title: A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation.
abstract: The frequency of A3669G single nucleotide polymorphism (SNP) of human glucocorticoid receptor has been reported increased in polycythemia vera. We investigated the frequency of A3669G SNP and its impact on disease phenotype and progression in 499 patients with primary myelofibrosis (PMF). The distribution of the A3669G allele differed between PMF patients and 2 healthy control populations (odds ratio, 1.6 and 1.8). The variant allele at the homozygous state (G/G) was associated with higher white blood cell count, larger spleen index, and higher frequency of circulating CD34(+) cells at diagnosis. The latter association remained significant after correction for the JAK2V617F genotype. In patients JAK2V617F mutated, the G/G genotype was associated with shorter overall survival (77.6 months vs 298 months, P = .049) and blast transformation (BT)-free survival (76.7 months vs 261 months; P = .018). The latter association remained significant after correction for the known BT risk factors, such as age, sex, white blood cell count, percentage of blasts, IPSS prognostic score, and homozygosity for JAK2V617F (hazard ratio = 3.3; P = .006). In conclusion, the glucocorticoid receptor A3669G is a susceptibility allele for PMF: it contributes to confer the phenotype of excess myeloproliferation, and it cooperates with the JAK2V617F mutation in determining BT.
authors.affiliation: Unit of Clinical Epidemiology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico S. Matteo Foundation, Pavia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Poletto
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rosti
authors.forename: Laura
authors.initials: L
authors.lastname: Villani
authors.forename: Paolo
authors.initials: P
authors.lastname: Catarsi
authors.forename: Adriana
authors.initials: A
authors.lastname: Carolei
authors.forename: Rita
authors.initials: R
authors.lastname: Campanelli
authors.forename: Margherita
authors.initials: M
authors.lastname: Massa
authors.forename: Myriam
authors.initials: M
authors.lastname: Martinetti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Viarengo
authors.forename: Alberto
authors.initials: A
authors.lastname: Malovini
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Migliaccio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barosi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D015996:Survival Rate; D055815:Young Adult
chemical_list: D011965:Receptors, Glucocorticoid; C507924:JAK2 protein, human; D053614:Janus Kinase 2