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      Journal of Pain Research (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on reporting of high-quality laboratory and clinical findings in all fields of pain research and the prevention and management of pain. Sign up for email alerts here.

      52,235 Monthly downloads/views I 2.832 Impact Factor I 4.5 CiteScore I 1.2 Source Normalized Impact per Paper (SNIP) I 0.655 Scimago Journal & Country Rank (SJR)

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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.

          Most cited references21

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          Pain in sickle cell disease. Rates and risk factors.

          O S Platt, B D Thorington, D Brambilla … (1991)
          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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            Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure.

            A. Nackley, S. Shabalina, I. E. Tchivileva … (2006)
            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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              Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

              Mark Gladwin, Vandana Sachdev, Maria Jison … (2004)
              The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated. Copyright 2004 Massachusetts Medical Society
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Pain Res
                Journal ID (iso-abbrev): J Pain Res
                Journal ID (publisher-id): Journal of Pain Research
                Title: Journal of Pain Research
                Publisher: Dove Medical Press
                ISSN (Electronic): 1178-7090
                Publication date Collection: 2018
                Publication date (Electronic): 12 March 2018
                Volume: 11
                Pages: 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
                Publisher ID: jpr-11-537
                DOI: 10.2147/JPR.S149958
                PMC ID: 5856032
                PubMed ID: 29559808
                SO-VID: 61e0e8e4-d227-4da9-8b66-5673343a6fd8
                Copyright © © 2018 Zhang et al. This work is published and licensed by Dove Medical Press Limited
                License:

                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.

                History
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Anesthesiology & Pain management
                Keywords: er visit,catechol-o-methyltransferase,haplotype,voe,snp
                Data availability:
                ScienceOpen disciplines: Anesthesiology & Pain management
                Keywords: er visit, catechol-o-methyltransferase, haplotype, voe, snp

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