br Four SNPs in different genes remained significant in the
Four SNPs in 3 different genes remained significant in the multivariate logistic regression analyses: COMT rs165656, HTR2A rs2770298 and rs9534511, and HTR3A rs1985242 (Table 4). Figures 2A through 2D show the differences between the no arm pain and moderate arm pain Cisplatin in the percentage of patients who were homozygous for the common allele or heterozygous or homozygous for the rare allele for each of the signifi-cant polymorphisms. For COMT rs165656, carrying 2 doses of the rare G allele (ie, CC+CG vs GG) was associ-ated with a 63% decrease in the odds of belonging in the moderate arm pain class. Two SNPs in HTR2A were associated with membership in the moderate arm pain class. For HTR2A rs2770298, carrying 2 doses of the rare G allele (ie, CC+CG vs GG) was associated with a 5.08-fold increase in the odds of belonging to the moderate arm pain class. In the same regression analysis, for HTR2A rs9534511, carrying 1 or 2 doses of the rare T allele (CC vs CT+TT) was associated with a 1.89-fold increase in the odds of belonging to the moderate arm pain class. For HTR3A rs1985242, carrying 2 doses of the rare A allele (ie, TT+TA vs AA) was associated with an
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Knisely et al The Journal of Pain 7
Figure 1. (A−D) Differences between no arm pain and mild arm pain classes in the percentage of patients who were homozygous 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.
85% decrease in the odds of belonging to the moderate arm pain class.
This exploratory study evaluated for associations between variations in genes involved in the catachola-minergic and serotonergic pathways and persistent arm pain after breast cancer surgery. Our findings suggest that several genetic variations in these 2 pathways may play a role in the occurrence and severity of persistent arm pain. A discussion of the differences in demo-graphic and clinical characteristics among the arm pain classes was reported in detail elsewhere.43 This discus-sion focuses on the genetic findings.
Variations in 3 genes (ie, COMT, HTR2A, and HTR3A) were associated with membership in both the mild and moderate arm pain classes. COMT is an enzyme that
effects the metabolism of epinephrine, norepineph-rine, and dopamine.3,61 In this study, women who were
homozygous for the rare T allele in COMT rs4633 had a decreased odds of belonging to the mild arm pain class. Located in exon 3 of the COMT gene, rs4633 is a nonsynonymous SNP that is implicated in pediatric postoperative pain,55 pain after a motor vehicle acci-
dent,7 pain associated with lumbar disc disease,13 pain after lumbar spine surgery,54 fibromyalgia,38,65 pain in
women with major depressive disorder,17 and low back pain.49
In many studies,3,7,13,15 rs4633 is evaluated as part of a pain haplotype. In combination with polymorphisms in rs6269, rs4818, and rs4680 (ie Val/Met), rs4633 was associated with low, average, and high pain sensitivity phenotypes. COMT rs4680 is the only SNP in this haplo-type that changes an amino acid sequence and result-ing protein. Although in the bivariate analyses the average pain sensitivity haplotype demonstrated a sig-nificant association with the mild arm pain phenotype and the average pain sensitivity and high pain sensitiv-ity haplotypes demonstrated a significant association with the moderate arm pain phenotype, these associa-tions did not remain significant in the multivariate analyses. Conflicting evidence exists on the associations between various pain conditions and the COMT pain haplotype. For example, in 1 study,47 no differences in the frequencies of the COMT haplotype were found between patients with chronic widespread pain and controls. In addition, the COMT haplotype was not associated with experimental pain thresholds in a sam-ple of Chinese men.68
Women who were homozygous for the rare G allele in COMT rs165656 had a decreased odds of belonging to the moderate arm pain class. Of note, in a small study, COMT rs165656, located in the promoter region of the COMT gene was associated with an 80% decrease in the likelihood of having a temporomandib-ular disorder.44 Additional research on rs165656 and other polymorphisms in the COMT gene may increase
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8 The Journal of Pain Genetic Associations With Persistent Arm Pain
Table 4. Multiple Logistic Regression Analyses for COMT, HTR2A, and HTR3A Candidate Genes and Membership in the No Arm Pain (n = 129) Versus Moderate Arm Pain (n = 102) Classes