Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster.
In a genome-wide association study of 848 blacks with sickle cell anemia, we identified single nucleotide polymorphisms (SNPs) associated with fetal hemoglobin concentration. The most significant SNPs in a discovery sample were tested in a replication set of 305 blacks with sickle cell anemia and in subjects with hemoglobin E or beta thalassemia trait from Thailand and Hong Kong. A novel region on chromosome 11 containing olfactory receptor genes OR51B5 and OR51B6 was identified by 6 SNPs (lowest P = 4.7E-08) and validated in the replication set. An additional olfactory receptor gene, OR51B2, was identified by a novel SNP set enrichment analysis. Genome-wide association studies also validated a previously identified SNP (rs766432) in BCL11A, a gene known to affect fetal hemoglobin levels (P = 2.6E-21) and in Thailand and Hong Kong subjects. Elements within the olfactory receptor gene cluster might play a regulatory role in gamma-globin gene expression.
Solovieff
Nadia
N
Department of Biostatistics, Boston University School of Public Health, MA, USA.
Milton
Jacqueline N
JN
Hartley
Stephen W
SW
Sherva
Richard
R
Sebastiani
Paola
P
Dworkis
Daniel A
DA
Klings
Elizabeth S
ES
Farrer
Lindsay A
LA
Garrett
Melanie E
ME
Ashley-Koch
Allison
A
Telen
Marilyn J
MJ
Fucharoen
Supan
S
Ha
Shau Yin
SY
Li
Chi-Kong
CK
Chui
David H K
DH
Baldwin
Clinton T
CT
Steinberg
Martin H
MH
D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism*; D055106:Genome-Wide Association Study; D006446:Hemoglobin E / Q000235:genetics; D006723:Hong Kong; D006801:Humans; D008297:Male; D005810:Multigene Family; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018035:Receptors, Odorant / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins; D013785:Thailand; D055815:Young Adult; D017086:beta-Thalassemia / Q000235:genetics
C486563:BCL11A protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D018035:Receptors, Odorant; D012097:Repressor Proteins; D006446:Hemoglobin E; D005319:Fetal Hemoglobin