TY - JOUR
T1 - Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders
AU - Pardanani, Animesh
AU - Fridley, Brooke L.
AU - Lasho, Terra L.
AU - Gilliland, D. Gary
AU - Tefferi, Ayalew
PY - 2008/3/1
Y1 - 2008/3/1
N2 - J4K2V617F is an acquired mutation associated with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We tested the hypothesis that the paradox of a single disease allele associated with 3 distinctive clinical phenotypes could be explained in part by host-modifying influences. We screened for genetic variation within 4 candidate genes involved in JAK-STAT signaling, including receptors for erythropoietin (EPOR), thrombopoi-etin (MPL), and granulocyte colony-stimulating factor (GCSFR), and JAK2. We genotyped 32 linkage disequilibrium tag single nucleotide polymorphism (SNP) loci in 179 white patients: 84 had PV, 58 had PMF, and 37 had ET. Genotype-phenotype analysis showed 3 JAK2 SNPs (rs7046736, rs10815148, and rs12342421) to be significantly but reciprocally associated with PV (P < .001 for all; odds ratio = 0.16, 2.72, and 2.46, respectively) and ET (P < .001 for all; odds ratio = 3.05, 0.29, and 0.30, respectively) but not with PMF. Three additional JAK2 SNPs (rs10758669, rs3808850, and rs10974947) and a single EPOR SNP (rs318699) were also significantly associated with PV but not with ET or PMF. Finally, intragene haplotypes in JAK2 were significantly associated with PV only. Thus, host genetic variation may contribute to pheno-typic diversity among myeloproliferative disorders, including in the presence of a shared disease allele.
AB - J4K2V617F is an acquired mutation associated with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We tested the hypothesis that the paradox of a single disease allele associated with 3 distinctive clinical phenotypes could be explained in part by host-modifying influences. We screened for genetic variation within 4 candidate genes involved in JAK-STAT signaling, including receptors for erythropoietin (EPOR), thrombopoi-etin (MPL), and granulocyte colony-stimulating factor (GCSFR), and JAK2. We genotyped 32 linkage disequilibrium tag single nucleotide polymorphism (SNP) loci in 179 white patients: 84 had PV, 58 had PMF, and 37 had ET. Genotype-phenotype analysis showed 3 JAK2 SNPs (rs7046736, rs10815148, and rs12342421) to be significantly but reciprocally associated with PV (P < .001 for all; odds ratio = 0.16, 2.72, and 2.46, respectively) and ET (P < .001 for all; odds ratio = 3.05, 0.29, and 0.30, respectively) but not with PMF. Three additional JAK2 SNPs (rs10758669, rs3808850, and rs10974947) and a single EPOR SNP (rs318699) were also significantly associated with PV but not with ET or PMF. Finally, intragene haplotypes in JAK2 were significantly associated with PV only. Thus, host genetic variation may contribute to pheno-typic diversity among myeloproliferative disorders, including in the presence of a shared disease allele.
UR - http://www.scopus.com/inward/record.url?scp=41949128334&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41949128334&partnerID=8YFLogxK
U2 - 10.1182/blood-2007-06-095703
DO - 10.1182/blood-2007-06-095703
M3 - Article
C2 - 18006699
AN - SCOPUS:41949128334
SN - 0006-4971
VL - 111
SP - 2785
EP - 2789
JO - Blood
JF - Blood
IS - 5
ER -