The role of the IL 6 190 C/T and IL/6 174 C/G polymorphisms in the development of gastritis in children Authors: Mărginean Maria Oana, Cosmin Oprea, Ioan.

The role of the IL 6 190 C/T and IL/6 174 C/G polymorphisms in the

development of gastritis in childrenAuthors: Mărginean Maria Oana, Cosmin Oprea, Ioan

Serban Fanfaret, Cristian Dan Mărginean

Coordinators: Professor Bănescu Claudia, Assistant professor Pitea Ana Maria

Introduction

• Polymorphisms in the promoter region of the proinflammatory cytokine, interleukin (IL)-6 have been related to several chronic inflammatory diseases, including children gastritis

• Genetic variability:– of the gene IL-6-190 - allele T or C – of the gene IL/6 174 – allele C or G

• Asociated with various hereditary diseases, including gastritis

Introduction

Gastritis

•inflammatory process in the gastric mucosa, with histopathological modifications•commonly associated with peptic ulcer and duodenitis•great importance and certain actuality in the field of pediatric pathology because of its increased incidence in children and its complications

Background

Recent data suggests that gastritis• may have an inflammatory etiology • associates a low degree proinflammatory

status

• Some cases of gastritis associated with H. pylori infection do not heal despite the correct application of treatment regimens due to the virulence of microorganisms in association with the hosts` genetic predisposition

Pathogenesis

• imbalance between aggressive factors and the defense mechanisms

• aggressive factors– acid secretion, pepsin secretion, stress, aspirin,

NSAIDs, H. pylori

• defense mechanisms– mucus and bicarbonate secretion

– mucosal blood flow

– prostaglandines (PG)- stimulate other mechanisms

Pathogenesis• The etiology of gastroduodenal diseases

– environmental factors– genetic predisposition consisting of genetic

susceptibility to infection– DNA repair mechanisms related to

carcinogenesis• host polymorphism

– influence the pharmacokinetics– efficacy of treatment with proton

pump inhibitors

Background• Genetic polymorphisms of several inflammatory and

immunoregulatory cytokines are investigated for possible association with risk for specific H. pylori-associated disease

• Il-6 is a multifunctional cytokine produced by immune or nonimmune cells, and functions as an inflammatory endocrine and metabolic function mediator

• There is a correlation between H. pylori and IL-6, as mRNA levels of this cytokine in the gastric mucosa have been correlated with the level of inflammation.

• Normally, IL-6 plays an important role in host defense mechanisms as a messenger between innate and adaptative systems by stimulating interferon gamma production in T-cells, by promoting immunoglobulin secretion in activated B-cells, and through polymorphoneutrophil activation

Objective

• to establish the role of IL 6 in children gastritis • to establish correlations between the

polymorphisms of the gene IL 6 190 C/T, IL 6 174 C/G and children gastritis

• to determine whether patients differ from children without digestive pathology regarding genotype polymorphisms distribution.

Material and method

• 123 children admited in the Pediatrics Clinic I

– from january 2014 through march 2015 with symptoms such as:

» abdominal pain

» nausea, vomiting

» Pirozis

-we correlated these symptoms with endoscopical changes, histopatological changes and Helicobacter Pylori infection

The patients were divided according to their histopathological changes into:• a control group - 55 children without histopathological changes• a study group – 68 children with histopathological changes

The following were evaluated: - clinical symptoms

- IL-6 190 T/C , IL 6 174 C/G polymorphism analysis (using specific primers)

Material and method• Inclusion criteria:

– Children with symptoms which were characteristic for gastritis (pirosis, nausea, vomiting)

• Control group – children without histopathological changes in the antral region

• Study group - children with histopathological changes of the gastric mucosa

• Exclusion criteria:

– children with infectious diseases

– children with an acuta abdomen

– children without any symptoms than those which were already mentioned

Material and method• Statistical calculation

– for the entire statistical calculation

• Graph Pad 3.6 Software, San Diego, California, USA

– T Student test was used to assess the differences between the means of continuous variables (expressed as mean ± SD)

– The differences among constant variables and three genotype groups of the IL 6 190 C/T, IL/6 174 C/G and polymorphisms were estimated using ANOVA and Kruskal Wallis tests, an analysis which is appropriate for more than two groups.

Results

• Average age of the children included in the study:

– 9.67 ± 3.52 years in the control group

– 9.21± 2.11 years in the study group

• without a statistically significant diference between the two groups

Results

• The distribution of the cases according to the IL 6 190 C/T genotypes was the following:

We observed that the genotype CT was more frequent in the study group, while the genotype CC was more frequent in the control group, but with a statistically insignificant p value( p = 0.47/0.16).

Results- polymorphism IL 6 190 C/T

• No correlation between this polimorphism, clinical symptoms and histopatological changes was observed.

p = 0.20

Results- polymorphism IL 6 190 T/C

P = 0.34

P = 0.15

Results- polymorphism IL 6 190 C/T

  HPylori+ HPylori- OR IC (95%) P VALUE

TT REF 2 19 - - -CT 10 41 2.31 0.46-11.6 0.48CC 7 44 1.51 0.8-7.96 0.95

TC+CC 17 85 1.9 0.40-8.93 0.52Allela T 14 79 - - -Allela C 24 129 1.05 0.51-2.5 0.89

The IL 6 190 C/T polimorphism does not correlate with the risk of developing an H. Pylori infection.

Results- polymorphism IL 6 174 C/G

• The distribution of the cases according to the IL 6 174 C/G genotypes was the following:

A higher frequence of the CG genotype of the IL 6 174 polymorphism was observed in the study group (p<0.05), while the genotype GG was more frequent in the control group (p < 0.05).

Results- polymorphism IL 6 174 C/G

P = 0.03/0.05

Vomiting is correlated with the genotype CG and GG of the IL 6 174 C/G gene in the study group (with histopathological changes)

Rezultate polimorfism IL 6 174 C/G

Loss of appetite is correlated with the genotypes CG and GG of the IL 6 174 C/G gene in the study group

P = 0.001

• There is a risk of developing an H Pylori infection for those who have the CG and GG polymorphism ( p < 0.05)

Results- polimorphism IL 6 174 C/G

Results- polymorphism IL 6 174 C/G

Alelle C of the IL 6 174 C/G polymorphism is statistically significant correlated with H Pylori infection[OR of 1.73, 95% CI (0.36-2,50)] ( p = 0.05).

p-0.05

GC GG0

20

40

60

80H Pylori+H Pylori-

p-0.05

Allela C Allela G0

50

100

150H Pylori+H Pylori-

Conclusions

• IL 6 174 is an important parameter of inflammation, correlated with inflamation and child gastritis.

• Gastritis is more frequently found in the children which have the CG genotype of the IL 6 174 gene polymorphism

• Vomiting, appetite loss and histopathological changes were correlated especially with genotypes CG and GG of the IL 6 174 gene.

• The disease was not correlated with the IL 6 190 gene polymorphism.

• Further studies are warranted to investigate the relation between IL 6 polymorphism, H. pylori infection and response to terapy.