A GCH1 haplotype confers sex‐specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia. Issue 2 (February 2014)

• Record Type: Journal Article
• Authors: Belfer, Inna; Youngblood, Victoria; Darbari, Deepika S.; Wang, Zhengyuan; Diaw, Lena; Freeman, Lita; Desai, Krupa; Dizon, Michael; Allen, Darlene; Cunnington, Colin; Channon, Keith M.; Milton, Jacqueline; Hartley, Stephen W.; Nolan, Vikki; Kato, Gregory J.; Steinberg, Martin H.; Goldman, David; Taylor, James G.
• Is Part Of: American journal of hematology. Volume 89:Issue 2(2014:Feb.)
• Page Start: 187
• Page End: 193
• Publication Date: 2014-02
• Subjects: Hematology -- Periodicals; 616.15
• DOI: 10.1002/ajh.23613
• Languages: English
• ISSNs: 0361-8609

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. <italic>GCH1</italic> polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined <italic>GCH1</italic> and pain in sickle cell anemia where <italic>GCH1</italic> rs8007267 was a risk factor for pain crises in discovery (<italic>n</italic> = 228; odds ratio [OR] 2.26; <italic>P</italic> = 0.009) and replication (<italic>n</italic> = 513; OR 2.23; <italic>P</italic> = 0.004) cohorts. <italic>In vitro</italic>, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. <italic>In vivo</italic> physiological studies of traits likely to be modulated by <italic>GCH1</italic> showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; <italic>P</italic> = 0.002). The <italic>GCH1</italic> 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; <italic>P</italic> = 0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a <italic>GCH1</italic> 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 <italic>GCH1</italic> and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry. Am. J. Hematol. 89:187–193, 2014. © 2013 Wiley Periodicals, Inc.</p> </abstract>