Shweta Tripathi

Gastric carcinogenesis: Possible role of polymorphisms of GSTM1, GSTT1, and GSTP1 genes

Objective. Although Helicobacter pylori infection is associated with gastric cancer (GC), only 1% of patients develop a malignancy, which suggests a role of host genetic factors. The aim of this study was to investigate the role of polymorphisms of GSTM1, GSTT1, and GSTP1 genes, which encode for carcinogen-detoxifying enzymes, in gastric mutagenesis. Material andmethods. Genotyping of GSTT1 and GSTM1 was done using PCR, while PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) was used for genotyping of GSTP1 in 76 patients with gastric neoplasm (GN), 67 with non-ulcer dyspepsia (NUD), 44 with peptic ulcer (PU), and 100 healthy controls (HC). Results. The study population included: GN (intestinal 40 (53%), diffuse 26 (34%), primary gastric lymphoma 8 (11%) and unclassified 2 (2%)), PU (duodenal ulcer (DU) 33 (75%), gastric ulcer (GU) 10 (23%), both PU and DU 1 (2%)). GSTT1 null genotype (GSTT1*0) was more common in patients with GN (30/76 (40%)) than in those with PU (5/44 (11%); p=0.001, odds ratio (OR) 5; 95% CI=1–4) and HC (23/100 (23%); p=0.02, OR 2; 95% CI=1–4). GSTT1*0 conferred a higher cancer risk for patients with DU (2/33 (6%), OR 10; 95% CI=2–45; p=0.00). GSTM1*0 and GSTP1 variant genotypes (ile/val and val/val) not alone but in combination with GSTT1*0 conferred a higher risk in PU patients (21 (28%) versus 5 (11%); OR 3; 95% CI=1–9; p=0.04). Both GSTM1*0 (16/26 (61%) versus 10/40 (25%); p=0.003, OR 5; 95% CI=2–14) and GSTT1*0 (12/26 (46%) versus 13/40 (33%); p=0.2, OR 2; 95% CI=0.6–5) were associated with a higher risk of diffuse tumor than of intestinal tumor. Conclusions. GSTT1*0 alone and in combination with GSTM1*0 and GSTP1 variant genotypes is a risk factor for GN in the Indian population. Low GSTT1*0 in DU patients may play a protective role against GN. GSTM1*0 and GSTT1*0 are risk factors for diffuse GC.

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 Indian Enigma of Frequent H. pylori Infection but Infrequent Gastric Cancer: Is the Magic Key in Indian Diet, Host's Genetic Make Up, or Friendly Bug?

The Indian Enigma of Frequent H. pylori Infection but Infrequent Gastric Cancer: Is the Magic Key in Indian Diet, Hosts Genetic Make Up, or Friendly Bug?

Association between gastric mucosal glutathione-S-transferase activity, glutathione-S-transferase gene polymorphisms and Helicobacter pylori infection in gastric cancer

AimHelicobacter pylori infection, though common, leads to gastric cancer (GC) in less than 1% individuals, suggesting the role of host factors. We previously reported the role of glutathione–S–transferase (GST) polymorphisms, the gene encoding a carcinogen–detoxifying enzyme, in GC. This study was aimed to evaluate GST enzyme activity, GST polymorphism, glutathione (GSH) levels and H. pylori in patients with GC.MethodsGST and GSH levels were estimated in gastric biopsies of 52 patients with GC, 37 functional dyspepsia (FD) and 39 peptic ulcer (PU), and correlated with H. pylori (ELISA) infection and GST polymorphisms. GST polymorphisms were separately analyzed in relationship to H. pylori in 82 GC, 72 FD, 53 PU and 89 healthy controls (HC).ResultsGST activity was lower in patients with GC in comparison to PU (p = 0.03), but GSH levels were comparable. GSTT1 null genotype (GSTT1*0) and simultaneous deletion of both GSTT1 and GSTM1 genes was associated with lower enzyme activity (p = 0.02 and 0.01, respectively). GST and GSH levels in H. pylori positive and negative patients with GC, FD and PU were comparable. Presence of H. pylori infection along with GSTT1*0 (p = 0.006) and GSTM1*0 (p = 0.05) was associated with lower enzyme activity. GSTT1*0 was associated with higher odds ratio (OR) of GC in presence of H. pylori (GC vs. HC: p = 0.02, OR 2.6 [95% CI = 1–6] vs. p = 0.7, 1.3 [0.4–5.0]; GC vs. PU: p = 0.04, OR 3 [95% CI = 1–9] vs. not applicable (OR could not be computed as frequency of GSTT1*0 in H. pylori negative patients with PU was zero)].ConclusionsGC is associated with reduced GST activity. Odds ratio of GC associated with GSTT1*0 is enhanced in presence of H. pylori probably due to combined effect of both on enzyme activity.

