RGD Reference Report - A GCH1 haplotype confers sex-specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia. - Rat Genome Database

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

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 
Citation: Belfer I, etal., Am J Hematol. 2014 Feb;89(2):187-93. doi: 10.1002/ajh.23613.
RGD ID: 329961567
Pubmed: PMID:24136375   (View Abstract at PubMed)
PMCID: PMC4281092   (View Article at PubMed Central)
DOI: DOI:10.1002/ajh.23613   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GCH1Humansickle cell anemia sexual_dimorphismIAGP DNA:SNP and haplotype:rs8007267 (human)RGD 
Gch1Ratsickle cell anemia sexual_dimorphismISOGCH1 (Homo sapiens)DNA:SNP and haplotype:rs8007267 (human)RGD 
Gch1Mousesickle cell anemia sexual_dimorphismISOGCH1 (Homo sapiens)DNA:SNP and haplotype:rs8007267 (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gch1  (GTP cyclohydrolase 1)

Genes (Mus musculus)
Gch1  (GTP cyclohydrolase 1)

Genes (Homo sapiens)
GCH1  (GTP cyclohydrolase 1)


Additional Information