title: Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders.
abstract: JAK2V617F 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), thrombopoietin (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 phenotypic diversity among myeloproliferative disorders, including in the presence of a shared disease allele.
authors.affiliation: Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. pardanani.animesh@mayo.edu
authors.forename: Animesh
authors.initials: A
authors.lastname: Pardanani
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: Terra L
authors.initials: TL
authors.lastname: Lasho
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003710:Demography; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype; D011087:Polycythemia Vera / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012044:Regression Analysis; D013920:Thrombocythemia, Essential / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics
chemical_list: D053614:Janus Kinase 2