B. R. Achyut

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-1β, 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-1β 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-1β 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-1β 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-1β 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-1β 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-1β levels.

The role of mast cells and eosinophils in chronic gastritis.

AbstractThe role of mast cells and eosinophils in influencing the pathology of chronic gastritis remains unclear. We attempted to study the relationship between endoscopy and the mast cell and eosinophil infiltrate. We also studied the role of gene polymorphisms, Helicobacter pylori density and the CagA antibody status in influencing the mast cell and eosinophil infiltrate. One hundred and twenty consecutive patients were studied. Endoscopic evaluation was done and 3 antral biopsies were taken from each patient and were assessed for eosinophilic and mast cell infiltration, H. pylori density and the density of the other inflammatory cells as per the revised Sydney system. Cytokine gene polymorphisms (IL-1β, IL-1RA and TNF-α) were done on the DNA extracted from the peripheral blood by PCR-RFLP. ELISA was done on the patients’ serum for the anti-CagA antibody titres. Nodularity is strongly associated with the presence and density of eosinophils on biopsy (P< 0.05). Eosinophil density is strongly associated with the density of H. pylori, neutrophils, lymphocytes, plasma cells, atrophy, ulceration, foveolitis and lymphoid follicles. The mast cell density is not associated with any of the other histopathological variables. Gene polymorphisms and the CagA antibody titres have no relationship to the mast cell and eosinophil density. Eighty-one patients showed positive anti-CagA antibody titres but there was no association with the eosinophilic or the mast cell infiltrate. It is likely that eosinophilic infiltration is influenced by the H. pylori density but the CagA protein has no role to play in influencing the grade of the eosinophilic infiltrate in the Indian context. Cytokine gene proinflammatory polymorphisms have no role to play in influencing the eosinophilic or the mast cell response. It is likely that other mediators are involved in the inflammatory cell responses.

Transforming Growth Factor-B1 and Matrix Metalloproteinase-7 Promoter Variants Induce Risk for Helicobacter pylori–Associated Gastric Precancerous Lesions

The expression of growth factors, proteolytic enzymes, fibrogenic factors, and cytokines is altered in the Helicobacter pylori-infected gastric mucosa. Therefore, we aimed to evaluate the association of functional promoter variants of transforming growth factor (TGF)-B1 and matrix metalloproteinase (MMP)-7 genes with gastritis and gastric precancerous lesions. After upper gastrointestinal endoscopy, a total of 130 rapid urease test-positive patients with nonulcer dyspepsia were examined for H. pylori infection using modified Giemsa stain and IgG anti-CagA ELISA. All patients and 200 asymptomatic controls were genotyped for TGF-B1 (-509 C>T) and MMP-7 (-181 A>G) substitutions using PCR-RFLP. The genotype and allele frequencies of TGF-B1 and MMP-7 polymorphisms did not differ between patients and controls (p > 0.05). However, the CagA-positive patients with TGF-B1 -509 T allele had higher risk for gastric atrophy (p = 0.026, odds ratio [OR] = 2.38) and lymphoid follicle development (p = 0.028, OR = 2.29). In addition, CagA-positive patients carrying MMP-7 -181 G allele had risk for lymphoid follicle formation (p = 0.027, OR = 2.30). Thus, the present study revealed significant association of functional MMP-7 and TGF-B1 gene variants toward susceptibility to H. pylori-induced precancerous gastric lesions.

Genetic association of interleukin-1 haplotypes with gastritis and precancerous lesions in North Indians

BackgroundWe evaluated the association of functional variants of IL-1 genes with the development of gastritis and precancerous lesions, which are known to be influenced by inflammatory response against Helicobacter pylori.MethodsAfter upper gastrointestinal (GI) endoscopy, 120 patients with gastritis were tested for H. pylori infection using rapid urease test, modified Giemsa staining and IgG anti-CagA ELISA. All patients and 243 healthy controls were genotyped for IL-1B (-511 C/T) and IL-IRN (VNTR) genes using PCR-RFLP/PCR.Results IL-1B(−511 C/T) genotype/allele were not associated with gastritis. IL-1RN 1/2 genotype carriers had susceptibility to gastritis (p = 0.025, OR = 1.7). Individuals with the IL-1RN 1/1 genotype (p = 0.05, OR = 0.65) and IL-1B −511*T-IL-1RN *1 haplotype were at low risk for gastritis (p = 0.043, OR = 0.72). High secretor haplotype combinations (C1-/T2+, C1-T1+ and T1+/T2+) did not influence neutrophilic infiltration, glandular atrophy or intestinal metaplasia.ConclusionsWe identified that individuals with the IL-1RN 1/2 genotype had increased risk for gastritis. IL-1B −511*T-IL-1RN *1 (T1) haplotype carriers were at decreased risk for gastritis and no significant association was observed for precancerous lesions in North Indians.

Association of beta2-adrenergic receptor and insulin receptor substrate-1 polymorphisms with obesity in a Northern Indian population.

BACKGROUND: Imbalance in hormonal levels, regulated by host genetic factors, are known to be a major cause of obesity. Therefore, we aimed to evaluate association of genetic polymorphisms of β2-adrenergic receptor (β2-AR) and insulin receptor substrate-1 (IRS-1) with hormonal levels in northern Indian obese. METHODS: A total of 111 obese and 89 age matched non-obese subjects were studied after taking detailed clinical profile. Hormonal assays in serum/plasma for different hormones were done using IRMA and RIA kits. Genetic analysis of β2-AR (-47 and -20, T to C) and IRS-1 (Arg972Gly) was done using PCR-RFLP. STATISTICAL ANALYSIS: Statistical analysis was performed by SPSS (version 11.5) software. All continuous variables were expressed as mean ± SD and tested by ANOVA test. Comparisons of categorical variables were assessed using X2 tests or Fishers exact test. P-value <0.05 was considered as significant. RESULTS: Analysis showed that obese subjects had significantly higher value of blood pressure (systolic), WHR, leptin insulin and glucagon and lower value of GH. In β2-AR (-47) T/C and IRS-1 Gly972Arg gene polymorphisms we did not found significant differences in genotype or allele frequencies. Moreover, none of the studied hormonal or metabolic parameters showed any association with the gene polymorphisms. CONCLUSIONS: Study reveals no significant association of β2-AR (-47 and -20, T to C) and IRS-1 Gly 972 Arg polymorphisms with obesity in northern Indians.