Association of Genetic Variation in the Catechol-O-Methyl Transferase Gene with Pain and Six Minute Walk Distance in Sickle Cell Anemia Patients From the Walk-PHaSST Study

Pain crisis is the hallmark of sickle cell disease (SCD) but varies in frequency and severity. Variation in pain sensitivity and perception among individuals is partially attributed to genetic factors. Catechol-O-methyltransferase (COMT) regulates neurotransmission and plays an important role in the perception of pain sensation. Three major COMT haplotypes are associated with COMT activity and correlate with high, average and low pain sensitivity (HPS, APS, and LPS) in Caucasians. However, the role of COMT genetic variants in SCD pain has not been explored.

This study utilizes a cohort of African American patients with hemoglobin SS from the walk-PHaSST study (n=438). Pain phenotypes were obtained at the screening visit including description of pain, presence of chronic and acute pain, and associated treatments. Acute pain crises were classified as a) mild (may or may not require pain medicine and did not prevent normal daily activity), b) moderate (required medications and caused significant changes in daily activities, c) severe (patient went to the ER but was not admitted and d) extremely severe (required hospital admission). Patients also reported the number of each type of pain in the week, month and year prior to screening.

Five single nucleotide polymorphisms (SNPs), rs6269, rs4633, rs4818, rs4680, and rs165599, of the COMT gene were genotyped. Haplotypes were constructed based on the SNP genotypes. Single SNP and haplotype associations with pain phenotypes and 6-minute walk distances (6MWD) were analyzed. Chi-square test and ANOVA or multinomial logistic regression analysis were used for categorical and continuous variables, respectively.

Of the 438 patients, the median age was 35 years (12 to 69 years) and 52% were females. Acute pain crisis was reported for 50%, 72%, and 91% of the subjects in the week, month, and year prior to screening. Over 36% of the patients reported chronic pain. The median intensity of acute and chronic pain on a scale of 1–10 was 8 and 6, respectively. Severe and extremely severe pain in the year prior to screening was not affected by age and gender. However, the self-reported use of hydroxyurea (HU) treatment was associated with pain episodes in the year prior to screening (p=0.0001). The least number of episodes was reported by patients who were never received HU, while the most number of episodes was reported by patients who were previously on HU. Subjects who reported current HU use had intermediate pain frequencies compared to the other two groups.

The genotype frequencies of rs6269, rs4633, rs4818, rs4680 and rs165599 were in Hardy–Weinberg equilibrium (p<0.1) with minor allele frequency of 37.4%, 30.5%, 19.4%, 28.6% and 28.1%, respectively. Associations were identified for rs6269 and rs4633 with moderate pain in the week (p=0.0261) and month (p=0.0290) prior to screening, respectively. Chronic pain was associated with rs165599, and less patients experienced chronic pain for the GG genotype compared to AA or AG genotype carriers (34% vs 40%, p=0.0152). Differences were detected in chronic pain rate for the genotypes of rs6269 (p=0.0097) and rs4680 (p= 0.0719).

Nine haplotypes with frequencies of >3% accounted for 97.6% of all haplotypes in this cohort, six of which corresponded to HPS, LPS and APS haplotypes described in Caucasians. The GCCGG haplotype that was not common in Caucasians had an 18.8% frequency in this African American SCD cohort. Haplotype ACCGA (HPS) was associated with severe pain in the month prior to screening (p=0.0330) and haplotype GCGGA (LPS) was associated with mild pain in the year prior to screening (p=0.0302). The degree of acute pain rate was associated with haplotype GCGGG (LPS) (p=0.0251).

Although association between SNPs and 6MWD was not detected, haplotype ATCGG was significantly associated with the 6MWD. Twenty-nine percent of the patients with zero copies of this haplotype (114/399) walked >=500 meters while only 9% (3/33) of the subjects with this haplotypes were able to walk >=500 meters (p=0.0267).

These data demonstrate that COMT variants are associated with pain phenotypes in SCD. Unique haplotypes and haplotype distributions were observed for the African American population. Further study of COMT and other genetic factors associated with pain in SCD may provide insights into the molecular pathobiology associated with SCD pain and ultimately lead to better SCD management.

Barst:Actelion and Pfizer.: Consultancy. Hassell:NIH: Research Funding.