Abstract
Background
Pain is one of the most common and deleterious symptoms experienced by individuals with sickle cell disease (SCD). There is a paucity of studies identifying potential genetic mechanisms of pain in this population.
Aim
Examine associations between 11 functional single nucleotide polymorphisms in 9 candidate genes with reports of average pain intensity in individuals with sickle cell disease.
Method
Cross-sectional analyses were performed on data and blood samples collected through the Duke SCD Implementation Consortium Registry. Participants were asked to rate their pain “on the average” using an 11-point numeric rating scale (0 = no pain; 10 = pain as bad as you can imagine). We genotyped 11 single nucleotide polymorphisms in 9 pain-related genes using TaqMan® Genotyping Assays. Associations between each polymorphism and reports of average pain were evaluated.
Results
The 86 participants (mean age: 28.7 years; 64% female) included in this study reported moderate pain on average (Mean = 4, Standard Deviation = 2.4). ICAM1 rs1799969 was the only genetic polymorphism that was significantly associated with pain (p = .01). Individuals with one or more minor alleles had lower average pain (Mean = 1.25, Standard Deviation = 1.50) than individuals without a minor allele (Mean = 4.13, Standard Deviation = 2.25). The effect size for ICAM1 rs1799969 was 1.30, which is considered large. The effect sizes for all other single nucleotide polymorphisms ranged from small to medium (range: 0–0.3).
Conclusions
Our findings provide preliminary evidence that the minor allele in ICAM1 rs1799969 had protective effects against experiencing more severe pain in sickle cell disease.
Keywords
Individuals with sickle cell disease (SCD), a group of inherited chronic blood cell disorders, experience severe pain throughout their lifespan. SCD has a complex pathophysiology that involves a genetic variation in the hemoglobin beta globin gene. This genetic variation results in misshapen red blood cells, often referred to as sickled cells due to their crescent shape, which are likely to clump and stick to blood vessel walls, causing multifaceted processes such as vaso-occlusion, ischemia-reperfusion injury, endothelial dysfunction of the vasculature, and chronic inflammation (
Conran and De Paula, 2020
; Odièvre et al., 2011
). These processes ultimately result in significant medical complications such as vascular and organ damage. Although severe acute pain episodes that correspond with vaso-occlusive events (VOEs) are the hallmark of SCD, research highlights the occurrence of persistent pain in this population; a majority of adults with SCD report experiencing pain on most days in addition to acute episodes (Matthie et al., 2020
; Smith et al., 2008
).Hyperexcitability and hypersensitivity of the central and peripheral nervous systems, known as central and peripheral sensitization, are thought to contribute to development of SCD pain. It is suspected that recurrent vaso-occlusion leads to persistent inflammation and nociceptive input, which promotes pain sensitization (
Gupta et al., 2018
; Tran et al., 2017
). The molecular basis for this alteration in pain processing in SCD is not well understood; therefore, studying genetic variations known to influence inflammatory processes and neurotransmission can help delineate underlying biologic mechanisms of pain in this population.Inflammation is a putative mechanism of pain in individuals with SCD. Dysregulation of cytokines (proteins that mediate inflammatory and immune processes and can serve as excitatory mediators in pain modulation) has been implicated in the development of persistent pain syndromes (e.g., fibromyalgia, neuropathic pain) (
Ji et al., 2018
; Kraychete et al., 2009
; Ramesh et al., 2013
; Sturgill et al., 2014
). Research has shown that individuals with SCD have elevated cytokine levels that increase further during acute VOEs (Francis and Haywood, 1992
; Graido-Gonzalez et al., 1998
; Hibbert et al., 2005
; Pathare et al., 2004
; Qari et al., 2012
). Furthermore, a study evaluating associations between experimentally induced pain and cytokines in adults with SCD identified that cytokines, such as interleukin-4 (IL-4), interleukin-8 (IL-8), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), were all associated with pain severity (Campbell et al., 2016
).The complex inflammatory processes in SCD are influenced by activation of the endothelium during VOEs. The endothelium is the lining of blood vessel walls; it consists of endothelial cells that become adhesive and recruit platelets and leukocytes to the area when activated (
Conran and Belcher, 2018
; Conran and De Paula, 2020
). These interactions induce pro-inflammatory mediators, including cytokines (e.g., TNF- α, IL-1β) and other inflammatory molecules (e.g., chemokines, growth factors), further increasing the expression of endothelial surface adhesion molecules (e.g., intercellular cell adhesion molecule-1 [ICAM-1], E-selectin, and P-selectin) that lead to clot formation and/or leukocyte diapedesis (Conran and De Paula, 2020
; Harjunpää et al., 2019
). In our previous pilot study of 74 adults with SCD, we identified that plasma concentration of soluble E-selectin was elevated in individuals who reported more frequent occurrence of severe persistent pain (Knisely et al., 2022
).Alterations in neurotransmitters such as brain-derived neurotrophic factor (BDNF) and the reduced activity of catecholamines (epinephrine and norepinephrine) breakdown the enzyme catechol-O-methyltransferase (COMT) and contribute to neuroinflammation, the molecular process that induces and maintains central sensitization (
Ji et al., 2018
). Decreased COMT activity is associated with increased risk of orofacial pain (Slade et al., 2015
) and increased pain sensitivity in individuals with fibromyalgia (Barbosa et al., 2012
; - Barbosa F.R.
