Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM

BACKGROUND: Indolent systemic mastocytosis (ISM) without skin lesions (ISMs-) shows a higher prevalence in males, lower serum baseline tryptase levels, and KIT mutation more frequently restricted to bone marrow (BM) mast cells (MCs) than ISM with skin lesions (ISMs+). Interestingly, in almost one-half of ISMs- patients, MC-mediator release episodes are triggered exclusively by insects. OBJECTIVE: We aimed to determine the clinical and laboratory features of ISMs- associated with insect-induced anaphylaxis (insectISMs-) versus other patients with ISM. METHODS: A total of 335 patients presenting with MC activation syndrome, including 143 insectISMs-, 72 ISMs- triggered by other factors (otherISMs-), 56 ISMs+, and 64 nonclonal MC activation syndrome, were studied. RESULTS: Compared with otherISMs- and ISMs+ patients, insectISMs- cases showed marked male predominance (78% vs 53% and 46%; P < .001), a distinct pattern of MC-related symptoms, and significantly lower median serum baseline tryptase levels (22.4 vs 28.7 and 45.8 \u3bcg/L; P 64 .009). Moreover, insectISMs- less frequently presented BM MC aggregates (46% vs 70% and 81%; P 64 .001), and they systematically showed MC-restricted KIT mutation. CONCLUSIONS: ISMs- patients with anaphylaxis triggered exclusively by insects display clinical and laboratory features that are significantly different from other ISM cases, including other ISMs- and ISMs+ patients, suggesting that they represent a unique subgroup of ISM with a particularly low BM MC burden in the absence of adverse prognostic factors

Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P\u200a=\u200a2.32 710(-12), OR\u200a=\u200a0.75). Also, rs12540874 in GRB10 gene (P\u200a=\u200a1.27 7 10(-6), OR\u200a=\u200a1.15) and rs11047102 in SOX5 gene (P\u200a=\u200a1.39 710(-7), OR\u200a=\u200a1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P\u200a=\u200a1.79 710(-61), OR\u200a=\u200a2.48), in the HLA-DPA1/B1 loci with ATA (P\u200a=\u200a4.57 710(-76), OR\u200a=\u200a8.84), and in NOTCH4 with ACA P\u200a=\u200a8.84 710(-21), OR\u200a=\u200a0.55) and ATA (P\u200a=\u200a1.14 710(-8), OR\u200a=\u200a0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc