IL1B Promoter Polymorphism Regulates The Expression Of Gastric Acid Stimulating Hormone Gastrin
1Susanta Roychoudhury, 2Meenakshi Chakravorty, 1Dipanjana Datta De, 3Abhijit Choudhury
1Human Genetics and Genomics Division,Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata -700032, India, 2Department Of Pediatrics and Molecular Biology, UT Southwestern Medical Center, 6000 Harry Hines Blvd.Rm. NA8.124, Dallas, Texas-75390-9148, United States of America, 3Department of Medicine,Institute of Postgraduate Medicine and Experimental Research, 244, AJC Bose Road, Kolkata-700020, India
Several genetic studies have implicated a number of functional single nucleotide polymorphisms (SNPs) as disease susceptibility alleles and functional differences between the two alternative alleles have been established. However, it is of importance not only to dissect the functional aspect of each these SNPs but also to understand the pathway through which this genetic cue is propagated such that the influence of these polymorphisms on each of the downstream genes in a biochemical pathway can be delineated. In the present study, we report that altered expression of IL1B due a specific polymorphism in its promoter modulates the expression of a far down stream gene gastrin, one of the hormonal factors that regulates gastric acid secretion. We reported earlier that two polymorphisms -511 C>T and -31 C>T in the IL1B promoter as potential susceptibility loci for Helicobacter pylori associated duodenal ulcer. Among H. pylori infected individuals, carriers of the IL1B -31C/C genotype, have significantly lower IL1B levels than carriers of C/T (p<0.001) and T/T genotypes (p<0.001). It is therefore important to understand the mechanism by which the differential secretion of IL1B promoter variants modulates gastric acid secretion. Since gastrin is a potent regulator of acid secretion by the gastric parietals cells, we sought to determine the effect of altered expression of IL1B on gastrin expression. Results presented in this study established that proinflammatory cytokine IL1B inhibits the expression of gastrin and partly this inhibitory process is mediated via activation of NFkB. We have also shown that a single base substitution at the -31 position of the IL1B promoter brought about differential expression of IL1B which in turn differentially altered both NFkB activation and gastrin expression. We hypothesized that one of the contributing factor for the individuals with -31CC genotype at the IL1B promoter to be more susceptible to H. pylori associated duodenal ulcer is the lower expression of IL1B by these individuals resulting in high gastrin expression which in turn causes higher acid production in their gastric lumen. This study has successfully simulated at least part of the in vivo scenario resulting from genetic polymorphisms through in vitro biochemical assays. Thus the study serves as an example of dissection of the functional aspect of the polymorphisms not only on their own gene regulation but also upon the genetic cue that they propagate towards the modulation of downstream genes.