No association between myeloproliferative neoplasms and the Crohn's disease-associated STAT3 predisposition SNP rs744166.
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ABSTRACT:
SUBMITTER: Jones AV
PROVIDER: S-EPMC2895051 | biostudies-literature | 2010 Jul
REPOSITORIES: biostudies-literature
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No association between myeloproliferative neoplasms and the Crohn's disease-associated STAT3 predisposition SNP rs744166.
Jones Amy V AV Cross Nicholas C P NC
Haematologica 20100701 7
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Project description:Myeloproliferative neoplasms (MPNs) are haematological disorders characterized by an overproduction of mature myeloid cells with a tendency to transform to acute myeloid leukaemia. Clonal proliferation of myeloid progenitor cells is driven by somatically acquired mutations, most notably JAK2 V617F, but there are important features relating to pathogenesis and phenotypic diversity that cannot be explained by acquired mutations alone. In this review we consider what is currently known about the role that inherited factors play in the development and biology of both sporadic and familial forms of MPN. Although most MPN cases appear to be sporadic, familial predisposition has been recognized for many years in a subset of cases and epidemiological studies have indicated the presence of common susceptibility alleles. Currently the JAK2 46/1 haplotype (also referred to as 'GGCC') is the strongest known predisposition factor for sporadic MPNs carrying a JAK2 V617F mutation, explaining a large proportion of the heritability of this disorder. Less is known about what genetic variants predispose to MPNs that lack JAK2 V617F, but there have been recent reports of interesting associations in biologically plausible candidates, and more loci are set to emerge with the application of systematic genome-wide association methodologies. Several highly penetrant predisposition variants that affect erythropoietin signalling, thrombopoietin signalling or oxygen sensing have been characterized in families with nonclonal hereditary erythrocytosis or thrombocytosis, but much less is known about familial predisposition to true clonal MPN. The heterogeneous pattern of inheritance and presumed genetic heterogeneity in these families makes analysis difficult, but whole exome or genome sequencing should provide novel insights into these elusive disorders.
| S-EPMC3734902 | biostudies-literature
Project description:Polycythemia vera, essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms (MPN) characterized by multilineage clonal hematopoiesis. Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene (JAK2(V617F)) is observed in most individuals with polycythemia vera, essential thrombocythemia and primary myelofibrosis, there likely are additional genetic events that contribute to the pathogenesis of these phenotypically distinct disorders. Moreover, family members of individuals with MPN are at higher risk for the development of MPN, consistent with the existence of MPN predisposition loci. We hypothesized that germline variation contributes to MPN predisposition and phenotypic pleiotropy. Genome-wide analysis identified an allele in the JAK2 locus (rs10974944) that predisposes to the development of JAK2(V617F)-positive MPN, as well as three previously unknown MPN modifier loci. We found that JAK2(V617F) is preferentially acquired in cis with the predisposition allele. These data suggest that germline variation is an important contributor to MPN phenotype and predisposition.
| S-EPMC3676425 | biostudies-literature
Project description:BackgroundMany studies have investigated the associations between the signal transducer and activator of transcription 3 (STAT3) in the susceptibility to ulcerative colitis (UC) and Crohn's disease (CD). However, the results remain inconsistent. This meta-analysis determined the risk of STAT3 rs744166 polymorphism-conferred UC and CD susceptibility.Materials and methodsElectronic databases, including PubMed, EMBASE and the Cochrane Library, were searched for all eligible studies that evaluated the association between STAT3 rs744166 polymorphisms with UC and CD risk up to August 21, 2014. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using fixed- or random-effects models.ResultsTwelve studies containing 10298 patients with CD, 4244 patients with UC and 11191 controls were included in this meta-analysis. The results indicated that the STAT3 rs744166 polymorphism was associated with CD and UC susceptibility (CD: GA+AA vs. GG, OR = 1.20, 95%CI, 1.11-1.30, I2 = 0%, Punadjusted<0.00001, PBonferroni<0.00005, PFDR<0.00001; UC: GA+AA vs. GG, OR = 1.21, 95%CI, 1.08-1.36, I2 = 1%, Punadjusted = 0.001, PBonferroni = 0.005, PFDR = 0.00125). In subgroup analyses by ethnicity, the significant association was found only among Caucasians. However, when grouped by age of onset, positive associations were found both among adults and children. In addition, when stratified by study design and genotyping methods, the risk of CD was significantly associated with the STAT3 rs744166 polymorphism in hospital-based and population-based groups and in SNP Array and SNPlex groups. For UC, significant associations were also found in population-based, PCR-RFLP and SNPlex groups. Moreover, these findings were sufficiently robust to withstand the Bonferroni correction and false discovery rate (FDR).ConclusionThis meta-analysis indicates that carriers of the STAT3 rs744166 'A' allele have a significantly greater risk of CD and UC, especially among Caucasians.
