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Repeat polymorphisms in the Homo sapiens heme oxygenase-1 gene in diabetic and idiopathic gastroparesis.

ABSTRACT: Idiopathic and diabetic gastroparesis in Homo sapiens cause significant morbidity. Etiology or risk factors have not been clearly identified. Failure to sustain elevated heme oxygenase-1 (HO1) expression is associated with delayed gastric emptying in diabetic mice and polymorphisms in the HO1 gene (HMOX1, NCBI Gene ID:3162) are associated with worse outcomes in other diseases.Our hypothesis was that longer polyGT alleles are more common in the HMOX1 genes of individuals with gastroparesis than in controls without upper gastrointestinal motility disorders.Repeat length was determined in genomic DNA. Controls with diabetes (84 type 1, 84 type 2) and without diabetes (n = 170) were compared to diabetic gastroparetics (99 type 1, 72 type 2) and idiopathic gastroparetics (n = 234). Correlations of repeat lengths with clinical symptom sub-scores on the gastroparesis cardinal symptom index (GCSI) were done. Statistical analyses of short (<29), medium and long (>32) repeat alleles and differences in allele length were used to test for associations with gastroparesis.The distribution of allele lengths was different between groups (P = 0.016). Allele lengths were longest in type 2 diabetics with gastroparesis (29.18±0.35, mean ± SEM) and longer in gastroparetics compared to non-diabetic controls (28.50±0.14 vs 27.64±0.20 GT repeats/allele, P = 0.0008). Type 2 diabetic controls had longer alleles than non-diabetic controls. In all gastroparetic groups, allele lengths were longer in African Americans compared to other racial groups, differences in the proportion of African Americans in the groups accounted for the differences between gastroparetics and controls. Diabetic gastroparetics with 1 or 2 long alleles had worse GCSI nausea sub-scores (3.30±0.23) as compared to those with 0 long alleles (2.66±0.12), P = 0.022.Longer poly-GT repeats in the HMOX1 gene are more common in African Americans with gastroparesis. Nausea symptoms are worse in subjects with longer alleles.

SUBMITTER: Gibbons SJ

PROVIDER: S-EPMC5697813 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Repeat polymorphisms in the Homo sapiens heme oxygenase-1 gene in diabetic and idiopathic gastroparesis.

Gibbons Simon J SJ Grover Madhusudan M Choi Kyoung Moo KM Wadhwa Akhilesh A Zubair Adeel A Wilson Laura A LA Wu Yanhong Y Abell Thomas L TL Hasler William L WL Koch Kenneth L KL McCallum Richard W RW Nguyen Linda A B LAB Parkman Henry P HP Sarosiek Irene I Snape William J WJ Tonascia James J Hamilton Frank A FA Pasricha Pankaj J PJ Farrugia Gianrico G

PloS one 20171121 11

<h4>Background</h4>Idiopathic and diabetic gastroparesis in Homo sapiens cause significant morbidity. Etiology or risk factors have not been clearly identified. Failure to sustain elevated heme oxygenase-1 (HO1) expression is associated with delayed gastric emptying in diabetic mice and polymorphisms in the HO1 gene (HMOX1, NCBI Gene ID:3162) are associated with worse outcomes in other diseases.<h4>Aim</h4>Our hypothesis was that longer polyGT alleles are more common in the HMOX1 genes of indivi ...[more]

PMID: 29161307

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Project description:Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in diabetic mice. Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages has been reported in full-thickness gastric biopsies from gastroparesis patients. We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients. Additionally, we determined correlations between protein expressions, gastric emptying, and symptoms. Full-thickness gastric antrum biopsies were obtained from nine DG patients, seven IG patients, and five nondiabetic controls. Aptamer-based SomaLogic tissue scan that quantitatively identifies 1,305 human proteins was used. Protein fold changes were computed, and differential expressions were calculated using Limma. Ingenuity pathway analysis and correlations were carried out. Multiple-testing corrected P < 0.05 was considered statistically significant. Seventy-three proteins were differentially expressed in DG, 132 proteins were differentially expressed in IG, and 40 proteins were common to DG and IG. In both DG and IG, "Role of Macrophages, Fibroblasts and Endothelial Cells" was the most statistically significant altered pathway [DG false discovery rate (FDR) = 7.9 × 10-9; IG FDR = 6.3 × 10-12]. In DG, properdin expression correlated with GCSI bloating (r = -0.99, FDR = 0.02) and expressions of prostaglandin G/H synthase 2, protein kinase C-? type, and complement C2 correlated with 4 h gastric retention (r = -0.97, FDR = 0.03 for all). No correlations were found between proteins and symptoms or gastric emptying in IG. Protein expression changes suggest a central role of macrophage-driven immune dysregulation in gastroparesis, specifically, complement activation in diabetic gastroparesis.NEW & NOTEWORTHY This study uses SOMAscan, a novel proteomics assay for determination of altered proteins and associated molecular pathways in human gastroparesis. Seventy-three proteins were changed in diabetic gastroparesis, 132 in idiopathic gastroparesis compared with controls. Forty proteins were common in both. Macrophage-based immune dysregulation pathway was most significantly affected in both diabetic and idiopathic gastroparesis. Proteins involved in the complement and prostaglandin synthesis pathway were associated with symptoms and gastric emptying delay in diabetic gastroparesis.

Dataset Information

Repeat polymorphisms in the Homo sapiens heme oxygenase-1 gene in diabetic and idiopathic gastroparesis.

Publications

Repeat polymorphisms in the Homo sapiens heme oxygenase-1 gene in diabetic and idiopathic gastroparesis.

Similar Datasets

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