Genetic variants of <i>PKLR</i> are associated with acute pain in sickle cell disease

Wang, Xunde; Gardner, Kate; Tegegn, Mickias; Dalgard, Clifton L.; Alba, Camille; Menzel, Stephan; Patel, Hamel; Pirooznia, Mehdi; Fu, Yi-Ping; Seifuddin, Fayaz; Thein, Swee Lay

doi:10.1182/bloodadvances.2021006668

Cited by 9 publications

(4 citation statements)

References 26 publications

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“…Conversely, when heterozygous HbS (“sickle trait”) and PKD coincide, an SCD phenotype emerges. In two independent cohorts of child and adult patients with HbSS or HbSβo (beta-thalassemia) SCD, certain PKLR variants were demonstrated to associate with the frequency of acute pain episodes requiring hospitalization ( Wang et al, 2022 ). These findings underscore a modulatory role for RBC PK (PKR) in SCD outcomes and symptoms and are supportive of investigation of the use of PKR activators in reducing the frequency of such acute pain episodes and other pathophysiology, especially in individuals with such PKLR variants ( Wang et al, 2022 ).…”

Section: Red Blood Cells In Disease Statesmentioning

confidence: 99%

Modulation of the allosteric and vasoregulatory arms of erythrocytic oxygen transport

Wise,

Ott,

Joseph

et al. 2024

Front. Physiol.

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Efficient distribution of oxygen (O2) to the tissues in mammals depends on the evolved ability of red blood cell (RBC) hemoglobin (Hb) to sense not only O2 levels, but metabolic cues such as pH, PCO2, and organic phosphates, and then dispense or take up oxygen accordingly. O2 delivery is the product of not only oxygen release from RBCs, but also blood flow, which itself is also governed by vasoactive molecular mediators exported by RBCs. These vascular signals, including ATP and S-nitrosothiols (SNOs) are produced and exported as a function of the oxygen and metabolic milieu, and then fine-tune peripheral metabolism through context-sensitive vasoregulation. Emerging and repurposed RBC-oriented therapeutics can modulate either or both of these allosteric and vasoregulatory activities, with a single molecule or other intervention influencing both arms of O2 transport in some cases. For example, organic phosphate repletion of stored RBCs boosts the negative allosteric effector 2,3 biphosphoglycerate (BPG) as well as the anti-adhesive molecule ATP. In sickle cell disease, aromatic aldehydes such as voxelotor can disfavor sickling by increasing O2 affinity, and in newer generations, these molecules have been coupled to vasoactive nitric oxide (NO)-releasing adducts. Activation of RBC pyruvate kinase also promotes a left shift in oxygen binding by consuming and lowering BPG, while increasing the ATP available for cell health and export on demand. Further translational and clinical investigation of these novel allosteric and/or vasoregulatory approaches to modulating O2 transport are expected to yield new insights and improve the ability to correct or compensate for anemia and other O2 delivery deficits.

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Section: Red Blood Cells In Disease Statesmentioning

confidence: 99%

Modulation of the allosteric and vasoregulatory arms of erythrocytic oxygen transport

Wise,

Ott,

Joseph

et al. 2024

Front. Physiol.

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“…Four studies sampled only adults (19,(20)(21)(22) aged 18-70 years with a median sample size of n = 200. Thirteen studies sampled both children and adults (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) with a median sample size of n = 134. Of the 21 articles providing sufficient age data, we calculated a mean age of 24.8 ± 11.1 years (range 5-70) for most of the participants included in our review.…”

Section: Population Characteristicsmentioning

confidence: 99%

“…Synthesis of the 22 articles revealed evidence of statistically suggestive associations between SCD-related acute pain heterogeneity in 20 gene regions with 48 respective SNPs (see Table 1) (14, 16,20,22,23,25,26,28,29,[31][32][33][34][35]. Additionally, there is evidence suggestive of a significant association between SCD-related chronic pain heterogeneity in 4 gene regions with 13 respective SNPs (see Table 2) (24,27,28,33).…”

Section: Genetic Associations With Scd-related Painmentioning

confidence: 99%

Single nucleotide polymorphisms and sickle cell disease-related pain: a systematic review

Gehling,

Powell-Roach,

Wilkie

et al. 2023

Front. Pain Res.

