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      Association of genetic variation in COMT gene with pain related to sickle cell disease in patients from the walk-PHaSST study

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          Abstract

          Background

          Vaso-occlusive pain episodes (VOEs) are the hallmark of sickle cell disease (SCD), and our current understanding of disease biology, treatment, and psychological covariates does not adequately explain the variability of pain in SCD. Functional variants in catechol- O-methyltransferase ( COMT) gene contribute to variability in pain perception, but their impact on pain perception in African American SCD patients is not well known.

          Methods

          We studied COMT single-nucleotide polymorphisms (SNPs) rs6269, rs4633, rs4818, rs4680, and rs165599 to determine their relationship to patient self-reported pain, the number of acute VOEs, and their impact on daily life and health care utilization in 438 hemoglobin SS patients who participated in the walk-PHaSST study.

          Results

          In women, two risk SNPs (rs4633 and rs165599) and the corresponding haplotype (A TCA A) were associated with increased frequency of pain-related emergency room visit.

          Conclusion

          COMT functional variants may predispose SCD patients to worse acute pain in women. The association of COMT variants with the intensity of self-reported acute pain warrants further genetic study of pain perception in SCD.

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          Most cited references 21

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          Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure.

          Catechol-O-methyltransferase (COMT) is a key regulator of pain perception, cognitive function, and affective mood. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous position, code for differences in COMT enzymatic activity and are associated with pain sensitivity. Haplotypes divergent in synonymous changes exhibited the largest difference in COMT enzymatic activity, due to a reduced amount of translated protein. The major COMT haplotypes varied with respect to messenger RNA local stem-loop structures, such that the most stable structure was associated with the lowest protein levels and enzymatic activity. Site-directed mutagenesis that eliminated the stable structure restored the amount of translated protein. These data highlight the functional significance of synonymous variations and suggest the importance of haplotypes over single-nucleotide polymorphisms for analysis of genetic variations.
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            Pain in sickle cell disease. Rates and risk factors.

            Acute episodes of pain are the principal symptom of sickle cell disease, but little is known about the epidemiologic features of these episodes or risk factors for them, nor is it known whether patients with high rates of such episodes die prematurely. We prospectively studied the natural history of sickle cell disease in 3578 patients ranging from newborns to persons up to 66 years old who were followed at clinical centers across the United States. There were 12,290 episodes of pain in 18,356 patient-years. The average rate was 0.8 episode per patient-year in sickle cell anemia, 1.0 episode per patient-year in sickle beta 0-thalassemia, and 0.4 episode per patient-year in hemoglobin SC disease and sickle beta(+)-thalassemia. The rate varied widely within each of these four groups--e.g., 39 percent of patients with sickle cell anemia had no episodes of pain, and 1 percent had more than six episodes per year. The 5.2 percent of patients with 3 to 10 episodes per year had 32.9 percent of all episodes. Among patients with sickle cell anemia who were more than 20 years old, those with high rates of pain episodes tended to die earlier than those with low rates. High rates were associated with a high hematocrit and low fetal hemoglobin levels. alpha-Thalassemia had no effect on pain apart from its association with an increased hematocrit. The "pain rate" (episodes per year) is a measure of clinical severity and correlates with early death in patients with sickle cell anemia over the age of 20. Even when the fetal hemoglobin level is low, one can predict that small increments in the level may have an ameliorating effect on the pain rate and may ultimately improve survival. This outcome is particularly encouraging to investigators studying hydroxyurea and other treatments designed to increase the fetal hemoglobin level.
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              COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor.

              Responses to pain and other stressors are regulated by interactions between multiple brain areas and neurochemical systems. We examined the influence of a common functional genetic polymorphism affecting the metabolism of catecholamines on the modulation of responses to sustained pain in humans. Individuals homozygous for the met158 allele of the catechol-O-methyltransferase (COMT) polymorphism (val158met) showed diminished regional mu-opioid system responses to pain compared with heterozygotes. These effects were accompanied by higher sensory and affective ratings of pain and a more negative internal affective state. Opposite effects were observed in val158 homozygotes. The COMT val158met polymorphism thus influences the human experience of pain and may underlie interindividual differences in the adaptation and responses to pain and other stressful stimuli.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2018
                12 March 2018
                : 11
                : 537-543
                Affiliations
                [1 ]Division of Pulmonary, Allergy, and Critical Care Medicine
                [2 ]Department of Human Genetics
                [3 ]Department of Anesthesiology, University of Pittsburgh
                [4 ]Department of Pathology and Laboratory Medicine
                [5 ]Department of Pediatrics, Division of Pediatric Hematology/Oncology, Weill Cornell Medicine
                [6 ]Division of Hematology/Oncology, Children’s Hospital of Pittsburgh, Pittsburgh, PA
                [7 ]AFLAC Center for Cancer and Blood Disorders, Children’s Healthcare of Atlanta, Atlanta, GA, USA
                Author notes
                Correspondence: Lakshmanan Krishnamurti, AFLAC Center for Cancer and Blood Disorders, Children’s Healthcare of Atlanta, 2015 Uppergate Drive, Atlanta, GA 30322, USA, Tel +1 404 727 0710, Email lakshmanan.krishnamurti@ 123456emory.edu
                Article
                jpr-11-537
                10.2147/JPR.S149958
                5856032
                © 2018 Zhang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Anesthesiology & Pain management

                er visit, catechol-o-methyltransferase, haplotype, voe, snp

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