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Galata, Gabriella; Garcia-Montero, Andres C.; Kristensen, Thomas; Dawoud, Ahmed A. Z.; Munoz-Gonzalez, Javier I.; Meggendorfer, Manja; Guglielmelli, Paola; Hoade, Yvette; Alvarez-Twose, Ivan; Gieger, Christian; Strauch, Konstantin; Ferrucci, Luigi; Tanaka, Toshiko; Bandinelli, Stefania; Schnurr, Theresia M.; Haferlach, Torsten; Broesby-Olsen, Sigurd; Vestergaard, Hanne; Moller, Michael Boe; Bindslev-Jensen, Carsten; Vannucchi, Alessandro M.; Orfao, Alberto; Radia, Deepti; Reiter, Andreas; Chase, Andrew J.; Cross, Nicholas C. P. and Tapper, William J. (2021): Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis. In: American Journal of Human Genetics, Vol. 108, No. 2: pp. 284-294

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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 (p(meta) = 1.37 x 10(-15), OR = 1.52), rs4662380 (pmeta = 2.11 x 10(-12), OR = 1.46), and rs13077541 (p(meta) = 2.10 x 10(-9), OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (p(eQTL) = 2.3 x 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 (p(eQTL) = 2.55 x 10(-11)), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (b)-like 1 X-linked receptor 1 (p(eQTL) = 5.70 x 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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