms
The prevalence of IL-1β and TNF-α polymorphisms in seven distinct symptomatic subtypes are shown in Table III. The frequency of the IL-1β -31 CC genotype was found to be significantly lower amongst subjects with upper abdominal pain when compared with subjects without symptoms (P=0.003). The OR and 95% CI of the IL-1β -31 CC genotype were 0.28 and 0.12–0.67. However, the other genotypes investigated (TT and TC) were associated with a significantly higher risk of upper abdominal pain (OR, 3.60; 95% CI, 1.50–8.68) than that of the CC. It was also demonstrated that the frequency of the IL-1β -31 CC genotype was lower in subjects with nausea and burning sensations, but this association was not significant (P=0.09 and 0.07, respectively). The prevalence of IL-1β and TNF-α polymorphisms, and distinct symptomatic subtypes according to the Rome III criteria are shown in Table IV. It was revealed that the frequency of the IL-1β -31CC genotype was significantly lower amongst subjects with EPS-like symptoms (P=0.003). The OR and 95% CI of the CC genotype were 0.14 and 0.07–0.28. Conversely, the other genotypes investigated (TT and TC) were associated with a significantly higher risk of upper abdominal pain (OR, 7.25; 95% CI, 3.60–14.61) compared with that of the CC genotype.
Logistic regression analysis
As a significant correlation between female gender and positive H. pylori infection and symptoms of dyspepsia, logistic regression analysis with adjustments for these factors was performed in order to verify the associations between the IL-1β -31 genotype and susceptibility to dyspeptic symptoms, including upper abdominal pain and EPS-like symptoms. It was revealed that the association between IL-1β -31 genotype and all dyspeptic symptoms did not remain following logistic regression analysis (P=0.078; adjusted OR and 95% CI for CC: 0.62 and 0.36–1.06; adjusted OR and 95% CI for TT+TC: 1.62, and 0.95–2.98).
However, the associations between IL-1β -31 genotype and upper abdominal pain and EPS-like symptoms remained following logistic regression analysis (upper abdominal pain: P=0.014, adjusted OR and 95% CI for CC were 0.34 and 0.14–0.80, adjusted OR and 95% CI for TT+TC were 2.94, and 1.25–6.94; and EPS-like symptoms: P=0.015, adjusted OR and 95% CI for CC were 0.41 and 0.20–0.84, adjusted OR and 95% CI for TT+TC were 2.44 and 1.19–4.98).
Discussion
The results of the present study indicated that the IL-1β -31 polymorphism was associated with susceptibility to dyspeptic symptoms; in particular, upper abdominal pain and EPS-like symptoms. The CC genotype homozygous variant was associated with a significantly lower risk of all dyspeptic symptoms, abdominal pain and EPS-like symptoms. The associations with upper abdominal pain and EPS-like symptoms were also retained as an independent factor following logistic regression analysis. Conversely, the other genotypes investigated (TT and TC) were associated with a significantly higher risk of these symptoms.
The IL-1β -31 C allele had previously been reported to be in linkage disequilibrium with the IL-1β -511 T allele in ethnically diverse populations (28,29). The IL-1β -511 TT and CT variant genotypes have also been reported to be associated with increased IL-1β production in comparison to that of the IL-1β -511 CC genotype (25,26). Wang et al (19) found that enhanced IL-1 gene expression was associated with more severe corpus gastritis and suppressed gastric acid secretion. Their group also reported that the IL-1β -511 variant allele, a high IL-1β-producing genotype, was associated with lower gastric acid secretion and atrophic gastritis in H. pylori-infected subjects (33). Therefore, increased production of IL-1β by high-producing genotypes, resulted in enhanced suppression of gastric acid secretion (25,26). It has also been demonstrated that direct acid infusion into the stomach or duodenum affects gastroduodenal motility, as well as sensation, and a role for gastric acid in FD has been suggested (23,24). In this context, it may be reasonable to hypothesize that the IL-1β -31 CC genotype, a high-producing genotype, may be associated with enhanced suppression of gastric acid secretion and therefore a reduction in the risk of developing dyspeptic symptoms. In addition, since IL-1β is important in initiating and amplifying inflammatory responses in the stomach, particularly following H. pylori infection, inter-individual variations in the inflammatory immune response generated by IL-1β -31 polymorphisms may also explain the results observed in the present study.
Notably, no significant associations were detected between TNF-α -857 polymorphisms and dyspeptic symptoms, including the various subtypes, which suggested that the TNF-α -857 polymorphism was unlikely to be an influencing factor in the development of dyspeptic symptoms.
Amongst the symptomatic subtypes, the IL-1β -31 polymorphism was closely associated with upper abdominal pain and EPS-like symptoms, which suggested that symptomatic subgroups of FD may have distinct genetic backgrounds. FD is varied in its pathophysiology, clinical progression, prognosis and response to treatment; thus, it was hypothesized that FD may be a syndrome in which multiple pathogenic mechanisms converge to generate diverse clinical phenotypes. A greater emphasis on disease heterogeneity may be required in order to improve the diagnosis and treatment of FD. The results of the present study suggested that the IL-1β -31 polymorphism may be an influencing factor for specific subgroups of FD, including upper abdominal pain and EPS-like symptoms.
