Association of the functionally significant polymorphisms of the MMP9 gene with H. pylori-positive gastric ulcer in the Caucasian population of Central Russia.

Volodymyr Dvornyk,Irina Ponomarenko,Mikhail Churnosov,Oksana Minyaylo,Evgeny Reshetnikov

doi:10.1371/journal.pone.0257060

Volodymyr Dvornyk, Irina Ponomarenko + Show 3 more

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https://doi.org/10.1371/journal.pone.0257060

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Abstract

Background and purposeThe study analyzed the association of functionally significant polymorphisms of matrix metalloproteinases (MMPs) genes with the development of gastric ulcer (GU) in Caucasians from Central Russia.MethodsThe 781 participants, including 434 patients with GU (196 Helicobacter pylori (H. pylori)-positive and 238 H. pylori-negative) and 347 controls (all H. pylori-negative) were recruited for the study. Ten SNPs of the MMP1 (rs1799750), MMP2 (rs243865), MMP3 (rs679620), MMP8 (rs1940475), and MMP9 (rs3918242, rs3918249, rs3787268, rs17576, rs17577, and rs2250889) genes were considered for association with GU using multiple logistic regression. The SNPs associated with GU and loci linked (r2≥0.8) to them were analyzed in silico for their functional assignments.ResultsThe SNPs of the MMP9 gene were associated with H. pylori-positive GU: alleles C of rs3918249 (OR = 2.02, pperm = 0.008) and A of rs3787268 (OR = 1.60–1.82, pperm ≤ 0.016), and eight haplotypes of all studied MMP9 gene SNPs (OR = 1.85–2.04, pperm ≤ 0.016) increased risk for H. pylori-positive GU. None of the analyzed SNPs was independently associated with GU and H. pylori-negative GU. Two haplotypes of the MMP9 gene (contributed by rs3918242, rs3918249, rs17576, and rs3787268) increased risk for GU (OR = 1.62–1.65, pperm ≤ 0.006). Six loci of the MMP9 gene, which are associated with H. pylori-positive GU, and 65 SNPs linked to them manifest significant epigenetic effects, have pronounced eQTL (17 genes) and sQTL (6 genes) values.ConclusionSNPs of the MMP9 were associated with H. pylori-positive GU but not with H. pylori-negative GU in Caucasians of Central Russia.

Highlights

Gastric ulcer (GU), a disease occurring in the stomach mucosa, is the mucosal inflammation and necrotic lesion that extend to the underlying smooth muscles and are caused by multiple pathogenic factors [1]
The SNPs of the MMP9 gene were associated with H. pylori-positive GU: alleles C of rs3918249 (OR = 2.02, pperm = 0.008) and A of rs3787268 (OR = 1.60–1.82, pperm 0.016), and eight haplotypes of all studied MMP9 gene SNPs (OR = 1.85–2.04, pperm 0.016) increased risk for H. pylori-positive GU
Six loci of the MMP9 gene, which are associated with H. pylori-positive GU, and 65 SNPs linked to them manifest significant epigenetic effects, have pronounced eQTL (17 genes) and sQTL (6 genes) values

Summary

Introduction

Gastric ulcer (GU), a disease occurring in the stomach mucosa, is the mucosal inflammation and necrotic lesion that extend to the underlying smooth muscles and are caused by multiple pathogenic factors [1]. The development of GU is a complex process that involves secretion of acids, generation of the reactive oxygen species, inhibition of prostaglandins, and degradation of the extracellular matrix (ECM) [5]. Damage of gastric mucosa is associated with ECM degradation in which matrix metalloproteinases (MMPs) play a key role [6]. MMPs are calcium-dependent endopeptidases involved in various processes, including ECM remodeling, cell proliferation, and inflammation. Remodeling of the ECM by MMPs is thought to be one of the important factors contributing to gastric ulceration [8, 9]. The study analyzed the association of functionally significant polymorphisms of matrix metalloproteinases (MMPs) genes with the development of gastric ulcer (GU) in Caucasians from Central Russia

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