| S-EPMC4186844 | biostudies-literature
Project description:SNP arrays allow for genome-wide profiling of copy-number alterations (CNAs) and copy-neutral runs of homozygosity (ROH) at high resolution. To identify novel genetic lesions in myeloproliferative neoplasms (MPN), a large series of 151 clinically well-characterized patients was analyzed in our study. CNAs were rare in essential thrombocythemia and polycythemia vera. In contrast, approximately one third of myelofibrosis patients exhibited small genomic losses (< 5 Mb). In two secondary myelofibrosis cases the tumor suppressor gene NF1 in 17q11.2 was affected. Sequencing analyses revealed a mutation in the remaining NF1 allele of one patient. In terms of ROH, no chromosomes other than 9p were recurrently affected. In conclusion, in our study we identified novel genomic aberrations in MPN, in particular in patients with myelofibrosis. Further analyses on single-gene level are necessary to uncover the mechanisms that are involved in the pathogenesis of MPN.
2009-10-01 | GSE18197 | GEO
Project description:The aim of the present study was to determine the association between sirtuin 1 (SIRT1), fibroblast growth factor receptor 2 (FGFR2) and signal transducer and activator of transcription 3 (STAT3) polymorphisms, and pituitary adenoma (PA) development, invasiveness, hormonal activity and recurrence. The present study included 143 patients with a diagnosis of PA. The reference group involved 808 healthy subjects. The genotyping of SIRT1 rs12778366, FGFR2 rs2981582 and STAT3 rs744166 was performed using the quantitative polymerase chain reaction method. The SIRT1 rs12778366 polymorphism analysis in the overall group revealed differences in the genotype distribution between patients with PA and control group subjects. The rs12778366 T/C genotype was observed to be different in non-invasive, non-recurrent and inactive PA subgroups compared with the control group, while the C/C genotype was observed to be different in invasive, recurrent and active PA subgroups compared with the control group. STAT3 rs744166 polymorphism analysis in the overall group revealed differences in the genotype distribution between patients with PA and the control groups. The rs744166 G/G genotype was observed to be different in invasive, non-recurrent and active PA subgroups compared with the control group, while the rs744166 A/A genotype was observed to be different in the active PA subgroup compared with the control group, and was also different in terms of invasiveness and recurrence in PA subgroups. The present study demonstrated that SIRT1 rs12778366 is associated with pituitary adenoma development while STAT3 rs744166 is associated with PA invasiveness, hormonal activity and recurrence.
| S-EPMC5431252 | biostudies-literature
Project description:Abnormalities of chromosome 7q are common in myeloid malignancies but no specific target genes have been identified. Here we describe the finding of homozygous EZH2 mutations in 9 of 12 cases with 7q acquired uniparental disomy. Screening of a total of 614 cases with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals, most commonly myelodysplastic/myeloproliferative neoplasms (27/219; 12%) and myelofibrosis (4/30; 13%). EZH2 encodes the catalytic subunit of the Polycomb repressive complex 2 (PRC2), the highly conserved histone H3 lysine 27 methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity and its overexpression has been causally linked to differentiation blocks in epithelial tumors. Unexpectedly, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.
2010-06-30 | GSE21990 | GEO
Project description:Haplotype 46/1 (GGCC) consists of a set of genetic variations distributed along chromosome 9p.24.1, which extend from the Janus Kinase 2 gene to Insulin like 4. Marked by four jointly inherited variants (rs3780367, rs10974944, rs12343867, and rs1159782), this haplotype has a strong association with the development of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) because it precedes the acquisition of the JAK2V617F variant, a common genetic alteration in individuals with these hematological malignancies. It is also described as one of the factors that increases the risk of familial MPNs by more than five times, 46/1 is associated with events related to inflammatory dysregulation, splenomegaly, splanchnic vein thrombosis, Budd-Chiari syndrome, increases in RBC count, platelets, leukocytes, hematocrit, and hemoglobin, which are characteristic of MPNs, as well as other findings that are still being elucidated and which are of great interest for the etiopathological understanding of these hematological neoplasms. Considering these factors, the present review aims to describe the main findings and discussions involving the 46/1 haplotype, and highlights the molecular and immunological aspects and their relevance as a tool for clinical practice and investigation of familial cases.