- Matsuda J.B.
- Mazucato M.
- de Castro França S.
- Zingaretti S.M.
- da Silva L.M.
- Martinez-Rossi N.M.
- Júnior M.F.
- Marins M.
- Fachin A.L.
Influence of catechol-O-methyltransferase (COMT) gene polymorphisms in pain sensibility of Brazilian fibromialgia patients.
Rheumatology International. 2012; 32: 427-430
Cohen et al., 2009
). In a study evaluating associations between genetic variation and pain related to SCD, investigators found that two genetic polymorphisms in the COMT gene were associated with increased frequency in pain-related emergency room visits (Zhang et al., 2018
). Furthermore, preclinical studies in BDNF knockout mice suggest that BDNF may play an important role in acute to chronic pain transition (Sikandar et al., 2018
).Although evidence suggests that several biologic mechanisms likely contribute to the pain experiences of individuals with SCD, few studies have explored genetic variations associated with pain in this population. Determining functional polymorphisms associated with pain is an essential step in elucidating potential mechanisms and biomarkers of pain. Functional polymorphisms are variations in an individual's DNA which are thought to influence the structure, function, or level of a gene product (
Albert, 2011
). The purpose of this exploratory study was to examine associations between functional single nucleotide polymorphisms (SNPs) in candidate genes and reports of average pain intensity in individuals with SCD. This hypothesis-generating study can advance nursing science and practice by: (a) improving the ability to identify mechanisms that place patients at greater risk for high pain burden, and (b) identifying potential new targets for interventions for pain relief in people with SCD.Methods
Design & Setting
This exploratory, cross-sectional, genetic ancillary study leveraged recruitment and data collected for the Sickle Cell Disease Implementation Consortium (SCDIC) Research Registry at Duke University. This comprehensive research registry includes prospective, longitudinally collected patient-reported and electronic health record (her) data (
DiMartino et al., 2018
; - DiMartino L.D.
- Baumann A.A.
- Hsu L.L.
- Kanter J.
- Gordeuk V.R.
- Glassberg J.
- Treadwell M.J.
- Melvin C.L.
- Telfair J.
- Klesges L.M.
- King A.
- Wun T.
- Shah N.
- Gibson R.W.
- Hankins J.S.
The sickle cell disease implementation consortium: Translating evidence-based guidelines into practice for sickle cell disease.
American Journal of Hematology. 2018; 93: E391-E395
Glassberg et al., 2020
). Data were collected at enrollment in the registry and yearly thereafter. A subset of participants also provided blood specimens.- Glassberg J.A.
- Linton E.A.
- Burson K.
- Hendershot T.
- Telfair J.
- Kanter J.
- Gordeuk V.R.
- King A.A.
- Melvin C.L.
- Shah N.
- Hankins J.S.
- Epié A.Y.
- Richardson L.D.
Publication of data collection forms from NHLBI funded sickle cell disease implementation consortium (SCDIC) registry.
Orphanet Journal of Rare Diseases. 2020; 15: 178
Sample
Inclusion criteria for the registry were the following: (a) aged 15–45 years; (b) live in North Carolina; and (c) a genetically confirmed SCD diagnosis. This study used patient-reported data and biospecimens collected at the 1-year follow-up assessment for the research registry. This study was reviewed and approved by the Duke University institutional review board and participants provided written informed consent.
Data Collection & Management Procedures
Demographic & disease-related characteristics
Demographic and clinical data were used to describe the sample. Demographic data included age, sex, marital status, education, and employment. Clinical characteristics included SCD genotype, whether participant was taking pain medications daily, number of pain attacks (VOEs) in past year, and time since most recent pain attack.
