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.
OBJECTIVE
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.
Chourasia
Dipti
D
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
Achyut
B R
BR
Tripathi
Shweta
S
Mittal
Balraj
B
Mittal
Rama D
RD
Ghoshal
Uday C
UC
D000328:Adult; D001707:Biopsy, Needle; D016022:Case-Control Studies; D016001:Confidence Intervals; D004797:Enzyme-Linked Immunosorbent Assay; D004945:Esophagoscopy / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D005764:Gastroesophageal Reflux / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D016481:Helicobacter Infections / Q000175:diagnosis / Q000453:epidemiology; D016480:Helicobacter pylori / Q000302:isolation & purification; D006801:Humans; D007150:Immunohistochemistry; D015994:Incidence; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D053583:Interleukin-1beta / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011336:Probability; D011446:Prospective Studies; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta