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

Affiliation

Galatà G(1), García-Montero AC(2), Kristensen T(3), Dawoud AAZ(1), Muñoz-González JI(2), Meggendorfer M(4), Guglielmelli P(5), Hoade Y(1), Alvarez-Twose I(6), Gieger C(7), Strauch K(8), Ferrucci L(9), Tanaka T(9), Bandinelli S(10), Schnurr TM(11), Haferlach T(4), Broesby-Olsen S(12), Vestergaard H(13), Møller MB(3), Bindslev-Jensen C(12), Vannucchi AM(5), Orfao A(2), Radia D(14), Reiter A(15), Chase AJ(16), Cross NCP(17), Tapper WJ(1).
Author information:
(1)School of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
(2)Institute of Biomedical Research of Salamanca, Salamanca 37007, Spain; Servicio de Citometría, Departamento de Medicina, CIBERONC, and Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca 37007, Spain.
(3)Department of Pathology, Odense University Hospital, 5000 Odense, Denmark; Mastocytosis Centre Odense University Hospital, 5000 Odense, Denmark.
(4)Munich Leukemia Laboratory, 81377 Munich, Germany.
(5)Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliera Universitaria Careggi, Dipartimento di Medicina Sperimentale e Clinica, Università Degli Studi di Firenze, 50134 Firenze, Italy.
(6)Instituto de Mastocitosis de Castilla La Mancha, Hospital Virgen del Valle, 45071 Toledo, Spain.
(7)Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; German Centre for Cardiovascular Research Partner Site Munich Heart Alliance, 80802 Munich, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Germany Research Center for Environmental Health, 85764 Neuherberg, Germany; German Center for Diabetes Research, 85764 Neuherberg, Germany.
(8)Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, 80539 Munich, Germany; Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany.
(9)Longitudinal study section, Translation Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA.
(10)Geriatric Unit, Azienda USL Toscana centro, 50137 Firenze, Italy.
(11)Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
(12)Mastocytosis Centre Odense University Hospital, 5000 Odense, Denmark; Department of Dermatology and Allergy Centre, Odense University Hospital, 5000 Odense, Denmark; Odense Research Center for Anaphylaxis, Odense University Hospital, 5000 Odense, Denmark.
(13)Mastocytosis Centre Odense University Hospital, 5000 Odense, Denmark; Department of Hematology, Odense University Hospital, 5000 Odense, Denmark.
(14)Department of Clinical Haematology, Guy's and St Thomas' NHS Hospitals, London SE1 9RT, UK.
(15)University Hospital Mannheim, Heidelberg University, 68167 Mannheim, Germany.
(16)School of Medicine, University of Southampton, Southampton SO17 1BJ, UK; Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury SP2 8BJ, UK.
(17)School of Medicine, University of Southampton, Southampton SO17 1BJ, UK; Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury SP2 8BJ, UK. Electronic address: [Email]

Abstract

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.