Assessment of pain
The primary outcome for the current study was average pain intensity. Participants were asked to rate their pain “on the average” using an 11-point numeric rating scale (0 = no pain; 10 = pain as bad as you can imagine) from the National Institutes of Health's Toolbox that is commonly used to measure pain intensity in clinical trials (
Cook et al., 2013
). The rating for this item was used as the outcome in the data analysis.Candidate gene selection & data collection
Eleven functional SNPs in nine genes of interest (candidate genes) involved in pathways that likely influence pain (inflammation, immunoregulation, neuroregulation) were identified through a review of the literature and findings from our previous studies (
Knisely et al., 2019
; Knisely et al., 2022
) and included in this study (Table 1). We included polymorphisms (genetic variations) if they had a known functional consequence on the gene and/or gene product or had been associated previously with pain in other chronic conditions (e.g., cancer).Table 1Selected Pain-related Candidate Genes and Functional Polymorphisms
| Pain-related pathway | Gene(gene symbol) | Functional SNP | Minor allele | MAF | Functional consequence |
|---|---|---|---|---|---|
| Inflammation/Immunoregulation | FKBP prolyl isomerase 5 (FKBP5) | rs3800373 | C | 0.419 | Intron variant associated with greater FKBP5 induction by cortisol and decreased glucocorticoid-receptor sensitivity ( Fudalej et al., 2015 ; Tatro et al., 2009 ) |
| E-selectin (SELE) | rs5361 | G | 0.034 | Missense variant associated with higher levels of plasma E-selectin levels ( Mlekusch et al., 2004 ) | |
| Intercellular adhesion molecule 1 (ICAM1) | rs5498 | G | 0.204 | Missense variant associated with increased levels of soluble ICAM-1 ( Bielinski et al., 2011 ) | |
| Intercellular adhesion molecule 1 (ICAM1) | rs1799969 | A | 0.026 | Missense variant associated with ICAM-1 concentrations ( Albert et al., 2009 ;
Candidate genetic variants in the fibrinogen, methylenetetrahydrofolate reductase, and intercellular adhesion molecule-1 genes and plasma levels of fibrinogen, homocysteine, and intercellular adhesion molecule-1 among various race/ethnic groups: data from the Women's Genome Health Study. American Heart Journal. 2009; 157 (.e771): 777-783 Schnabel et al., 2009 )
The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations. Circulation. Cardiovascular Genetics. 2009; 2: 229-237 | |
| Interleukin 1 beta (IL-1β) | rs1143634 | A | 0.142 | Synonymous variant with some evidence the T allele is associated with increased production of IL-1β ( Pociot et al., 1992 ) | |
| Interleukin 6 (IL-6) | rs1800795 | C | 0.069 | Intron variant with evidence C allele is associated with decreased IL-6 levels ( Bull et al., 2009 ;
Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. Molecular Psychiatry. 2009; 14: 1095-1104 Paul-Samojedny et al., 2010 ) | |
| Interleukin 8 (IL-8) | rs4073 | T | 0.210 | 2KB upstream variant with evidence A allele is associated with increased IL-8 production ( Hull et al., 2000 ; Taguchi et al., 2005 ) | |
| Tumor necrosis factor alpha (TNF-α) | rs1799964 | C | 0.164 | 2KB upstream variant with evidence C allele is associated with increased production of TNF-α ( Nourian et al., 2017 ;
Evaluation of tumor necrosis factor (TNF)-alpha mRNA expression level and the rs1799964 polymorphism of the TNF-alpha gene in peripheral mononuclear cells of patients with inflammatory bowel diseases. Biomedical Reports. 2017; 6: 698-702 Sandoval-Pinto et al., 2016 ) | |
| Tumor necrosis factor alpha (TNF-α) | rs1800629 | A | 0.124 | 2KB upstream variant with evidence A allele is associated with an increase in the binding of nuclear factors and heightened transcription of the gene ( Kroeger et al., 1997 ; Wilson et al., 1997 ) | |
| Neuroregulation | Brain derived neurotrophic factor (BDNF) | rs6265 | T | 0.045 | Missense variant linked to impairment of BDNF secretion in nervous system ( Chen et al., 2004 ;
Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. Journal of Neuroscience. 2004; 24: 4401-4411 Egan et al., 2003 ) |
| Catechol-O-methyltransferase (COMT) | rs4680 | A | 0.309 | Missense variant that reduces the function of the COMT enzyme, resulting in higher dopamine levels ( Stein et al., 2006 ) |
a As reported in Black populations in dbSNP database (https://www.ncbi.nlm.nih.gov/snp/).SNP = single nucleotide polymorphism; MAF = minor allele frequency.
DNA samples from whole blood were collected as part of the SCDIC research registry. DNA was extracted from whole blood in the Duke University School of Nursing Biomarker Laboratory using the protocol and reagents from the Gentra Puregene blood kit (Qiagen, Germantown, MD). Genotypes were determined in the Molecular Genomics Core at the Duke Molecular Physiology Institute using the TaqMan allele discrimination platform (Thermo Fisher Scientific Inc., Waltham, MA). Duplication of a subset of samples (n = 3) and standard controls (n = 2) was completed for validation of genotyping processes. Genotypes were coded as two doses of major allele versus one or two doses of minor allele present for each functional SNP. The major allele, also considered the common allele, is present more frequently than the minor allele in a population of interest.
