Association of narcolepsy-cataplexy with HLA-DRB1 and DQB1 in Mexican patients: A relationship between HLA and gender is suggested

<p>Abstract</p> <p>Background</p> <p>Narcolepsy-cataplexy is characterized by excessive daytime sleepiness with recurrent episodes of irresistible sleep, cataplexy, hallucinations and sleep paralysis. Its aetiology is unknown, but it is positively associated with the human leukocyte antigens (HLA) in all studied populations. The purpose of the present study was to investigate the association of HLA class II <it>DRB1</it>/<it>DQB1 </it>alleles with narcolepsy-cataplexy in Mexican Mestizo patients.</p> <p>Methods</p> <p>This is a case-control study of consecutive patients and ethnically matched controls. We included 32 patients diagnosed with typical narcolepsy-cataplexy, of the National Institute of Neurology, of the Institute of Psychiatry and at the Center of Narcolepsy at Stanford University. As healthy controls, 203 Mexican Mestizos were included. <it>DRB1 </it>alleles were identified using sequence based typing. A PCR-SSOP reverse dot blot was used for <it>DQB1 </it>typing. Allele frequency was calculated by direct counting and the significance of the differences was assessed using the Yates Chi square. Odds ratio and confidence intervals were evaluated.</p> <p>Results</p> <p>HLA-<it>DRB1</it>*1501 (OR = 8.2; pc < 0.0001) and <it>DQB1</it>*0602 (OR = 8.4; pc < 0.0001) were found positively associated with narcolepsy. When deleting <it>DQB1</it>*0602+ patients from the analysis, <it>DQB1</it>*0301 was also found increased (OR = 2.7; p = 0.035; pc = NS). <it>DQB1</it>*0602/<it>DQB1</it>*0301 genotype was present in 15.6% of the cases (OR = 11.5; p = 0.00035), conferring a high risk. <it>DRB1</it>*0407 (OR = 0.2; p = 0.016 pc = NS) and <it>DQB1</it>*0302(OR = 0.4; p = 0.017, pc = NS) were found decreased in the patients. The gender stratification analysis showed a higher risk in females carrying <it>DRB1</it>*1501 (OR = 15.8, pc < 0.0001) and <it>DQB1</it>*0602 (OR = 19.8, pc < 0.0001) than in males (OR = 5.0 for both alleles; p = 0.012, pc = NS for <it>DRB1 </it>& p = 0.0012, pc = 0.017 for <it>DQB1</it>). The susceptibility alleles found in Mexicans with narcolepsy are also present in Japanese and Caucasians; <it>DRB1</it>*04 linked protection has also been shown in Koreans. A stronger HLA association is suggested in females, in accordance with the sexual dimorphism claimed previously.</p> <p>Conclusion</p> <p>This knowledge may contribute to a better understanding of the disease pathogenesis in different populations. The evaluation of the risk to develop narcolepsy-cataplexy in carriers of the described alleles/genotypes may also be possible. A larger sample should be analysed in Mexican and in other Hispanic patients to confirm these results.</p

Failing to Make Ends Meet: The Broad Clinical Spectrum of DNA Ligase IV Deficiency. Case Series and Review of the Literature

DNA repair defects are inborn errors of immunity that result in increased apoptosis and oncogenesis. DNA Ligase 4-deficient patients suffer from a wide range of clinical manifestations since early in life, including: microcephaly, dysmorphic facial features, growth failure, developmental delay, mental retardation; hip dysplasia, and other skeletal malformations; as well as a severe combined immunodeficiency, radiosensitivity, and progressive bone marrow failure; or, they may present later in life with hematological neoplasias that respond catastrophically to chemo- and radiotherapy; or, they could be asymptomatic. We describe the clinical, laboratory, and genetic features of five Mexican patients with LIG4 deficiency, together with a review of 36 other patients available in PubMed Medline. Four out of five of our patients are dead from lymphoma or bone marrow failure, with severe infection and massive bleeding; the fifth patient is asymptomatic despite a persistent CD4+ lymphopenia. Most patients reported in the literature are microcephalic females with growth failure, sinopulmonary infections, hypogammaglobulinemia, very low B-cells, and radiosensitivity; while bone marrow failure and malignancy may develop at a later age. Dysmorphic facial features, congenital hip dysplasia, chronic liver disease, gradual pancytopenia, lymphoma or leukemia, thrombocytopenia, and gastrointestinal bleeding have been reported as well. Most mutations are compound heterozygous, and all of them are hypomorphic, with two common truncating mutations accounting for the majority of patients. Stem-cell transplantation after reduced intensity conditioning regimes may be curative

Mutational Landscape of CEBPA in Mexican Pediatric Acute Myeloid Leukemia Patients: Prognostic Implications