To the best of our knowledge, the present study was the first to investigate the potential association between IL-1β -31 polymorphisms and symptoms of dyspepsia. However, there were certain limitations to this preliminary study. In the present study, all participants were recruited from subjects who were undergoing upper gastroscopy. Therefore, ulcer disease, reflex esophagitis and malignancies that may be associated with abdominal symptoms were able to be excluded. However, the patient cohort comprised a majority of subjects of greater age than that of the general population of patients with FD (34), who were undergoing upper gastroscopy for a health check or a secondary complete check up of stomach cancer following barium radiography.
In addition, the dyspeptic subjects recruited had a primary complaint of either continuous or intermittent dyspepsia for three months. However, the Rome III classification could not be completely applied in a significant percentage of subjects as the onset of symptoms occurred <6 months prior to diagnosis.
Furthermore, the association between IL-1β -31 polymorphisms, and upper abdominal pain and EPS-like symptoms was obtained from a relatively small sample size in the subgroup analysis, and, it should be noted that the effect of type II errors cannot be excluded in such a small sample size. Therefore, a replication study, using larger samples, including ethnically diverse populations, which may be more representative of patients with FD is required.
Abbreviations:
|
FD |
functional dyspepsia |
|
H. pylori |
Helicobacter pylori |
|
EPS |
epigastric pain syndrome |
|
PDS |
postprandial distress syndrome |
|
Il-1β |
interleukin-1β |
|
TNF-α |
tumor necrosis factor-α |
|
PCR |
polymerase chain reaction |
|
RFLP |
restricted fragment length polymorphism |
References
|
Locke GR III: Prevalence, incidence and natural history of dyspepsia and functional dyspepsia. Baillieres Clin Gastroenterol. 12:435–442. 1998. View Article : Google Scholar | |
|
Talley NJ, Zinsmeister AR, Schleck CD and Melton LJ III: Dyspepsia and dyspepsia subgroups: a population-based study. Gastroenterology. 102(4 Pt 1): 1259–1268. 1992.PubMed/NCBI | |
|
Tack J, Talley NJ, Camilleri M, Holtmann G, Hu P, Malagelada JR and Stanghellini V: Functional gastroduodenal disorders. Gastroenterology. 130:1466–1479. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Stanghellini V, Tosetti C, Paternico A, Barbara G, Morselli-Labate AM, Monetti N, Marengo M and Corinaldesi R: Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology. 110:1036–1042. 1996. View Article : Google Scholar : PubMed/NCBI | |
|
Tack J, Piessevaux H, Coulie B, Caenepeel P and Janssens J: Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology. 115:1346–1352. 1998. View Article : Google Scholar : PubMed/NCBI | |
|
Holtmann G, Goebell H, Jockenhoevel F and Talley NJ: Altered vagal and intestinal mechanosensory function in chronic unexplained dyspepsia. Gut. 42:501–506. 1998. View Article : Google Scholar : PubMed/NCBI | |
|
Coffin B, Azpiroz F, Guarner F and Malagelada JR: Selective gastric hypersensitivity and reflex hyporeactivity in functional dyspepsia. Gastroenterology. 107:1345–1351. 1994. View Article : Google Scholar : PubMed/NCBI | |
|
Drossman DA, McKee DC, Sandler RS, Mitchell CM, Cramer EM, Lowman BC and Burger AL: Psychological factors in the irritable bowel syndrome. A multivariate study of patients and nonpatients with irritable bowel syndrome. Gastroenterology. 95:701–708. 1988.PubMed/NCBI | |
|
Drossman DA: Personality and psychological factors in the irritable bowel syndrome. Gastroenterol Clin Biol. 14(5 Pt 2): 49C–53C. 1990.(In French). | |
|
Holtmann G, Siffert W, Haag S, Mueller N, Langkafel M, Senf W, Zotz R and Talley NJ: G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology. 126:971–979. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Camilleri CE, Carlson PJ, Camilleri M, Castillo EJ, Locke GR III, Geno DM, Stephens DA, Zinsmeister AR and Urrutia R: A study of candidate genotypes associated with dyspepsia in a U.S. community. Am J Gastroenterol. 101:581–592. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Tahara T, Arisawa T, Shibata T, Wang F, Nakamura M, Sakata M, Hirata I and Nakano H: Homozygous 825 T allele of the GNB3 protein influences the susceptibility of Japanese to dyspepsia. Dig Dis Sci. 53:642–646. 2008. View Article : Google Scholar | |
|
Delafoy L, Gelot A, Ardid D, Eschalier A, Bertrand C, Doherty AM and Diop L: Interactive involvement of brain derived neurotrophic factor, nerve growth factor and calcitonin gene related peptide in colonic hypersensitivity in the rat. Gut. 55:940–945. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
No authors listed. NIH Consensus Conference. Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. JAMA. 272:65–69. 1994. View Article : Google Scholar : PubMed/NCBI | |
