Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1β production in Helicobacter pylori infection

doi:10.1053/gast.2002.37043

Gastroenterology

Volume 123, Issue 6, December 2002, Pages 1793-1803

https://doi.org/10.1053/gast.2002.37043 Get rights and content

Abstract

Background & Aims: Although epidemiological studies suggest that interleukin (IL)-1 genetic polymorphisms are involved in Helicobacter pylori–related gastric carcinogenesis, the data are conflicting regarding the effects of these polymorphisms on IL-1β production. Methods: IL-1B-511 polymorphism was genotyped by polymerase chain reaction (PCR)–restriction fragment length polymorphism, and IL-1RN variable number of tandem repeats was determined by PCR. Mucosal IL-1β levels were measured by enzyme-linked immunosorbent assay. To determine which factors influence mucosal IL-1β levels, gastric inflammation, and atrophy, multiple regression analyses were performed. Results: We studied 117 H. pylori–infected Japanese patients. Carriers of the IL-1B-511T/T genotype or IL-1RN*2 allele had higher mucosal IL-1β levels than noncarriers (partial regression coefficient [PRC] ± SE), TT versus CC: 37.6 ± 6 [antrum] and 32.1 ± 6 [corpus] pg/mg protein (P < 0.001 for each), *1/*2 versus *1/*1: 24 ± 8 [antrum] (P <0.01) and 36.5 ± 7 [corpus] (P <0.001). Simultaneous carriers of IL-1B-511T/T genotype and IL-1RN*2 allele had the highest IL-1β levels (82.9 ± 12 [antrum] and 87.2 ± 11 [corpus]) and showed a synergistic effect between 2 loci. The *1/*2 carriers were closely related to atrophy (PRC ± SE; 0.87 ± 0.4 [antrum] and 0.93 ± 0.4 [corpus], P < 0.05), whereas being a carrier of the -511T/T genotype was related to severe gastric inflammation. Conclusions: IL-1 genetic polymorphisms influenced H. pylori–related gastric mucosal IL-1β levels and were related to gastric inflammation and atrophy, factors thought to be important in gastric carcinogenesis.

GASTROENTEROLOGY 2002;123:1793-1803

Section snippets

Patients

We studied H. pylori–infected patients who underwent upper endoscopy in Kyoto Prefectural University Hospital, Kyoto, Japan between January 1995 and July 1995. Active H. pylori infection was confirmed by culture and histology. No subject had received treatment for H. pylori infection. Informed consent was obtained from all patients, and the protocol was approved by the ethical committee of Kyoto Prefectural University of Medicine. Three biopsy specimens were taken from the antrum (pyloric gland

Results

One hundred seventeen patients were studied including 73 men and 44 women, mean age 55.3 ± 17 years. Clinical diagnoses were: 19 patients with gastric adenocarcinoma, 34 with duodenal ulcer (25 without gastric ulcer and 9 with gastric ulcer), 30 with gastric ulcer (without duodenal ulcer), 28 with simple gastritis, 4 with gastric adenoma, and 2 with MALT lymphoma. All patients were infected with cag pathogenecity island–positive, vacA s1-m1 type H. pylori strains.

Table 1 shows the genotype

Neutrophil infiltration

In the univariate analyses, the scores for neutrophil infiltration in the corpus were significantly higher (P < 0.05) in the carriers of the T/T genotype than those of the T/C genotype or the C/C genotype at IL-1B-511 (T/T = 4 [3–5], T/C = 3 [2–3], and C/C = 3 [1–4] among 3 groups). However, the scores in antrum were not significantly different among the genotypes (T/T = 4 [3–5], T/C = 3 [2–4], and C/C = 3 [2–4]) (P = 0.1). There was no difference in the score of neutrophil infiltration between

Discussion

Recent epidemiological studies have suggested that IL-1 genetic polymorphism may contribute to H. pylori–related gastric carcinogenesis.12, 18 Carriers of the IL-1B-511T allele and IL-1RN*2/*2 have been reported to be at increased risk of hypochlorhydria and gastric cancer.12, 18 These findings have been primarily related to intestinal-type gastric adenocarcinoma in whites. We tested the hypothesis that IL-1 genetic polymorphisms influenced the gastric mucosal IL-1β levels in human H. pylori

Acknowledgements

We also acknowledge the generous support of Hilda Schwartz. We thank Dr. Michael Osato (Department of Medicine, Baylor College of Medicine, Houston, TX) for helpful comments.

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^☆: Supported in part by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs and by Public Health Service grants DK-53659 and DK56338, funds the Texas Gulf Coast Digestive Diseases Center. Linkage disequilibrium analysis by LEP was supported by National Cancer Institute grant CA-78199-04.

^☆☆: Address requests for reprints to: Yoshio Yamaoka, M.D., Ph.D., Veterans Affairs Medical Center (111D), Room 3A-320, 2002 Holcombe Boulevard, Houston, Texas 77030. e-mail: [email protected]; fax: (713) 790-1040.

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Clinical–Alimentary TractEffect of interleukin 1 polymorphisms on gastric mucosal interleukin 1β production in Helicobacter pylori infection☆,☆☆

Abstract

Section snippets

Patients

Results

Neutrophil infiltration

Discussion

Acknowledgements

Gastroenterology

Gastroenterology

Gastroenterol Clin North Am

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Hum Pathol

Cytokine

Kidney Int

Am J Hum Genet

Gastroenterology

Helicobacter pylori infection and the development of gastric cancer

N Engl J Med

Local acid production and Helicobacter pylori: a unifying hypothesis of gastroduodenal disease

Eur J Gastroenterol Hepatol

Clinical impact of routine biopsies of the gastric antrum and body

Endoscopy

Mucosal tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 production in patients with Helicobacter pylori infection

Scand J Gastroenterol

Secretagogue-specific effects of interleukin-1 on gastric acid secretion

Am J Physiol

Interleukin (IL)-1 is the likely mediator of reduced acid secretion associated with corpus gastritis

Gut

Interleukin-1 polymorphisms associated with increased risk of gastric cancer

Nature

Effects of Helicobacter pylori infection on gastric acid secretion and serum gastrin levels in Mongolian gerbils

Gut

Single base polymorphism at −511 in the human interleukin-1β gene

Hum Mol Genet

Five genetic markers in the interleukin 1 family in relation to inflammatory bowel disease

Gut

Polymorphism in human IL-1 receptor antagnoist gene intron 2 is caused by variable numbers of an 86-base pair tandem repeat

Hum Genet

Clinical–Alimentary Tract
Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1β production in Helicobacter pylori infection☆,☆☆