BackgroundIn Mexico, the incidence of acute myeloid leukemia (AML) has increased in the last few years. Mortality is higher than in developed countries, even though the same chemotherapy protocols are used. CCAAT Enhancer Binding Protein Alpha (CEBPA) mutations are recurrent in AML, influence prognosis, and help to define treatment strategies. CEBPA mutational profiles and their clinical implications have not been evaluated in Mexican pediatric AML patients.Aim of the StudyTo identify the mutational landscape of the CEBPA gene in pediatric patients with de novo AML and assess its influence on clinical features and overall survival (OS).Materials and MethodsDNA was extracted from bone marrow aspirates at diagnosis. Targeted massive parallel sequencing of CEBPA was performed in 80 patients.ResultsCEBPA was mutated in 12.5% (10/80) of patients. Frameshifts at the N-terminal region were the most common mutations 57.14% (8/14). CEBPA biallelic (CEBPABI) mutations were identified in five patients. M2 subtype was the most common in CEBPA positive patients (CEBPAPOS) (p = 0.009); 50% of the CEBPAPOS patients had a WBC count &gt; 100,000 at diagnosis (p = 0.004). OS &gt; 1 year was significantly better in CEBPA negative (CEBPANEG) patients (p = 0.0001). CEBPAPOS patients (either bi- or monoallelic) had a significantly lower OS (p = 0.002). Concurrent mutations in FLT3, CSF3R, and WT1 genes were found in CEBPAPOS individuals. Their contribution to poor OS cannot be ruled out.ConclusionCEBPA mutational profiles in Mexican pediatric AML patients and their clinical implications were evaluated for the first time. The frequency of CEBPAPOS was in the range reported for pediatric AML (4.5–15%). CEBPA mutations showed a negative impact on OS as opposed to the results of other studies

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

Three heat shock protein 70 (HSP70) genes, HSPA1L, HSPA1A, and HSPA1B, are located within the human leukocyte antigen (HLA) class III region. HSPs act as stress signals and regulate natural killer cell response to cancer. HSP70 gene polymorphisms show disease associations partly due to their linkage disequilibrium with HLA alleles. To systematically evaluate their associations with childhood acute lymphoblastic leukemia (ALL), we examined the three functional single nucleotide polymorphisms (SNPs) rs2227956 (T493M) in HSPA1L, rs1043618 in HSPA1A 5′UTR, and rs1061581 (Q351Q) in HSPA1B by TaqMan assays or polymerase chain reaction–restriction fragment length polymorphism in 114 ALL cases and 414 controls from Wales (UK), in 100 Mexican Mestizo ALL cases and 253 controls belonging to the same ethnic group, and in a panel of 82 HLA-typed reference cell line samples. Homozygosity for HSPA1B rs1061581 minor allele G was associated with protection (odds ratio (OR) = 0.37, 95% confidence interval (CI) = 0.16–0.78; P = 0.007) with gene-dosage effect (additive model) reaching significance (P = 0.0001) in the Welsh case–control group. This association was replicated in the second case–control group from Mexico (OR (recessive model) = 0.49, 95% CI = 0.24–0.96; P = 0.03), and the pooled analysis yielded a strong association (Mantel–Haenszel OR = 0.43, 95% CI = 0.27–0.69, P = 0.0004). The association was stronger in males in each group and in the pooled analysis. A three-SNP haplotype including the major allele A of rs1061581 showed a highly significant increase in Welsh cases compared with respective controls (6.7% vs 1.8%; P = 0.0003) due to the difference between male cases and controls. The protective allele of rs1061581 occurred more frequently on the HLA-DRB3 haplotypes (especially DRB1*03) in the cell line panel, but the HSPA1B association was independent from the HLA-DRB4 association previously detected in the same case–control group from Wales (adjusted P = 0.001). Given the cancer promoting roles played by HSPs intracellularly as well as roles in immune surveillance when expressed on the cell surface and the known correlations between expression levels and the HSP polymorphisms, these results are likely to indicate a primary association and warrant detailed assessment in childhood ALL development

The global EPTO database : Worldwide occurrences of aquatic insects

Motivation: Aquatic insects comprise 64% of freshwater animal diversity and are widely used as bioindicators to assess water quality impairment and freshwater ecosystem health, as well as to test ecological hypotheses. Despite their importance, a comprehensive, global database of aquatic insect occurrences for mapping freshwater biodiversity in macroecological studies and applied freshwater research is missing. We aim to fill this gap and present the Global EPTO Database, which includes worldwide geo-referenced aquatic insect occurrence records for four major taxa groups: Ephemeroptera, Plecoptera, Trichoptera and Odonata (EPTO).Main type of variables contained: A total of 8,368,467 occurrence records globally, of which 8,319,689 (99%) are publicly available. The records are attributed to the corresponding drainage basin and sub-catchment based on the Hydrography90m dataset and are accompanied by the elevation value, the freshwater ecoregion and the protection status of their location.Spatial location and grain: The database covers the global extent, with 86% of the observation records having coordinates with at least four decimal digits (11.1 m precision at the equator) in the World Geodetic System 1984 (WGS84) coordinate reference system.Time period and grain: Sampling years span from 1951 to 2021. Ninety-nine percent of the records have information on the year of the observation, 95% on the year and month, while 94% have a complete date. In the case of seven sub-datasets, exact dates can be retrieved upon communication with the data contributors.Major taxa and level of measurement: Ephemeroptera, Plecoptera, Trichoptera and Odonata, standardized at the genus taxonomic level. We provide species names for 7,727,980 (93%) records without further taxonomic verification.Software format: The entire tab-separated value (.csv) database can be downloaded and visualized at . Fifty individual datasets are also available at , while six datasets have restricted access. For the latter, we share metadata and the contact details of the authors.Peer reviewe