|
Uemura N, Okamoto S, Yamamoto S, et al: Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 345:784–789. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Locke GR III, Weaver AL, Melton LJ III and Talley NJ: Psychosocial factors are linked to functional gastrointestinal disorders: a population based nested case-control study. Am J Gastroenterol. 99:350–357. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Mahadeva S and Goh KL: Epidemiology of functional dyspepsia: a global perspective. World J Gastroenterol. 12:2661–2666. 2006.PubMed/NCBI | |
|
Mearin F, Pérez-Oliveras M, Perelló A, Vinyet J, Ibañez A, Coderch J and Perona M: Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology. 129:98–104. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Wang M, Furuta T, Takashima M, Futami H, Shirai N, Hanai H and Kaneko E: Relation between interleukin-1beta messenger RNA in gastric fundic mucosa and gastric juice pH in patients infected with Helicobacter pylori. J Gastroenterol. 34(Suppl 11): S10–S17. 1999. | |
|
Yamaoka Y, Kita M, Kodama T, Sawai N, Kashima K and Imanishi J: Induction of various cytokines and development of severe mucosal inflammation by cagA gene positive Helicobacter pylori strains. Gut. 41:442–451. 1997. View Article : Google Scholar : PubMed/NCBI | |
|
Wolfe MM and Nompleggi DJ: Cytokine inhibition of gastric acid secretion - a little goes a long way. Gastroenterology. 102:2177–2178. 1992.PubMed/NCBI | |
|
Kondo S, Shinomura Y, Kanayama S, Kawabata S, Miyazaki Y, Imamura I, Fukui H and Matsuzawa Y: Interleukin-1 beta inhibits gastric histamine secretion and synthesis in the rat. Am J Physiol. 267:G966–G971. 1994.PubMed/NCBI | |
|
Lee KJ, Vos R, Janssens J and Tack J: Influence of duodenal acidification on the sensorimotor function of the proximal stomach in humans. Am J Physiol Gastrointest Liver Physiol. 286:G278–G284. 2004. View Article : Google Scholar | |
|
Miwa H, Nakajima K, Yamaguchi K, Fujimoto K, Veldhuyzen VAN Zanten SJ, Kinoshita Y, Adachi K, Kusunoki H and Haruma K: Generation of dyspeptic symptoms by direct acid infusion into the stomach of healthy Japanese subjects. Aliment Pharmacol Ther. 26:257–264. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Hwang IR, Kodama T, Kikuchi S, Sakai K, Peterson LE, Graham DY and Yamaoka Y: Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1beta production in Helicobacter pylori infection. Gastroenterology. 123:1793–1803. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Wallace JL, Cucala M, Mugridge K and Parente L: Secretagogue-specific effects of interleukin-1 on gastric acid secretion. Am J Physiol. 261(4 Pt 1): G559–G564. 1991.PubMed/NCBI | |
|
Zeng ZR, Hu PJ, Hu S, Pang RP, Chen MH, Ng M and Sung JJ: Association of interleukin 1B gene polymorphism and gastric cancers in high and low prevalence regions in China. Gut. 52:1684–1689. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
El-Omar EM, Carrington M, Chow WH, McColl KEL, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothaman N, et al: Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 404:398–402. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Hamajima N, Matsuo K, Saito T, Tajima K, Okuma K, Yamao K and Tominaga S: Interleukin 1 polymorphisms, lifestyle factors and Helicobacter pylori infection. Jpn J Cancer Res. 92:383–389. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Higuchi T, Seki N, Kamizono S, Yamada A, Kimura A, Kato H and Itoh K: Polymorphism of the 5′-flanking region of the human tumor necrosis factor (TNF)-alpha gene in Japanese. Tissue Antigens. 51:605–612. 1998. View Article : Google Scholar : PubMed/NCBI | |
|
Soga Y, Nishimura F, Ohyama H, Maeda H, Takashiba S and Murayama Y: Tumor necrosis factor-alpha gene (TNF-alpha)-1031/-863-857 single-nucleotide polymorphisms (SNPs) are associated with severe adult periodontitis in Japanese. J Clin Periodontol. 30:524–531. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Sugimoto M, Furuta T, Shirai N, Nakamura A, Xiao F, Kajimura M, Sugimura H and Hishida A: Different effects of polymorphisms of tumor necrosis factor-alpha and interleukin-1 beta on development of peptic ulcer and gastric cancer. J Gastroenterol Hepatol. 22:51–59. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Furuta T, El-Omar EM, Xiao F, Shirai N, Takashima M and Sugimura H: Interleukin 1beta polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan. Gastroenterology. 123:92–105. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Manabe N, Haruma K, Hata J, Imamura H, Kamada T, Kusunoki H, Sanuki E, Tsumaru S, Futagami Y, Sadamoto Y, et al: Clinical characteristics of Japanese dyspeptic patients: is the Rome III classification applicable? Scand J Gastroenterol. 45:567–572. 2010. View Article : Google Scholar : PubMed/NCBI |
