Background: DDX41 serves as a DNA sensor in innate immunity and mutated DDX41 is pathogenic, mainly for myeloid neoplasms. Methods: In this study, “ DDX41” was searched in PubMed and Web of Science between 1 January 2015 and 29 April 2021 with individual-patient data seeking. A meta-analysis was not valid here due to the absence of a large dataset. Thirty articles were finally included in the qualitative analysis and 277 patients from 20 studies without overlap were involved in the quantitative summary. Results: Pooled incidence was 3.3% (95% confidence interval 2.4–4.2%) of unselected myeloid neoplasms. Patients with hematologic disorders harboring mutated DDX41 were featured as 80% males, median 66 (20–88) years old at diagnosis, 75% acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 64% with normal karyotype. Eighty-five percent of patients had germline variants which were nationally diverse and more of frameshift type, whereas 64% of patients had somatic DDX41 variants where p.R525H and missense dominated. ASXL1 and TP53 were the top frequent concomitant somatic mutations. Therapeutically, 70% overall response rate was obtained of hypomethylating agents in MDS, 96% complete remission of chemotherapy in AML, and 8% of relapse in hematopoietic stem cell transplant. Neither overall survival nor progression-free survival could be summed. Conclusions: Several significant clinical differences were observed in different diagnosis groups, familial and sporadic cases, and p.R525H compared with other somatic variants. In conclusion, myeloid neoplasms carrying DDX41 mutations were mainly older, male, MDS, and AML patients who had promising responses to treatment. Both germline and somatic DDX41 variants possessed unique characteristics and groups of interest presented certain differences worth further research. (CRD42021228886)

Dysplasia and proliferation are histological properties that can be used to diagnose and categorize myeloid tumors in myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). However, these conditions are not exclusive, and overlap between them leads to another classification, MDS/MPN. As well as phenotype continuity, these three conditions may have genetic relationships that have not yet been identified. This study aimed to obtain their mutational profiles by meta-analysis and explore possible similarities and differences. We reviewed screening studies of gene mutations, published from January 2000 to March 2020, from PubMed and Web of Science. Fifty-three articles were eligible for the meta-analysis, and at most 9,809 cases were involved for any gene. The top mutant genes and their pooled mutation rates were as follows: SF3B1 (20.2% [95% CI 11.6-30.5%]) in MDS, TET2 (39.2% [95% CI 21.7-52.0%]) in MDS/MPN, and JAK2 (67.9% [95% CI 64.1-71.6%]) in MPN. Subgroup analysis revealed that leukemic transformation-related genes were more commonly mutated in high-risk MDS (MDS with multilineage dysplasia and MDS with excess blasts) than that in other MDS entities. Thirteen genes including ASXL1, U2AF1, SRSF2, SF3B1, and ZRSR2 had significantly higher mutation frequencies in primary myelofibrosis (PMF) compared with essential thrombocythemia and polycythemia vera; this difference distinguished PMF from MPN and likened it to MDS. Chronic myelomonocytic leukemia and atypical chronic myeloid leukemia were similar entities but showed several mutational differences. A heat map demonstrated that juvenile myelomonocytic leukemia and MDS/MPN with ring sideroblasts and thrombocytosis were two distinct entities, whereas MDS/MPN-unclassifiable was closest to high-risk MDS. Such genetic closeness or difference reflected features in the pathogenesis, diagnosis, treatment, and progression of these conditions, and could inspire future genetic studies.

BackgroundThere is very limited evidence on the causal effects of blood metabolites on pancreatitis risks. To reveal the causal associations between plasma metabolites and pancreatitis risks, we performed two-sample Mendelian randomization (MR) and Bayesian model averaging (MR-BMA) analyses in European ancestry.MethodsThe summary-level statistics from two genome-wide association studies with 249 and 123 metabolic traits derived from two separate cohorts involving ~115,000 (UK Biobank) and ~25,000 individuals from European ancestry were used for the analyses. The summary statistics of four pancreatitis datasets from FinnGen R5 and two pancreatitis datasets from UK Biobank were exploited as the outcome. We first performed univariable MR analysis with different metabolic GWAS data on multiple pancreatitis datasets to demonstrate the association pattern among different metabolites categories. Next, we exploited the MR-BMA method to pinpoint the dominating factors on the increased risk of pancreatitis.ResultsIn the primary analysis with 249 traits, we found that plasma triglycerides were positively associated with pancreatitis risk. Intriguingly, a large number of traits associated with saturation or unsaturation of fatty acids also demonstrated causal associations. The replication study analyzing 123 metabolic traits suggested that bisallylic groups levels and omega-3 fatty acids were inversely correlated with pancreatitis risk. MR-BMA analyses indicated that the ratio of triglycerides to total lipid in various HDL particles played leading roles in pancreatitis susceptibility. In addition, the degree of unsaturation, the ratio of polyunsaturated fatty acids to monounsaturated fatty acids and the level of monounsaturated fatty acids showed causal associations with either decreased or increased pancreatitis susceptibility.ConclusionsOur MR study provided an atlas of causal associations of genetically predicted blood metabolites on pancreatitis, and offered genetic insights showing intervention in triglycerides and the supplementation of unsaturated fatty acids are potential strategies in the primary prevention of pancreatitis.