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

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.

Effects of Primary Mast Cell Disease on Hemostasis and Erythropoiesis

“…Clinical signs of a bleeding diathesis, such as hematoma formation, bruising, prolonged bleeding after biopsies, gingival bleeding, epistaxis, gastrointestinal hemorrhage, conjunctival hemorrhage, menorrhagia or hemorrhagic ulcer disease occur in about 50% of patients with MC disease ( [7,19]; further references therein) and can contribute to deterioration in quality of life. Thus, bleeding diathesis represents a frequent and clinically relevant problem in MC disease, although severe or fatal bleeding seems to be rare [20][21][22][23].…”

“…The prevalence of MCAS, at least in Germany, is about 17% [4] and about 20% in the U.S. [5], and that of HAT was found to be 4-6% of the general population [6], hence both being common disorders. Two genome-wide association studies (GWAS; [7,8]) on patients with SM revealed different non-overlapping results with regard to the multiple mutations in a variety of genes. A recent GWAS on MCAS patients detected also a large number of SNPs without overlapping with the GWAS results in SM patients (Hänisch 2021, personal communication; manuscript in preparation).…”

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

“…To the best of our knowledge, 14 SNPs have been associated with the development or phenotype of human mastocytosis in published studies. [17][18][19][20][21][22] Of these, 11 were directly genotyped or could be imputed from our stage 1 data (Table S7), but only one of these was significant: rs1800925 in the promoter region of IL13 at 5q31 (p imputed ¼ 0.008). This SNP has been linked to the development of adult SM and serum interleukin-13 levels 18 and inflammatory disorders such as chronic obstructive pulmonary disease.…”

“…15,16 Several constitutional genetic variants have been associated with the development of different mastocytosis phenotypes in relatively small candidate gene studies [17][18][19][20][21] and a recent single-stage genome-wide association study (GWAS) of 234 affected individuals. 22 Finally, it has been clearly established that constitutional genetic variation at several loci predispose to other myeloproliferative neoplasms (MPN). 23,24 To determine whether common genetic variation plays a role in predisposition to mastocytosis, we have performed a robust two-stage GWAS focusing on affected individuals that tested positive for KIT D816V regardless of clinical subtype to help ensure a genetically homogeneous cohort.…”

Decoding the intricacies of the mast cell compartment

“…These consist of mutations associated with down-stream activation pathways (NRAS/KRAS), clonal epigenetic instability (TET2, DNMT3A, ASXL1) and survival (SRSF2, ASXL1, RUNX1). 45 These additional mutations should prompt the provider to rule out other associated neoplasms. Recent data have identified three mutations that are predictive of prognosis in patients with systemic disease and a more aggressive profile.…”