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Candidate gene association study suggests potential role of dopamine beta-hydroxylase in pain heterogeneity in sickle cell disease.

ABSTRACT: Introduction: Pain is a lifelong companion of individuals with sickle cell disease (SCD) and has a severe impact on their quality of life. Both acute crisis pain and chronic non-crisis pain exhibit high variability between individuals, making it difficult to effectively manage sickle cell-related pain. We investigated the role of dopamine beta-hydroxylase (DBH) gene polymorphisms on pain variability in SCD. DBH is a key enzyme in the catecholamine biosynthesis pathway that catalyzes the conversion of dopamine to norepinephrine, both of which are known mediators of pain and pain-related behaviors. Methods: Acute crisis pain-related utilization and non-crisis chronic pain scores of 131 African Americans with SCD were obtained. Results and discussion: Association analyses revealed that the T allele of upstream variant rs1611115 and downstream variant rs129882 correlated with higher severity of chronic pain in an additive model. On the other hand, the A allele of missense variant rs5324 associated with lower risk of both acute crisis pain and chronic pain. Similarly, the C allele of intronic variant rs2797849 was associated with lower incidence of acute crisis pain in the additive model. In addition, tissue-specific eQTL revealed that the T allele of rs1611115 correlated with decreased expression of DBH in the frontal cortex and anterior cingulate cortex (GTEx), and decreased expression of DBH-AS1 in blood (eQTLGen). Bioinformatic approaches predicted that rs1611115 may be altering a transcription factor binding site, thereby, contributing to its potential effect. Taken together, findings from this study suggest that potential functional polymorphisms of DBH may modulate pain perception in SCD.

SUBMITTER: Sadhu N

PROVIDER: S-EPMC10296203 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Candidate gene association study suggests potential role of dopamine beta-hydroxylase in pain heterogeneity in sickle cell disease.

Sadhu Nilanjana N He Ying Y Yao Yingwei Y Wilkie Diana J DJ Molokie Robert E RE Wang Zaijie Jim ZJ

Frontiers in genetics 20230613

<b>Introduction:</b> Pain is a lifelong companion of individuals with sickle cell disease (SCD) and has a severe impact on their quality of life. Both acute crisis pain and chronic non-crisis pain exhibit high variability between individuals, making it difficult to effectively manage sickle cell-related pain. We investigated the role of dopamine beta-hydroxylase (DBH) gene polymorphisms on pain variability in SCD. DBH is a key enzyme in the catecholamine biosynthesis pathway that catalyzes the c ...[more]

PMID: 37384335

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Project description:The mesotelencephalic dopamine system shows substantial genetic variation which fundamentally affects normal and pathological behaviors related to motor function, motivation, and learning. Our earlier radioenzyme assay studies demonstrated significantly higher activity of tyrosine hydroxylase (TH), the first and rate limiting enzyme in the biosynthesis of catecholamine neurotransmitters, in the substantia nigra-ventral tegmental area of BALB/cJ mice in comparison with that of C57BL/6ByJ mice. Here, using quantitative immunoblotting and immunocytochemistry, we tested the hypothesis that mesencephalic TH protein content and number of nigral TH-positive neurons show strain-dependent differences in C57BL/6ByJ and BALB/cJ parallel to those observed in the TH activity studies. Immunoblotting experiments detected significantly higher mesencephalic TH protein content in BALB/cJ in comparison to C57BL/6ByJ (P<0.05). Immunocytochemical studies demonstrated that the number of TH-positive cells in substantia nigra was 31.3% higher in BALB/cJ than that in C57BL/6ByJ (P<0.01), while the average dopamine neuron volume was not significantly different. In a search for candidate genes that modulate TH content and the size of mesencephalic dopamine neuron populations we also studied near-isogenic mouse sublines derived from the C57BL/6ByJ and BALB/cJ progenitor strains. A whole-genome scan with 768 single nucleotide polymorphism markers indicated that two sublines, C4A6/N and C4A6/B, were genetically very similar (98.3%). We found significantly higher mesencephalic TH protein content in C4A6/B in comparison to C4A6/N (P=0.01), and a tendency for higher number of dopamine neurons in the substantia nigra in C4A6/B in comparison to C4A6/N, which, however, did not reach statistical significance. To identify the genetic source of the TH content difference we analyzed the single nucleotide polymorphism (SNP) genotype data of the whole-genome scan, and detected two small differential chromosome segments on chr. 13 and chr. 14. Microarray gene expression studies and bioinformatic analysis of the two differential regions implicated two cis-regulated genes (Spock1 and Cxcl14, chr. 13), and two growth factor genes [bone morphogenetic protein 6 (Bmp6) (chr. 13), and fibroblast growth factor 14 (Fgf14) (chr. 14)]. Taken together, the results suggest that (1) nigral dopamine neuron number and TH protein content may be genetically associated but further studies are needed to establish unequivocally this linkage, and (2) Spock1, Cxcl14, Bmp6, and Fgf14 are novel candidates for modulating the expression and maintenance of TH content in mesencephalic dopamine neurons in vivo.

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Candidate gene association study suggests potential role of dopamine beta-hydroxylase in pain heterogeneity in sickle cell disease.

Publications

Candidate gene association study suggests potential role of dopamine beta-hydroxylase in pain heterogeneity in sickle cell disease.

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