Statistical Analysis
Initially a descriptive analysis of the demographic and clinical characteristics of the analytical sample was performed, in which means and standard deviations (SD) are reported for continuous variables and frequency and percentages reported for categorical variables. Independent-samples t test techniques were used to test for differences in pain scores between those with a minor allele present and those without any minor allele present for each specific gene of interest. For any specific gene, if the sample size was smaller than 20 in each group (or the data were non-Gaussian), Mann-Whitney U tests were performed instead. Effect size was assessed using Cohen's d. Given the exploratory nature of this study, p < .05 was considered statistically significant without adjusting for any multiple testing. All data analyses were performed using SPSS Version 24 (IBM, Armonk, NY).
Results
A total of 86 participants met the study inclusion criteria and were included for analysis. Table 2 summarizes the demographic and clinical characteristics of the sample. In summary, participants’ mean age was 28.7 years, and 64% were female. A large majority (77.9%) had never been married, and most (72.1%) had at least some college education or more. The most severe genotypes of SCD, HbSS or Sβ0 genotypes, were the most common. Nearly half (46.5%) of participants were taking pain medications daily. Most participants had experienced 4 or more pain attacks (VOEs) over the past year, with a majority (57%) having had a pain attack within the past 6 months.
Table 2Sample Demographic and Clinical Characteristics
| Total sample(n = 86) | |
|---|---|
| Demographic characteristics | |
| Age (y) | |
| Mean ± SD | 28.7 ± 7.9 |
| Range | 17-45 |
| n (%) | |
| Sex (female) | 55 (64.0%) |
| Marital status (never married) | 67 (77.9%) |
| Education | |
| High school graduate or less | 24 (27.9%) |
| Some college | 35 (40.7%) |
| College graduate | 17 (19.8%) |
| Graduate/Professional degree | 10 (11.6%) |
| Employment | |
| Student | 13 (15.1%) |
| Employed | 36 (41.9%) |
| Unemployed | 32 (37.2%) |
| Other | 5 (5.8%) |
| Clinical characteristics | |
| SCD genotype | |
| Hb SS or Sβ0 | 63 (73.3%) |
| Hb SC | 20 (23.3%) |
| Other (Hb Sβ+, S/HPFH, SE, SO, SD) | 3 (3.5%) |
| Taking pain medications every day (no) | 40 (46.5%) |
| Number of pain attacks (VOEs) in past year | |
| 0 | 10 (11.6%) |
| 1 | 7 (8.1%) |
| 2 | 11 (12.8%) |
| 3 | 10 (11.6%) |
| 4 or more | 48 (55.8%) |
| Time since most recent pain attack (VOE)* | |
| <1 week ago | 10 (11.6%) |
| 1-3 weeks ago | 17 (19.8%) |
| 1-6 months ago | 22 (25.6%) |
| 7-11 months ago | 24 (27.9%) |
| 1-5 years ago | 2 (2.3%) |
| 5+ years ago | 9 (10.5%) |
| Never had a pain attack | 2 (2.3%) |
SD = standard deviation; Hb = hemoglobin; SCD = sickle cell disease; VOE = vaso-occlusive events.
For the overall sample (N = 86), there was an average pain rating of 4.0 (SD = 2.4; range 0–10). Table 3 shows the differences in average pain scores between participants with and without any minor allele for each of the SNPs. Pain scores were significantly higher for those with no minor allele present for ICAM1 rs1799969 when compared with those with a minor allele present for the same SNP (4.13 [SD = 2.25] vs. 1.25 [SD = 1.50], p = .01). The effect size for ICAM1 rs1799969 is 1.30, which is conventionally considered a large effect size. The effect sizes for all the other SNPs were smaller and would be considered small to medium (Cohen's d range: 0.0–0.3; Table 3).
