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RESEARCH PRODUCT
Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis
Toshiko TanakaGabriella GalatàWilliam J. TapperSigurd Broesby-olsenYvette HoadeAhmed A. Z. DawoudCarsten Bindslev-jensenAlessandro M. VannucchiChristian GiegerTheresia M. SchnurrManja MeggendorferJavier I. Muñoz-gonzálezAndreas ReiterPaola GuglielmelliAndrés C. García-monteroTorsten HaferlachLuigi FerrucciIván ÁLvarez-twoseHanne VestergaardMichael Boe MøllerNicholas C.p. CrossNicholas C.p. CrossKonstantin StrauchKonstantin StrauchAndrew ChaseAndrew ChaseStefania BandinelliAlberto OrfaoThomas Kielsgaard KristensenDeepti Radiasubject
MaleAmino Acid Transport System y+TERTReceptors Cytoplasmic and NuclearGenome-wide association studySingle-nucleotide polymorphismDiseaseBiologyQuantitative trait locusPolymorphism Single NucleotideGermlineArticleGenetic variationCEBPACEBPAGeneticsHumansTBL1XR1Genetic Predisposition to DiseaseGeneTelomeraseGenetics (clinical)GeneticsInterleukin-13KITIntronsRepressor ProteinsProto-Oncogene Proteins c-kitD816VCebpa ; D816v ; Kit ; Mastocytosis ; Myeloid Cancer ; Tbl1xr1 ; TertCCAAT-Enhancer-Binding ProteinsDNA IntergenicFemaleRNA Long NoncodingTryptasesMyeloid cancerMastocytosisGenome-Wide Association Studydescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-02-04 |