Risk factors for gastroesophageal reflux disease and analysis of genetic contributors

Abstract

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder with an increasing prevalence. GERD develops when the reflux of stomach contents causes troublesome typical and atypical symptoms and/or complications. Several risk factors of GERD have been identified and evaluated over the years, including a considerable amount of genetic factors. Multiple mechanisms are involved in the pathogenesis of GERD including: (1) motor abnormalities, such as impaired lower esophageal sphincter (LES) resting tone, transient LES relaxations, impaired esophageal acid clearance and delayed gastric emptying; and (2) anatomical factors, such as hiatal hernia and obesity. Genetic contribution seems to play a major role in GERD and GERD- related disorders development such Barrett's esophagus and esophageal adenocarcinoma. Twin and family studies have revealed an about 31% heritability of the disease. Numerous single-nucleotide polymorphisms in various genes like FOXF1, MHC, CCND1, anti-inflammatory cytokine and DNA repair genes have been strongly associated with increased GERD risk. GERD, Barrett's esophagus and esophageal adenocarcinoma share several genetic loci. Despite GERD polygenic basis, specific genetic loci such as rs10419226 on chromosome 19, rs2687201 on chromosome 3, rs10852151 on chromosome 15 and rs520525 on the paired related homeobox 1 gene have been mentioned as potential risk factors. Further investigation on the risk genes may elucidate their exact function and role and demonstrate new therapeutic approaches to this increasingly common disease.

Keywords: Gastroesophageal reflux disease; Gastroesophageal reflux disease development; Genetic risk loci; Risk factors; Single nucleotide polymorphisms.

Figure 1

The presence of the genes IL-1B and IL-1RN combined with Helicobacter pylori infection is associated with hypochlorydria and thus reducing the risk for gastroesophageal reflux disease. GERD: Gastroesophageal reflux disease; H. pylori: Helicobacter pylori; IL-1B-511*T: Interleukin-1 beta T allele; IL-1RN: Gene encoding for a non-signaling molecule IL-1 receptor antagonist (IL-1Ra).

Figure 2

Susceptible risk genes for gastroesophageal reflux disease. Their increased or reduced (DNA repair genes) expression alters different biological pathways. GERD: Gastroesophageal reflux disease; IL-10: Anti-inflammatory cytokine interleukin 10; FOXF1: Forkhead BOX F1; GSTP1*b: Glutathione- S- transferases b allele; CCND1: Cyclin D1 gene; XRCC1: X-ray repair complementing defective repair in Chinese hamster cells 1; Hmlh1: Humal homolog of the E. coli DNA mismatch repair gene mutL; GNB3: Guanine nucleotide binding protein beta polypeptide 3; MHC: Major histocompatibility complex.

Figure 3

Genetic risk loci associated with the development of gastroesophageal reflux disease[32,38]. GERD: Gastroesophageal reflux disease; SNPs: Single-nucleotide polymorphisms.