Table 3Differences in Average Pain Score between Participants Individuals Without and With Presence of Minor Alleles
| Functional SNP | No minor allele present | Minor allele present | P | Cohen's d | ||||
|---|---|---|---|---|---|---|---|---|
| N | Mean | SD | N | Mean | SD | |||
| FKBP5 rs3800373 | 35 | 4.4 | 2.23 | 51 | 3.73 | 2.32 | .18 | 0.30 |
| SELE rs5361 | 77 | 4.04 | 2.19 | 9 | 3.67 | 3.20 | .77 | 0.16 |
| ICAM1 rs5498 | 52 | 4.08 | 2.07 | 34 | 3.88 | 2.64 | .70 | 0.08 |
| ICAM1 rs1799969 | 82 | 4.13 | 2.25 | 4 | 1.25 | 1.5 | .01 | 1.30 |
| IL-1β rs1143634 | 57 | 4.09 | 2.08 | 29 | 3.83 | 2.7 | .62 | 0.11 |
| IL-6 rs1800795 | 75 | 4.04 | 2.29 | 11 | 3.73 | 2.45 | .75 | 0.14 |
| IL-8 rs4073 | 57 | 3.93 | 2.37 | 29 | 4.14 | 2.12 | .69 | -0.09 |
| TNF-α rs1799964 | 61 | 3.85 | 2.35 | 25 | 4.36 | 2.16 | .36 | -0.22 |
| TNF-α rs1800629 | 65 | 4.06 | 2.33 | 21 | 3.81 | 2.23 | .67 | 0.11 |
| BDNF rs6265 | 82 | 4 | 2.29 | 4 | 4 | 2.83 | .79 | 0 |
| COMT rs4680 | 39 | 3.77 | 2.35 | 47 | 4.19 | 2.26 | .40 | -0.18 |
a Mann-Whitney U test was used to test for differences between the two groups.
b significant at the .05 level.SNP = single nucleotide polymorphism; SD = stamdard deviation.
Discussion
This exploratory study provides preliminary evidence of associations between functional SNPs with reports of pain among individuals with SCD. On average, participants reported moderate pain; however, of the candidate genes selected, only one SNP was identified as significantly associated with reports of pain. Specifically, individuals carrying one or two copies of the minor allele (A) for ICAM1 rs1799969 reported lower levels of severe pain on the average. This association had a large effect size (Cohen's d >1). That is more than one standard deviation difference between groups. Despite the small number of participants in the group with one or two copies of minor alleles, this finding was consistent with the observed allele frequencies in previously published estimates for African Americans (see Table 1).
Our findings provide preliminary evidence that the minor allele in ICAM1 rs1799969, a missense variant that changes amino acid 241 from glycine to arginine (G241R), may have protective effects against the likelihood of experiencing more severe pain in SCD. ICAM1 is an encoding gene that stimulates the synthesis of ICAM-1. ICAM-1 is one member of a large family of adhesion molecules. Adhesion molecules are proteins that span the cell membrane and have an extracellular portion that can interact with similar regions of adhesion molecules on other cells. ICAM-1 is expressed on endothelial cells and immune cells. Expression of ICAM1 is upregulated by inflammatory mediators (i.e., cytokines), resulting in the recruitment of leukocytes to sites of inflammation. The ICAM1 rs1799969 variant has been associated with normal ICAM-1 adhesion properties (
Bai et al., 2014
), increased cell surface expression of ICAM-1 (Bai et al., 2014
; Holder et al., 2008
), and lower levels of circulating ICAM-1 (Albert et al., 2009
; - Albert M.A.
- Pare G.
- Morris A.
- Rose L.
- Buring J.
- Ridker P.M.
- Zee R.Y.
Candidate genetic variants in the fibrinogen, methylenetetrahydrofolate reductase, and intercellular adhesion molecule-1 genes and plasma levels of fibrinogen, homocysteine, and intercellular adhesion molecule-1 among various race/ethnic groups: data from the Women's Genome Health Study.
American Heart Journal. 2009; 157 (.e771): 777-783
Ponthieux et al., 2003
; Zee et al., 2007
). This combination of increased ICAM-1 expression, yet decreased soluble ICAM-1 (sICAM-1), is somewhat paradoxical since sICAM-1 is a degradation product of cell surface ICAM-1 (- Zee R.Y.
- Cheng S.
- Erlich H.A.
- Lindpaintner K.
- Rifai N.
- Buring J.E.
- Ridker P.M.
Intercellular adhesion molecule 1 (ICAM1) Lys56Met and Gly241Arg gene variants, plasma-soluble ICAM1 concentrations, and risk of incident cardiovascular events in 23,014 initially healthy white women.
