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  • br PREDICTOR ODDS RATIO STANDARD ERROR CI

    2020-08-18


    PREDICTOR ODDS RATIO STANDARD ERROR 95% CI Z P VALUE
    Surgical drain placement
    Surgical drain placement
    Surgical drain placement
    Abbreviations: COMT, catechol-O-methyltransferase; HTR2A, 5-hydroxytryptamine receptor 2A, G protein coupled; HTR3A, 5-hydroxytryptamine receptor 3A, iono-tropic; CI, confidence interval; KPS, Karnofsky Performance Status.
    NOTE. Multiple logistic regression analyses of candidate gene associations with no arm pain versus moderate arm pain classes. For each model, the first 3 principal components identified from the analysis of ancestry informative markers, as well as self-reported race/ethnicity, were retained in all models to adjust for potential confounding owing to race/ethnicity (data not shown). Predictors evaluated in each model included Cisplatin (COMT rs165656: CC+CG vs GG; HTR2A rs2770298: CC+CG vs GG; HTR2A rs9534511: CC vs CT+TT; HTR3A rs1985242: TT+TA vs AA), functional status (KPS score in 10-unit increments), number of breast biopsies in the past year, placement of a surgical drain (no drain placed compared with drain placement only in the breast, drain placement only in the axilla, or drain placement in both in the breast and axilla), and receipt of physical therapy in the 6 months after surgery.
    our understanding of the role of this gene in persistent arm pain after breast cancer surgery.
    One haplotype and 2 SNPs in HTR2A were associated with membership in the mild or moderate arm pain clas-ses. HTR2A encodes for the G protein-coupled serotonin receptor 2A. Normal neurotransmission can be dis-rupted by variations in the density of this receptor, which alters the activity of serotonergic neurons.8 Poly-morphisms in this gene were associated with persistent breast pain in our previous report28 and chronic wide-spread pain,48 as well as with the regulation of mood,8 responses to antidepressant treatments,34,52 and altera-tions in cognitive function.41 In the current study, each additional dose of HTR2A Haplotype B02, which is com-posed of 2 SNPs (ie, rs1923886 [T common allele], rs7330636 [T rare allele]), was protective of belonging to the mild arm pain class. In contrast, carrying 2 doses of the rare G allele at rs2770298 and carrying 1 or 2 doses of the rare T allele at rs9534511 was associated with an increased odds of belonging to the moderate 
    arm pain class. All these SNPs on HTR2A are intron var-iants that have not been associated with other pain phe-notypes.
    One SNP in the HTR3A gene was associated with mem-bership in both the mild and moderate arm pain classes. HTR3A encodes for the subunit A of the type 3 receptor for 5-hydroxytryptamine (serotonin), a receptor that is involved in pain, anxiety, and immunomodulatory pro-cesses.36 These receptors mediate pain transmission in both the peripheral and central nervous systems. After
    activation, these receptors are responsible for fast and depolarizing responses in neurons.16,36,46 Our findings
    suggest that carrying 2 doses of the rare A allele at HTR3A rs1985242 is associated with a decrease in the odds of belonging to the mild and moderate arm pain classes. However, this intronic SNP has not been associ-ated with other pain conditions.
    A SNP in the gene that encodes for TH was associated with membership in only the mild arm pain class. TH is the enzyme that converts tyrosine to dopamine.
    ARTICLE IN PRESS
    Knisely et al The Journal of Pain 9
    Figure 2. (A−D) Differences between no arm pain and moderate arm pain classes in the percentage of patients who were homozy-gous for the common allele or heterozygous or homozygous for the rare allele for each significant polymorphism or number of doses of haplotypes identified. Values are plotted as unadjusted proportions with corresponding P values.
    Although the enzyme itself is not involved in pain, its effects on dopamine could influence pain mechanisms. For example, endogenous opioids are released in response to a noxious stimulus, which stimulates the release of dopamine.24 Stimulation of dopamine recep-tors results in the inhibition of nociception.24 Our find-ings suggest that carrying 1 or 2 doses of the rare C allele at TH rs2070762 is associated with an increased odds of belonging to the mild arm pain class. The C allele of this functional intronic polymorphism likely serves as a functional enhancer element that regulates gene expression.67 Although initial work suggested that this SNP was associated with migraine, this finding was not confirmed in a validation cohort.12 In another study, this SNP was associated with an increased risk of opioid addiction.53 As noted, our previous work suggests that persistent
    breast and arm pain after breast cancer surgery represent distinct pain phenotypes.30,42,43 As summarized in Table 5,