title: Common germline variation at the TERT locus contributes to familial clustering of myeloproliferative neoplasms.
abstract: The C allele of the rs2736100 single nucleotide polymorphism located in the second intron of the TERT gene has recently been identified as a susceptibility factor for myeloproliferative neoplasms (MPN) in the Icelandic population. Here, we evaluate the role of TERT rs2736100_C in sporadic and familial MPN in the context of the previously identified JAK2 GGCC predisposition haplotype. We have confirmed the TERT rs2736100_C association in a large cohort of Italian sporadic MPN patients. The risk conferred by TERT rs2736100_C is present in all molecular and diagnostic MPN subtypes. TERT rs2736100_C and JAK2 GGCC are independently predisposing to MPN and have an additive effect on disease risk, together explaining a large fraction of the population attributable fraction (PAF = 73.06%). We found TERT rs2736100_C significantly enriched (P = 0.0090) in familial MPN compared to sporadic MPN, suggesting that low-penetrance variants may be responsible for a substantial part of familial clustering in MPN.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Roland
authors.initials: R
authors.lastname: Jäger
authors.forename: Ashot S
authors.initials: AS
authors.lastname: Harutyunyan
authors.forename: Elisa
authors.initials: E
authors.lastname: Rumi
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.forename: Tiina
authors.initials: T
authors.lastname: Berg
authors.forename: Damla
authors.initials: D
authors.lastname: Olcaydu
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
mesh_terms: D000328:Adult; D015331:Cohort Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006239:Haplotypes; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007558:Italy; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D009196:Myeloproliferative Disorders / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D019683:Penetrance; D012306:Risk; D019098:Telomerase / Q000235:genetics*
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2; C509186:TERT protein, human; D019098:Telomerase