Stroke. 2007; 38: 3152-3157
Ramos et al., 2014
), and under normal regulation sICAM-1 levels parallel those of ICAM1 expression. However, sICAM-1 can also be produced from alternative splicing of ICAM-1 messenger RNA (Ramos et al., 2014
), which may be altered by the gene variant. Others have shown that ICAM1 rs1799969 is associated with increased susceptibility to some inflammatory diseases (Lee and Bae, 2016
; Paré et al., 2011
), but not others (Ponthieux et al., 2003
). Furthermore, it is not definitively known how ICAM1 genotype and disease type impact sICAM-1 levels.Insights into mechanisms by which ICAM1 rs1799969 may protect SCD patients against experiencing more severe pain in SCD comes from a recent review by
Müller, 2019
. This review examines the relationship between blood-brain-barrier permeability, microglial activation, and psychiatric disorders. Müller posited that an important aspect of ICAM-1 in psychiatric disorders may be through its regulation of the blood-brain-barrier and microglial activation (Müller, 2019
). In a 2014 review examining pain disorders and the blood-brain-barrier, DosSantos et al., 2014
noted that peripheral models of pain increase ICAM-1 expression and microglial activation in brain regions (thalamus, frontal and parietal cortices) responsible for pain processing and modulation. Additionally, investigators evaluating the efficacy of simvastatin (a drug that lowers cholesterol and protects against vascular injury by decreasing inflammation) for treatment of vaso-occlusive pain in SCD found that this drug caused a significant decrease in acute vaso-occlusive pain events, oral analgesic use, and circulating ICAM-1 among other circulating vascular markers (i.e., soluble E-selectin, vascular cell adhesion protein 1, vascular endothelial growth factor) (Hoppe et al., 2017
). The relationship between SCD pain and ICAM-1 is complex and could benefit from further study. However, the association between ICAM1 rs1799969 and protection against experiencing more severe pain in SCD may be related to effects on the blood-brain-barrier, microglia, and/or the endothelium.Although we did not identify significant associations between pain and the 10 other functional SNPs, FKBP5 rs3800373 did demonstrate a medium effect size in this study. FKBP5 is a gene that encodes a glucocorticoid receptor and plays an integral role in stress response and immune function (
Zannas et al., 2016
). Previous studies have shown that people with the minor allele are more susceptible to pain after exposure to trauma such as sexual assault or motor vehicle collision (Bortsov et al., 2014
; Linnstaedt et al., 2018
). However, in this study, participants with at least one dose of the minor allele had slightly lower pain scores compared with those with no minor alleles present. Further investigation with a larger sample size may delineate more clearly whether a statistically significant relationship between this functional SNP and pain exists in this population.- Linnstaedt S.D.
- Riker K.D.
- Rueckeis C.A.
- Kutchko K.M.
- Lackey L.
- McCarthy K.R.
- Tsai Y.H.
- Parker J.S.
- Kurz M.C.
- Hendry P.L.
- Lewandowski C.
- Datner E.
- Pearson C.
- O'Neil B.
- Domeier R.
- Kaushik S.
- Laederach A.
- McLean S.A.
A functional riboSNitch in the 3’ untranslated region of FKBP5 alters microRNA-320a binding efficiency and mediates vulnerability to chronic post-traumatic pain.
Journal of Neuroscience. 2018; 38: 8407-8420
Limitations
These findings should be interpreted with attention to the limitations of this study. This study consisted of a small sample, leading to some small groups with the presence of minor alleles; findings for these groups were, however, consistent with published estimates of minor allele frequencies (reported in Table 1). Additionally, we assessed associations in only a small number of SNPs in pain-related candidate genes which were supported by the literature. Future studies should consider a broader selection of SNPs and genes, as well as other potential mechanisms (e.g., gene expression) of pain in this population. In alignment with the exploratory nature of this study, we did not correct for multiple testing. We also assessed associations with only one dimension of pain (i.e., average pain intensity), and did not distinguish between acute and chronic pain in our assessments, as there are currently no validated diagnostic criteria to distinguish between acute and chronic pain in the SCD population. Despite these limitations, our findings provide important preliminary evidence of associations between average pain rating and functional polymorphisms in pain-related candidate genes. Future studies in larger and more geographically diverse samples are needed to replicate these findings and extend our understanding of genetic variations and other biopsychosocial mechanisms that contribute to the complexity of pain in this population.
Conclusions
This exploratory study is among the first to provide preliminary evidence linking genetic variation in the ICAM-1 gene to reports of severe pain in people with SCD. These results underscore the potential role played by endothelial function and inflammation in contributing to the variability in pain in this population. Further research with a larger, more geographically diverse sample is needed to extend and validate these findings. It is possible that further investigation will find functional genetic polymorphisms that can serve as biomarkers to assist the identification of individuals who are at risk for more severe pain and the development of strategies for personalized interventions.
Clinical Implications
Nurses are well positioned to lead the translation of genetic knowledge to pain management practice. Although further validation of our findings is needed, this study is an initial step in understanding how genetic variation contributes to experiences of pain, and it extends our knowledge of potential mechanisms of pain that can guide treatment approaches. For example, given that pain experiences are modifiable, it is plausible that, with further investigation, the ICAM-1 rs1799969 polymorphism could serve as a biomarker for risk stratifying patients who are less likely to experience severe pain. Additionally, this marker could serve as a potential target for pharmacologic and non-pharmacologic interventions.
Declaration of Competing Interest
Dr. Shah reports receiving fees from Novartis, Global Blood Therapeutics, Forma, and Alexion. Dr. Kenney has received research funds from Global Blood Therapeutics. No other authors report any potential conflicts of interest.
