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Galatà, G.* ; García-Montero, A.C.* ; Kristensen, T.* ; Dawoud, A.A.Z.* ; Muñoz-González, J.I.* ; Meggendorfer, M.* ; Guglielmelli, P.* ; Hoade, Y.* ; Alvarez-Twose, I.* ; Gieger, C. ; Strauch, K. ; Ferrucci, L.* ; Tanaka, T.* ; Bandinelli, S.* ; Schnurr, T.M.* ; Haferlach, T.* ; Broesby-Olsen, S.* ; Vestergaard, H.* ; Møller, M.B.* ; Bindslev-Jensen, C.* ; Vannucchi, A.M.* ; Orfao, A.* ; Radia, D.* ; Reiter, A.* ; Chase, A.J.* ; Cross, N.C.P.* ; Tapper, W.J.*

Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis.

Am. J. Hum. Genet. 108, 284-294 (2021)
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Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10−15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10−12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10−9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10−14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10−11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (β)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10−8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cebpa ; D816v ; Kit ; Mastocytosis ; Myeloid Cancer ; Tbl1xr1 ; Tert; Acute Myeloid-leukemia; C/ebp-alpha; Allele Burden; Disease; Expression; Variants; Annotation; Mutation; Classification; Polymorphisms
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Quellenangaben Volume: 108, Issue: 2, Pages: 284-294 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed
Grants Helmholtz Zentrum Munchen-German Research Center for Environmental Health
German Federal Ministry of Education and Research (BMBF)
State of Bavaria
Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ
Italian Ministry of Health
U.S. National Institute on Aging
Instituto de Salud Carlos III
Associazione Italiana per la Ricerca sul cancro, Mynerva project
Novo Nordisk Foundation
Lady Tata International Award
Blood Cancer UK
Wellcome Trust