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BackgroundScientists have speculated genetic variants may contribute to an individual's unique pain experience. Although research exists regarding the relationship between single nucleotide polymorphisms and sickle cell disease-related pain, this literature has not been synthesized to help inform future precision health research for sickle cell disease-related pain. Our primary aim of this systematic review was to synthesize the current state of scientific literature regarding single nucleotide polymorphisms and their association with sickle cell disease-related pain.MethodsUsing the Prisma guidelines, we conducted our search between December 2021–April 2022. We searched PubMed, Web of Science, CINAHL, and Embase databases (1998–2022) and selected all peer-reviewed articles that included reports of associations between single nucleotide polymorphisms and sickle cell disease-related pain outcomes.ResultsOur search yielded 215 articles, 80 of which were duplicates, and after two reviewers (GG, JD) independently screened the 135 non-duplicate articles, we retained 22 articles that met the study criteria. The synthesis of internationally generated evidence revealed that this scientific area remains predominantly exploratory in nature, with only three studies reporting sufficient power for genetic association. Sampling varied across studies with a range of children to older adults with SCD. All of the included articles (n = 22) examined acute pain, while only nine of those studies also examined chronic pain.ConclusionCurrently, the evidence implicating genetic variation contributing to acute and chronic sickle cell disease-related pain is characterized by modestly powered candidate-gene studies using rigorous SCD-pain outcomes. Effect sizes and directions vary across studies and are valuable for informing the design of future studies. Further research is needed to replicate these associations and extend findings with hypothesis-driven research to inform precision health research.

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“…24,25,55,110 Pain is a lifelong companion of people living with SCD. 88 The complex nature of SCD pain has been explored in several studies 50,52,58 with considerable progress in understanding the acute pain episodes experienced by patients with SCD 96,120 ; however, marked deficiencies in the knowledge regarding chronic pain mechanisms and the transition from acute to chronic pain in SCD have been realized and contribute to inadequate management of chronic pain in SCD. 8,39,76 Chronic inflammation and oxidative stress are central to SCD pathology.…”

Section: Introductionmentioning

confidence: 99%

Gut microbiota dysbiosis alters chronic pain behaviors in a humanized transgenic mouse model of sickle cell disease

Kashyap,

Wang

2023

Pain

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Pain is the most common symptom experienced by patients with sickle cell disease (SCD) throughout their lives and is the main cause of hospitalization. Despite the progress that has been made towards understanding the disease pathophysiology, major gaps remain in the knowledge of SCD pain, the transition to chronic pain, and effective pain management. Recent evidence has demonstrated a vital role of gut microbiota in pathophysiological features of SCD. However, the role of gut microbiota in SCD pain is yet to be explored. We sought to evaluate the compositional differences in the gut microbiota of transgenic mice with SCD and nonsickle control mice and investigate the role of gut microbiota in SCD pain by using antibiotic-mediated gut microbiota depletion and fecal material transplantation (FMT). The antibiotic-mediated gut microbiota depletion did not affect evoked pain but significantly attenuated ongoing spontaneous pain in mice with SCD. Fecal material transplantation from mice with SCD to wild-type mice resulted in tactile allodynia (0.95 ± 0.17 g vs 0.08 ± 0.02 g, von Frey test, P < 0.001), heat hyperalgesia (15.10 ± 0.79 seconds vs 8.68 ± 1.17 seconds, radiant heat, P < 0.01), cold allodynia (2.75 ± 0.26 seconds vs 1.68 ± 0.08 seconds, dry ice test, P < 0.01), and anxiety-like behaviors (Elevated Plus Maze Test, Open Field Test). On the contrary, reshaping gut microbiota of mice with SCD with FMT from WT mice resulted in reduced tactile allodynia (0.05 ± 0.01 g vs 0.25 ± 0.03 g, P < 0.001), heat hyperalgesia (5.89 ± 0.67 seconds vs 12.25 ± 0.76 seconds, P < 0.001), and anxiety-like behaviors. These findings provide insights into the relationship between gut microbiota dysbiosis and pain in SCD, highlighting the importance of gut microbial communities that may serve as potential targets for novel pain interventions.

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Genetic variants of PKLR are associated with acute pain in sickle cell disease

Cited by 9 publications

References 26 publications

Modulation of the allosteric and vasoregulatory arms of erythrocytic oxygen transport

Modulation of the allosteric and vasoregulatory arms of erythrocytic oxygen transport

Single nucleotide polymorphisms and sickle cell disease-related pain: a systematic review

Gut microbiota dysbiosis alters chronic pain behaviors in a humanized transgenic mouse model of sickle cell disease

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