A GCH1 haplotype confers sex‐specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia

Abstract

GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8007267 was a risk factor for pain crises in discovery (n = 228; odds ratio [OR] 2.26; P = 0.009) and replication (n = 513; OR 2.23; P = 0.004) cohorts. In vitro, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. In vivo physiological studies of traits likely to be modulated by GCH1 showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; P = 0.002). The GCH1 pain association is attributable to an African haplotype with where its sickle cell anemia pain association is limited to females (OR 2.69; 95% CI 1.21–5.94; P = 0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a GCH1 haplotype with high BH4 in populations of African ancestry could explain the association of rs8007267 with sickle cell anemia pain crises. The vascular effects of GCH1 and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry.

Research design considerations for chronic pain prevention clinical trials

“…Similarly, the A118G polymorphism of OPRM1 has been associated with experimental pain sensitivity and with clinical pain [53,71,123], including long-term outcomes of acute back pain [124]. Finally, GCH1 genotypes have been associated with experimental and clinical pain responses across several cohorts [15,28,159,160], and GCH1 genotypes have predicted outcomes from lumbar spine surgery [96,160]. Genetic factors can also impact postoperative analgesic responses, which may impact CPSP since acute pain severity is among the strongest predictors of CPSP.…”

“…For example, previous studies have reported that COMT, OPRM1 , and GCH1 show sex-specific associations with pain responses [14,15,124]. In addition, COMT haplotypes have been shown to interact with psychological functioning (i.e., pain catastrophizing) to predict both experimental and clinical shoulder pain outcomes [58,60].…”

Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway

“…SNP association studies carried out in 12 independent cohorts of patients have associated several polymorphisms within or close to the gene for GTP cyclohydroxylase 1 enzyme (GTPCH1; hereafter named GCH1) with reduced clinical and experimental pain sensitivity (Belfer et al, 2014; Kim et al, 2013; Latremoliere and Costigan, 2011). GCH1 catalyzes the initial and rate-limiting step in the synthetic pathway of the pteridin (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4).…”

An Expert Review of Pharmacogenomics of Sickle Cell Disease Therapeutics: Not Yet Ready for Global Precision Medicine

“…It exhibits a GT dinucleotide repeat in the promoter region, and long repeat lengths (>25 repeats) are associated with decreased activity and inducibility, and therefore higher rates of SCD patient hospitalization, but not directly associated with pain (Bean et al, 2013). It is reported that among African-Americans, a polymorphism in the GTP cyclohydrolase (GCH1) on chromosome 14 (rs8007267) is significantly associated with pain crises (Belfer et al, 2014). GCH1 catalyzes the rate-limiting step for tetrahydrobiopterin synthesis, thus variation in its gene is likely to have pathophysiological roles in pain.…”