Genotypic and functional roles of IL-1B and IL-1RN on the risk of gastroesophageal reflux disease: the presence of IL-1B-511*T/IL-1RN*1 (T1) haplotype may protect against the disease

OBJECTIVES: We aimed at evaluating the role of interleukin-1B (IL-1B) and IL-1RN polymorphisms, which may modulate the gastric mucosal expression of IL-1beta, thus altering acid secretion, which influences the severity of gastroesphageal reflux disease (GERD).

METHODS: In a prospective study, 144 patients with GERD (diagnosed by at least two of these criteria: Carlsson-Dent score of 6, endoscopic evidence of GERD, histopathological evidence of esophagitis, percentage time esophageal pH <4 for >5% on 24-h pH monitoring, and response to omeprazole 20 mg/day) and 368 healthy controls were genotyped for IL-1B-511 C/T and IL-1RN VNTR polymorphism (by PCR-restriction fragment length polymorphism (RFLP) and PCR, respectively). Gastric mucosal IL-1beta levels (picogram/milligram of biopsy sample) were measured (using enzyme-linked immunosorbent assay (ELISA)) in 71 patients. Helicobacter pylori diagnosis was conducted using anti-H. pylori immunoglobulin G (IgG) ELISA.

RESULTS: Patients (41.1+/-13.3 years old, 96 (66.7%) men) were comparable with healthy controls (43.4+/-11.8 years old, 238 (64.7%) men) with respect to age and gender. The IL-1B-511 CC genotype and C allele were associated with higher risk of GERD than the TT genotype (P=0.01, odds ratio (OR)=2.0, 95% confidence interval (CI)=1.12-3.57) and the T allele (P=0.04, OR=1.3, 95% CI=1.0-1.7), respectively. TT and C noncarriers had more IL-1beta than CT (33.2 (2.6-161.3) vs. 16.7 (2.8-121.9), P=0.04) and C carriers (33.2 (2.6-161.3) vs. 15.16 (1.5-121.9), P=0.04), respectively. IL-1RN "1,2" and "2 carriers" had higher risk (P<0.001, OR=2.0, 95% CI=1.31-3.1; P=0.01, OR=1.6, 95% CI=1.1-2.4, respectively). "2,2" Had lower IL-1beta levels than both "1,1" and "1,2" (9.2 (1.5-70.7) vs. 26.8 (5.7-161.3), P=0.006; 9.2 (1.5-70.7) vs. 24.4 (2.6-78.0), P=0.02). However, "2 carriers" tended to have lower IL-1beta levels than "2 noncarriers" (21.7 (1.5-78.0) vs. 26.8 (5.7-161.3), P=0.09). The IL-1B-511*T/IL-1RN*1 ("T1") haplotype showed lower risk (P=0.05, OR=0.7, 95% CI=0.5-1.0). "T1" had higher IL-1beta levels than both "T1 carriers" and "T1 noncarriers" (43.5 (18.2-161.3) vs. 23.9 (2.6-121.9), P=0.02; 43.5 (18.2-161.3) vs. 10.9 (1.5-82.6), P=0.06, respectively). The presence of H. pylori infection was associated with the stronger risk of the IL-1B-511*CC genotype. The "T1" haplotype was strongly protective against GERD among patients with H. pylori infection.

CONCLUSIONS: The T1 haplotype was associated with the reduced risk of GERD, particularly among patients with H. pylori infection, probably because of higher gastric mucosal IL-1beta levels.