Acknowledgments
Research reported in this publication was supported by the Rockefeller University Heilbrunn Center for Research Nursing and the National Heart, Lung, and Blood Institute (U01HL133964). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors would like to thank Donnalee Frega, PhD for her editorial assistance; Cyrus Lacuesta and Akhil Hegde, PhD of the Duke School of Nursing Biomarker Lab; and the staff in the Molecular Genetics Core of the Duke Molecular Physiology Institute for their contributions to this research. We are most grateful to all the people with SCD who provided data for this study.
References
- Candidate genetic variants in the fibrinogen, methylenetetrahydrofolate reductase, and intercellular adhesion molecule-1 genes and plasma levels of fibrinogen, homocysteine, and intercellular adhesion molecule-1 among various race/ethnic groups: data from the Women's Genome Health Study.American Heart Journal. 2009; 157 (.e771): 777-783
- What is a functional genetic polymorphism? Defining classes of functionality.Journal of Psychiatry & Neuroscience. 2011; 36: 363-365
- Role of ICAM-1 polymorphisms (G241R, K469E) in mediating its single-molecule binding ability: Atomic force microscopy measurements on living cells.Biochemical and Biophysical Research Communications. 2014; 448: 372-378
- Influence of catechol-O-methyltransferase (COMT) gene polymorphisms in pain sensibility of Brazilian fibromialgia patients.Rheumatology International. 2012; 32: 427-430
- Polymorphisms in the ICAM1 gene predict circulating soluble intercellular adhesion molecule-1(sICAM-1).Atherosclerosis. 2011; 216: 390-394
- Complex multilocus effects of catechol-O-methyltransferase haplotypes predict pain and pain interference 6 weeks after motor vehicle collision.Neuromolecular Medicine. 2014; 16: 83-93
- Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment.Molecular Psychiatry. 2009; 14: 1095-1104
- Quantitative sensory testing and pain-evoked cytokine reactivity: Comparison of patients with sickle cell disease to healthy matched controls.Pain. 2016; 157: 949-956
- Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons.Journal of Neuroscience. 2004; 24: 4401-4411
- The relationship between a common catechol-O-methyltransferase (COMT) polymorphism val(158) met and fibromyalgia.Clinical & Experimental Rheumatology. 2009; 27: S51-S56
- Inflammation in sickle cell disease.Clinical Hemorheology & Microcirculation. 2018; 68: 263-299
- Thromboinflammatory mechanisms in sickle cell disease - challenging the hemostatic balance.Haematologica. 2020; 105: 2380-2390
- Pain assessment using the NIH Toolbox.Neurology. 2013; 80: S49-S53
- The sickle cell disease implementation consortium: Translating evidence-based guidelines into practice for sickle cell disease.American Journal of Hematology. 2018; 93: E391-E395
- The role of the blood-brain barrier in the development and treatment of migraine and other pain disorders.Frontiers in Cellular Neuroscience. 2014; 8: 302
- The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.Cell. 2003; 112: 257-269
- Elevated immunoreactive tumor necrosis factor and interleukin-1 in sickle cell disease.Journal of the National Medical Association. 1992; 84: 611-615
- Association between FKBP5 functional polymorphisms and completed suicide.Neuropsychobiology. 2015; 72: 126-131
- Publication of data collection forms from NHLBI funded sickle cell disease implementation consortium (SCDIC) registry.Orphanet Journal of Rare Diseases. 2020; 15: 178
- Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis.Blood. 1998; 92: 2551-2555
- Targeting pain at its source in sickle cell disease.American Journal of Physiology, Regulatory, Integrative, & Comparative Physiology. 2018; 315: R104-R112
- Cell adhesion molecules and their roles and regulation in the immune and tumor microenvironment.Frontiers in Immunology. 2019; 10: 1078
- Proinflammatory cytokines and the hypermetabolism of children with sickle cell disease.Experimental Biology & Medicine (Maywood). 2005; 230: 68-74
- Expression of endothelial intercellular adhesion molecule-1 is determined by genotype: Effects on efficiency of leukocyte adhesion to human endothelial cells.Human Immunology. 2008; 69: 71-78
- Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial.British Journal of Haematology. 2017; 177: 620-629
- Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families.Thorax. 2000; 55: 1023-1027
- Neuroinflammation and central sensitization in chronic and widespread pain.Anesthesiology. 2018; 129: 343-366
- Symptom science: advocating for inclusion of functional genetic polymorphisms.Biological Research for Nursing. 2019; 21: 349-354