Relationship of severity of gastroesophageal reflux disease with gastric acid secretory profile and esophageal acid exposure during nocturnal acid breakthrough: A study using 24-h dual-channel pH-metry

Objective. In patients with gastroesophageal reflux disease (GERD), refluxed gastric juice can damage the esophagus, and hence the more acidic the juice, the more the expected damage. Nocturnal acid breakthrough (NAB) is known to occur in GERD patients on treatment with proton-pump inhibitors (PPIs); however, whether this causes esophageal acidification and symptoms is controversial. The aims of this study were to investigate the relationship between gastric acid and the severity of GERD and the esophageal acidification and symptoms during NAB. Material and methods. Patients with GERD were evaluated using endoscopy (graded according to the Los Angeles (LA) classification), manometry and 24-h dual-channel pH-metry for esophageal and gastric acid profile and follow-up pH-metry while on PPIs for NAB. Results. In 61 patients (39.2±12.8 years, 40 M) the endoscopic grading was endoscopy negative (ENRD) in 19 (32%), endoscopic (ERD) in 40 (68%), (LA-A in 25, 42.4%, LA-B in12, 20.3%, peptic stricture in 2, 3.4%, and Barretts esophagus in 1, 1.7%) and 2 patients were unclassified. Patients in the different groups had comparable gastric acid profiles, though esophageal acid exposure was different (LA-B and above versus ENRD, p=0.007; LA-B and above versus LA-A, p=0.003). Patients with NAB (7/18, 39%) had lower gastric pH than patients without NAB (p=0.003) though average esophageal pH and esophageal acid exposure were comparable. Frequency of nocturnal symptoms was comparable in patients with or without NAB (2/7 versus 3/11, p=NS). Lower esophageal sphincter (LES) pressure was negatively correlated with average gastric pH. Conclusions. Although severity of GERD is related to esophageal acid exposure, it does not correlate to gastric acid. No difference was found in esophageal acid exposure and nocturnal symptoms in patients with or without NAB.

Strongyloides stercoralis infestation in a patient with severe ulcerative colitis.

Asymptomatic infestation with Strongyloides stercoralis, common in the tropics, may result in potentially fatal hyperinfection during treatment with immunosuppressive drugs used to treat patients with severe ulcerative colitis (UC). Hence, importance of early recognition and treatment of this nematode in patients with UC before starting immunosuppressive drugs can not be overemphasized. We report a 23-yrs old man with UC who presented with acute severe attack. Since his UC did not respond to intravenous hydrocortisone over 6 days, oral cyclosporine was started on 7th day after repeating stool microscopy, which revealed larvae of Strongyloides stercoralis. Duodenal aspirate also confirmed presence of multiple larvae. He responded to treatment for Strongyloides stercoralis , continuation of hydrocortisone and cyclosporine. Importance of early diagnosis of infestation with Strongyloides stercoralis while on treatment with immunosuppressive drugs for severe UC is emphasized. Difficulties in diagnosis and management of Strongyloides stercoralis infestation in patients with UC are discussed.