AI Article Synopsis

  • Gastroparesis (GP) is a condition marked by delayed gastric emptying, and this study aimed to investigate the genetic factors contributing to it using a genome-wide association study (GWAS).
  • The research involved comparing genetic data from 880 GP patients and over 58,000 controls, leading to the identification of nine genomic loci that showed suggestive associations with GP, particularly focusing on immune and motor dysregulation pathways.
  • Notably, the gene PXDNL was linked to increased abdominal pain severity in GP patients, suggesting a possible target for future research on GP treatments.

Article Abstract

Background: Gastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction.

Objective: Genetic predisposition may play a role; however, investigation at the genome-wide level has not been performed.

Methods: We carried out a genome-wide association study (GWAS) meta-analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population-based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non-gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high-quality SNPs were tested on a total of 880 GP patients and 58,271 controls, using logistic mixed models adjusted for age, sex, and principal components. Gene mapping was obtained based on genomic position and expression quantitative trait loci, and a gene-set network enrichment analysis was performed. Genetic associations with clinical data were tested in GpCRC patients. Protein expression of selected candidate genes was determined in full thickness gastric biopsies from GpCRC patients and controls.

Results: While no SNP associations were detected at strict significance (p ≤ 5 × 10 ), nine independent genomic loci were associated at suggestive significance (p ≤ 1 × 10 ), with the strongest signal (rs9273363, odds ratio = 1.4, p = 1 × 10 ) mapped to the human leukocyte antigen region. Computational annotation of suggestive risk loci identified 14 protein-coding candidate genes. Gene-set network enrichment analysis revealed pathways potentially involved in immune and motor dysregulation (p ≤ 0.05). The GP risk allele rs6984536A (Peroxidasin-Like; PXDNL) was associated with increased abdominal pain severity scores (Beta = 0.13, p = 0.03). Gastric muscularis expression of PXDNL also positively correlated with abdominal pain in GP patients (r = 0.8, p = 0.02). Dickkopf WNT Signaling Pathway Inhibitor 1 showed decreased expression in diabetic GP patients (p = 0.005 vs. controls).

Conclusion: We report preliminary GWAS findings for GP, which highlight candidate genes and pathways related to immune and sensory-motor dysregulation. Larger studies are needed to validate and expand these findings in independent datasets.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10576603PMC
http://dx.doi.org/10.1002/ueg2.12453DOI Listing

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