- Severe persistent pain and inflammatory biomarkers in sickle cell disease: an exploratory study.Biological Research for Nursing. 2022; 24: 24-30
- Proinflammatory cytokines in patients with neuropathic pain treated with Tramadol.Revista Brasileira de Anestesiologia. 2009; 59: 297-303
- The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription.Molecular Immunology. 1997; 34: 391-399
- Intercellular adhesion molecule-1 polymorphisms, K469E and G261R and susceptibility to vasculitis and rheumatoid arthritis: A meta-analysis.Cellular & Molecular Biology (Noisy-le-Grand, France). 2016; 62: 84-90
- A functional riboSNitch in the 3’ untranslated region of FKBP5 alters microRNA-320a binding efficiency and mediates vulnerability to chronic post-traumatic pain.Journal of Neuroscience. 2018; 38: 8407-8420
- Prevalence and predictors of chronic pain intensity and disability among adults with sickle cell disease.Health Psychology Open. 2020; 72055102920917250
- E-Selectin and restenosis after femoropopliteal angioplasty: prognostic impact of the Ser128Arg genotype and plasma levels.Thrombosis & Haemostasis. 2004; 91: 171-179
- The role of intercellular adhesion molecule-1 in the pathogenesis of psychiatric disorders.Frontiers in Pharmacology. 2019; 10: 1251
- Evaluation of tumor necrosis factor (TNF)-alpha mRNA expression level and the rs1799964 polymorphism of the TNF-alpha gene in peripheral mononuclear cells of patients with inflammatory bowel diseases.Biomedical Reports. 2017; 6: 698-702
- Pathophysiological insights in sickle cell disease.Indian Journal of Medical Research. 2011; 134: 532-537
- Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci.PLoS Genetics. 2011; 7e1001374
- Cytokine profile of sickle cell disease in Oman.American Journal of Hematology. 2004; 77: 323-328
- Functional polymorphism in the interleukin-6 and interleukin-10 genes in patients with paranoid schizophrenia–a case-control study.Journal of Molecular Neuroscience. 2010; 42: 112-119
- A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro.European Journal of Clinical Investigation. 1992; 22: 396-402
- Association between Gly241Arg ICAM-1 gene polymorphism and serum sICAM-1 concentration in the Stanislas cohort.European Journal of Human Genetics. 2003; 11: 679-686
- Biomarkers of inflammation, growth factor, and coagulation activation in patients with sickle cell disease.Clinical & Applied Thrombosis/Hemostasis. 2012; 18: 195-200
- Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain.Mediators of Inflammation. 2013; 2013480739
- ICAM-1: isoforms and phenotypes.Journal of Immunology. 2014; 192: 4469-4474
- Association of the -1031T>C polymorphism and soluble TNF-alpha levels with Acute Coronary Syndrome.Cytokine. 2016; 78: 37-43
- The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations.Circulation. Cardiovascular Genetics. 2009; 2: 229-237
- Brain-derived neurotrophic factor derived from sensory neurons plays a critical role in chronic pain.Brain. 2018; 141: 1028-1039
- COMT diplotype amplifies effect of stress on risk of temporomandibular pain.Journal of Dental Research. 2015; 94: 1187-1195
- Daily assessment of pain in adults with sickle cell disease.Annals of Internal Medicine. 2008; 148: 94-101
- Warriors versus worriers: the role of COMT gene variants.CNS Spectrums. 2006; 11: 745-748
- Unique cytokine signature in the plasma of patients with fibromyalgia.Journal of Immunology Research. 2014; 2014938576
- Interleukin-8 promoter polymorphism increases the risk of atrophic gastritis and gastric cancer in Japan.Cancer Epidemiology Biomarkers & Prevention. 2005; 14: 2487-2493
- Differential expression of immunophilins FKBP51 and FKBP52 in the frontal cortex of HIV-infected patients with major depressive disorder.Journal of Neuroimmune Pharmacology. 2009; 4: 218-226
- Targeting novel mechanisms of pain in sickle cell disease.Blood. 2017; 130: 2377-2385
- Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation.Proceedings of the National Acadamies of Sciences of the USA. 1997; 94: 3195-3199
- Gene–stress–epigenetic regulation of FKBP5: Clinical and translational implications.Neuropsychopharmacology. 2016; 41: 261-274
- Intercellular adhesion molecule 1 (ICAM1) Lys56Met and Gly241Arg gene variants, plasma-soluble ICAM1 concentrations, and risk of incident cardiovascular events in 23,014 initially healthy white women.Stroke. 2007; 38: 3152-3157
- Association of genetic variation in COMT gene with pain related to sickle cell disease in patients from the walk-PHaSST study.Journal of Pain Research. 2018; 11: 537-543
Article info
Publication history
Published online: September 09, 2022
Accepted:
August 8,
2022
Received in revised form:
July 18,
2022
Received:
April 28,
2022
Identification
Copyright
© 2022 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.
