Results from a Genome-Wide Association Study (GWAS) in Mastocytosis Reveal New Gene Polymorphisms Associated with WHO Subgroups.

Bogusław Nedoszytko,Marek Niedoszytko,Magdalena Lange,Jasper Van Doormaal,Aleksandra Górska,Roman J Nowicki,Leszek Kalinowski,Marta Gruchała-Niedoszytko,Peter Valent,Dominik Strapagiel,Marta Sobalska-Kwapis,Joanne N G Oude Elberink,Marcin Słomka

doi:10.3390/ijms21155506

Abstract

Mastocytosis is rare disease in which genetic predisposition is not fully understood. The aim of this study was to analyze associations between mastocytosis and single nucleotide polymorphisms (SNPs) by a genome-wide association study (GWAS) approach. A total of 234 patients were enrolled in our study, including 141 with cutaneous mastocytosis (CM; 78 children and 63 adults) and 93 with systemic mastocytosis (SM, all adults). The control group consisted of 5606 healthy individuals. DNA samples from saliva or blood were genotyped for 551 945 variants using DNA microarrays. The prevalence of certain SNPs was found to vary substantially when comparing patients and healthy controls: rs10838094 of 5OR51Q1 was less frequently detected in CM and SM patients (OR = 0.2071, p = 2.21 × 10−29), rs80138802 in ABCA2 (OR = 5.739, p = 1.98 × 10−28), and rs11845537 in OTX2-AS1 (rs11845537, OR = 6.587, p = 6.16 × 10−17) were more frequently detected in CM in children and adults. Additionally, we found that rs2279343 in CYP2B6 and rs7601511 in RPTN are less prevalent in CM compared to controls. We identified a number of hitherto unknown associations between certain SNPs and CM and/or SM. Whether these associations are clinically relevant concerning diagnosis, prognosis, or prevention remains to be determined in future studies.

Highlights

Mastocytosis is a heterogeneous group of diseases defined by the abnormal accumulation of clonal mast cells (MC) in the skin, bone marrow, and/or other visceral organs
Four of the single nucleotide polymorphisms (SNPs) were more frequently found in mastocytosis patients compared to controls: rs80138802 in ABCA2 (OR = 5.739, p = 1.98 × 10−27), rs11845537 in OTX2-AS1 (OR = 5.625, p = 1.60 × 10−18), rs1611207 in HLA-V (OR = 2.105, p = 7.25 × 10−8), and rs1778155 in PDE4DIP (OR = 2.032, p = 3.26 × 10−6) genes (Table 1, Figure 1)
Five polymorphisms were found to be less frequently detectable in mastocytosis than in controls: rs61735841 in FTCD (OR = 0.026; 95% CI 0.003612–0.1833; p = 4.34 × 10−5), rs10838094 in OR51Q1 (OR = 0.2071; 95% CI 0.1572–0.2728; p = 2.21 × 10−29), rs2279343 in CYP2B6, OR = 0.2795; 95%CI; 0.199–0.3924; p = 2.32 × 10−10), rs76015112 in RPTN (OR = 2.965; 95% CI 0.205–0.4289; p = 2.94 × 10−7) genes and rs9828758 (OR = 0.1467; 95% CI 0.095–0.23; p = 2.94 × 10−7) near RP11 gene (Table 1, Figure 1, Figures S3 and S4)

Summary

Introduction

Mastocytosis is a heterogeneous group of diseases defined by the abnormal accumulation of clonal mast cells (MC) in the skin, bone marrow, and/or other visceral organs. The diagnosis of systemic mastocytosis (SM) is based on WHO criteria, including the basal serum tryptase level, histopathological and immunophenotypic (CD2/CD25) features of MCs, and somatic KIT mutations in codon 816. In most patients with SM, somatic mutations in the KIT gene are found, the most prevalent in SM being D816V (rs121913507, D [GAC] > V [GTC]). The KIT D816V mutation results in SCF-independent differentiation of MCs. KIT D816V is detected in more than 80% of all adults with SM. In children with CM, this mutation is less frequent (35%) and other mutations, located in gene regions encoding the external cellular domain of KIT, are more commonly found in childhood patients (45%) [7,9,10]

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