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

Am J Hum Genet. 2021 Feb 4;108(2):284-294. doi: 10.1016/j.ajhg.2020.12.007. Epub 2021 Jan 8.

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.

Keywords: CEBPA; D816V; KIT; TBL1XR1; TERT; mastocytosis; myeloid cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / genetics
  • CCAAT-Enhancer-Binding Proteins / genetics
  • DNA, Intergenic
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Humans
  • Interleukin-13 / genetics
  • Introns
  • Male
  • Mastocytosis / genetics*
  • Polymorphism, Single Nucleotide*
  • Proto-Oncogene Proteins c-kit / genetics*
  • RNA, Long Noncoding / genetics
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Repressor Proteins / genetics
  • Telomerase / genetics
  • Tryptases / genetics

Substances

  • Amino Acid Transport System y+
  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • DNA, Intergenic
  • IL13 protein, human
  • Interleukin-13
  • RNA, Long Noncoding
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • SLC7A10 protein, human
  • TBL1XR1 protein, human
  • KIT protein, human
  • Proto-Oncogene Proteins c-kit
  • TERT protein, human
  • Telomerase
  • TPSAB1 protein, human
  • Tryptases