| S-EPMC9604447 | biostudies-literature
Project description:Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms (MPNs); however, a considerable number of patients respond suboptimally. Here, we evaluated the efficacy of micheliolide (MCL), a natural guaianolide sesquiterpene lactone, alone or in combination with ruxolitinib in samples from patients with MPNs, JAK2V617F-mutated MPN cell lines, and a Jak2V617F knock-in mouse model. MCL effectively suppressed colony formation of hematopoietic progenitors in samples from patients with MPNs and inhibited cell growth and survival of MPN cell lines in vitro. Co-treatment with MCL and ruxolitinib resulted in greater inhibitory effects compared with treatment with ruxolitinib alone. Moreover, dimethylaminomicheliolide (DMAMCL), an orally available derivative of MCL, significantly increased the efficacy of ruxolitinib in reducing splenomegaly and cytokine production in Jak2V617F knock-in mice without evident effects on normal hematopoiesis. Importantly, MCL could target the Jak2V617F clone and reduce mutant allele burden in vivo. Mechanistically, MCL can form a stable covalent bond with cysteine residues of STAT3/5 to suppress their phosphorylation, thus inhibiting JAK/STAT signaling. Overall, these findings suggest that MCL is a promising drug in combination with ruxolitinib in the setting of suboptimal response to ruxolitinib.
| S-EPMC10629731 | biostudies-literature
Project description:Crohn's disease (CD) results from dysregulated immune responses to gut microbiota in genetically susceptible individuals, affecting multiple areas of the gastrointestinal tract. Innate lymphoid cells (ILCs) are tissue-resident innate effector lymphocytes which play crucial roles in mucosal immune defense, tissue repair, and maintenance of homeostasis. The accumulation of IFN-γ-producing ILC1s and increased level of proinflammatory cytokines produced by ILCs has been observed in the inflamed terminal ileum of CD patients. To date, the precise mechanisms of ILC plasticity and gene regulatory pathways in ILCs remain unclear. Signal transducer and activator of transcription 3 (STAT3) regulates gene expression in a cell-specific, cytokine-dependent manner, involving multiple immune responses. This study proposes the positive correlation between the prevalence of STAT3 rs744166 risky allele "A" with the severity of disease in a cohort of 94 CD patients. In addition, the results suggest an increased STAT3 activity in the inflamed ileum of CD patients, compared to unaffected ileum sections. Notably, IL-23 triggers the differentiation of CD117+NKp44- ILC3s and induces the activation of STAT3 in both CD117+NKp44- and CD117-NKp44- ILC subsets, implying the involvement of STAT3 in the initiation of ILC plasticity. Moreover, carriage of STAT3 "A" risk allele exhibited a higher basal level of STAT3 tyrosine phosphorylation, and an increased IL-23 triggered the pSTAT3 level. We also demonstrated that there was no delayed dephosphorylation of STAT3 in ILCs of both A/A and G/G donors. Overall, the results of this study suggest that IL-23-induced activation of STAT3 in the CD117-NKp44- ILC1s involves in ILC1-to-ILC3 plasticity and a potential regulatory role of ILC1 function. Those genetically susceptible individuals carried STAT3 rs744166 risky allele appear to have higher basal and cytokine-stimulated activation of STAT3 signal, leading to prolonged inflammation and chronic relapse.
| S-EPMC6610725 | biostudies-literature
Project description:Myeloproliferative neoplasms (MPNs) have estimated annual incidence rates for polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis of 0.84, 1.03, and 0.47 per 100,000. Prevalence is much higher, particularly for PV and ET, as mortality rates are relatively low. Patients are often concerned about why they developed an MPN and epidemiological studies enable the identification of potential causative factors. Previous work in small heterogeneous studies has identified a variety of risk factors associated with MPNs including family history of MPN, autoimmune conditions, some occupational exposures, and blood donation. At a population level, germline predisposition factors in various populations have been associated with MPNs. The pilot MOSAICC (Myeloproliferative Neoplasm: An In-depth Case-Control) study is one of the largest epidemiological studies in MPN ever carried out to date. It demonstrated the most effective methods for carrying out a significant epidemiological study in this patient group including the best way of recruiting controls, as well as how to evaluate occupational and lifestyle exposures, evaluate symptoms, and collect biological samples. Significant results linked to MPNs in the pilot study of 106 patients included smoking, obesity, and childhood socioeconomic status. The methodology is now in place for a much larger ongoing MOSAICC study which should provide further insight into the potential causes of MPNs.
| S-EPMC7408762 | biostudies-literature