Epidemiology of pain in sickle cell anemia and its association with a susceptibility marker in the gch1 gene

  • Darbari D
  • Belfer I
  • Youngblood V
  • et al.
ISSN: 0361-8609
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Abstract

The frequency of severe recurrent painful vaso-occlusive episodes (VOE) varies widely in sickle cell anemia (SCA). The Cooperative Study of Sickle Cell Disease (CSSCD) reported 39% of patients experience no VOEs while 5% experience 3-10 episodes per year (Piatt 1991). Reasons for this variability have not been clearly elucidated. Recently, Tegeder at al. described a haplotype of GTP cyclohydrolase {GCH1}, the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, that is associated with pain sensitivity in non-SCA animal and human models (Tegeder 2006), BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. We have recently reported an association between VOE and a different GCH1 haplotype defined by 3 linked SNPs in SCA (Taylor 2009). Here, we further analyze this association by examining the distribution of annual ED visits among those with SCA to define a severe pain phenotype. The lowest ED visit quartile (zero ED visits, termed the infrequent pain group was compared to all others over the 25th percentile (>1 ED visits, termed the frequent severe pain group) in an NIH cohort and a historical adult population from the CSSCD. The CSSCD analysis was limited to subjects over 25 years of age in order to match the age distribution in the NIH cohort. The infrequent pain group had 104 subjects while 160 were in the frequent severe pain group. Subjects with infrequent pain had lower median hemoglobin (8.4 vs 9.2 g/dl; P=0.0007), HDL (36 vs 39 mg/dl; P=0.02), but higher LDH (378 vs. 346 IU/L; P=0.004). Fetal hemoglobin, bilirubin and reticulocyte counts were not significantly different. Serum ferritin was significantly lower in the infrequent pain group (313 vs. 618 ng/L; P=0.009) which might be an indicator of a higher use of transfusion therapy in the treatment of severe VOE. A higher proportion of subjects with infrequent pain had tricuspid regurgitation jet velocities (TRV) > 2.5 m/s (56.6 % vs 42.4% P= 0.03), suggesting that pulmonary hypertension is more prevalent in those with infrequent pain. Survival analysis from over 6 years of follow-up showed 14.4% died in the frequent severe pain group compared to 6.7% among the infrequent group (P=0.06). The presence of frequent severe pain and a TRV >2.5 m/s showed a cumulative effect on mortality by survival analysis (P= 0,02), however only a high TRV remained a significant risk factor for mortality in a multivariate analysis adjusted for age, ferritin and pain. We then applied this severe pain phenotype to a case control analysis of markers in the GCHf gene. A GCHf haplotype defined by rs8007267 was more prevalent in those with frequent severe pain (odds ratio 2.51, adjusted P=0.008), although there were no associations with either pulmonary hypertension or premature mortality. This association with pain was also significant when hemoglobin SC subjects were included in the analysis. A replication study among SCA adults in the CSSCD also demonstrated a significant association between pain and one of 2 GGH1 pain haplotype markers tested (rs8007267 OR 2,2; P= 0.0088; rs2878172 P=0.14). Finally, we examined in vitro functional consequences in cell lines homozygous for GCHf haplotypes from the Yoruban Hapmap population. Cells with the GCH1 pain associated haplotype have higher GCH1 mRNA (P=0.02) and protein expression after stimulation to high levels of cAMP consistent with the model of Tegeder et. al. where high BH4 levels are associated with pain. Overall, we have defined a SCA pain phenotype which is associated with a GCHfpain susceptibility marker. Together, these data suggest that GCH1, and possibly BH4, may play an important role in the pathogenesis of pain and that BH4 dependent pathways might be exploited for future development of targeted therapies for pain in SCA.

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Darbari, D. S., Belfer, I., Youngblood, V., Desai, K., Diaw, L., Freeman, L., … Taylor, J. G. (2010). Epidemiology of pain in sickle cell anemia and its association with a susceptibility marker in the gch1 gene. American Journal of Hematology, 85(8), E27–E28. Retrieved from http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L70787283

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