Abstract

Inflammatory bowel diseases (IBD) are associated with altered neuronal regulation of the gastrointestinal (GI) tract and release of norepinephrine (NE). As sympathetic innervation of the GI tract modulates motility, blood flow, and immune function, changes in NE signaling may alter the risk of developing IBD. Dopamine beta-hydroxylase (DβH), the enzyme responsible for NE production, has been suggested to play a critical role in IBD, however the exact mechanism is unknown. We hypothesized that genetic variants of DβH could increase the risk of IBD. We performed genetic analysis on 45 IBD patients and 74 controls. IBD patients were screened by targeted exome sequencing and compared with NeuroX DβH single nucleotide polymorphism (SNP) genotyping data of the controls. Serum DβH protein levels for 15 IBD patients and 13 controls were evaluated using immunoblots and competitive ELISA. Seven SNPs were observed from DβH targeted exome sequencing in the 45 IBD patients. A single non-synonymous SNP, rs6271 (Arg549Cys), had a significant association with IBD patients; the odds ratio was a 5.6 times higher SNP frequency in IBD patients compared to controls (p = 0.002). We also examined the function and availability of the protein in both the IBD and control patients' sera bearing DβH Arg549Cys. Both control and IBD subjects bearing the heterozygote allele had statistically lower DβH protein levels while the intrinsic enzyme activity was higher. This is the first report of a noradrenergic genetic polymorphism (rs6271; Arg549Cys) associated with IBD. This polymorphism is associated with significantly lower levels of circulating DβH.

Original languageEnglish (US)
Article numbere0210175
JournalPloS one
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2019

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dopamine beta-monooxygenase
Dopamine beta-Hydroxylase
inflammatory bowel disease
Polymorphism
Inflammatory Bowel Diseases
single nucleotide polymorphism
Single Nucleotide Polymorphism
Nucleotides
Enzymes
enzymes
Bearings (structural)
norepinephrine
Exome
Norepinephrine
Gastrointestinal Tract
gastrointestinal system
genetic polymorphism
Proteins
proteins
Genetic Polymorphisms

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

@article{4d9a068881b14bb0ab78095eaaa81b5d,
title = "A single nucleotide polymorphism in dopamine beta hydroxylase (rs6271(C>T)) is over-represented in inflammatory bowel disease patients and reduces circulating enzyme",
abstract = "Inflammatory bowel diseases (IBD) are associated with altered neuronal regulation of the gastrointestinal (GI) tract and release of norepinephrine (NE). As sympathetic innervation of the GI tract modulates motility, blood flow, and immune function, changes in NE signaling may alter the risk of developing IBD. Dopamine beta-hydroxylase (DβH), the enzyme responsible for NE production, has been suggested to play a critical role in IBD, however the exact mechanism is unknown. We hypothesized that genetic variants of DβH could increase the risk of IBD. We performed genetic analysis on 45 IBD patients and 74 controls. IBD patients were screened by targeted exome sequencing and compared with NeuroX DβH single nucleotide polymorphism (SNP) genotyping data of the controls. Serum DβH protein levels for 15 IBD patients and 13 controls were evaluated using immunoblots and competitive ELISA. Seven SNPs were observed from DβH targeted exome sequencing in the 45 IBD patients. A single non-synonymous SNP, rs6271 (Arg549Cys), had a significant association with IBD patients; the odds ratio was a 5.6 times higher SNP frequency in IBD patients compared to controls (p = 0.002). We also examined the function and availability of the protein in both the IBD and control patients' sera bearing DβH Arg549Cys. Both control and IBD subjects bearing the heterozygote allele had statistically lower DβH protein levels while the intrinsic enzyme activity was higher. This is the first report of a noradrenergic genetic polymorphism (rs6271; Arg549Cys) associated with IBD. This polymorphism is associated with significantly lower levels of circulating DβH.",
author = "Eugene Gonzalez-Lopez and Yuka Kawasawa-Imamura and Lijun Zhang and Xuemei Huang and Walter Koltun and Matthew Coates and Kent Vrana",
year = "2019",
month = "2",
day = "1",
doi = "10.1371/journal.pone.0210175",
language = "English (US)",
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T1 - A single nucleotide polymorphism in dopamine beta hydroxylase (rs6271(C>T)) is over-represented in inflammatory bowel disease patients and reduces circulating enzyme

AU - Gonzalez-Lopez, Eugene

AU - Kawasawa-Imamura, Yuka

AU - Zhang, Lijun

AU - Huang, Xuemei

AU - Koltun, Walter

AU - Coates, Matthew

AU - Vrana, Kent

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Inflammatory bowel diseases (IBD) are associated with altered neuronal regulation of the gastrointestinal (GI) tract and release of norepinephrine (NE). As sympathetic innervation of the GI tract modulates motility, blood flow, and immune function, changes in NE signaling may alter the risk of developing IBD. Dopamine beta-hydroxylase (DβH), the enzyme responsible for NE production, has been suggested to play a critical role in IBD, however the exact mechanism is unknown. We hypothesized that genetic variants of DβH could increase the risk of IBD. We performed genetic analysis on 45 IBD patients and 74 controls. IBD patients were screened by targeted exome sequencing and compared with NeuroX DβH single nucleotide polymorphism (SNP) genotyping data of the controls. Serum DβH protein levels for 15 IBD patients and 13 controls were evaluated using immunoblots and competitive ELISA. Seven SNPs were observed from DβH targeted exome sequencing in the 45 IBD patients. A single non-synonymous SNP, rs6271 (Arg549Cys), had a significant association with IBD patients; the odds ratio was a 5.6 times higher SNP frequency in IBD patients compared to controls (p = 0.002). We also examined the function and availability of the protein in both the IBD and control patients' sera bearing DβH Arg549Cys. Both control and IBD subjects bearing the heterozygote allele had statistically lower DβH protein levels while the intrinsic enzyme activity was higher. This is the first report of a noradrenergic genetic polymorphism (rs6271; Arg549Cys) associated with IBD. This polymorphism is associated with significantly lower levels of circulating DβH.

AB - Inflammatory bowel diseases (IBD) are associated with altered neuronal regulation of the gastrointestinal (GI) tract and release of norepinephrine (NE). As sympathetic innervation of the GI tract modulates motility, blood flow, and immune function, changes in NE signaling may alter the risk of developing IBD. Dopamine beta-hydroxylase (DβH), the enzyme responsible for NE production, has been suggested to play a critical role in IBD, however the exact mechanism is unknown. We hypothesized that genetic variants of DβH could increase the risk of IBD. We performed genetic analysis on 45 IBD patients and 74 controls. IBD patients were screened by targeted exome sequencing and compared with NeuroX DβH single nucleotide polymorphism (SNP) genotyping data of the controls. Serum DβH protein levels for 15 IBD patients and 13 controls were evaluated using immunoblots and competitive ELISA. Seven SNPs were observed from DβH targeted exome sequencing in the 45 IBD patients. A single non-synonymous SNP, rs6271 (Arg549Cys), had a significant association with IBD patients; the odds ratio was a 5.6 times higher SNP frequency in IBD patients compared to controls (p = 0.002). We also examined the function and availability of the protein in both the IBD and control patients' sera bearing DβH Arg549Cys. Both control and IBD subjects bearing the heterozygote allele had statistically lower DβH protein levels while the intrinsic enzyme activity was higher. This is the first report of a noradrenergic genetic polymorphism (rs6271; Arg549Cys) associated with IBD. This polymorphism is associated with significantly lower levels of circulating DβH.

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