Essentials Genetic predisposition to acquired thrombotic thrombocytopenic purpura (aTTP) is mainly unknown. Genetic risk factors for aTTP were studied by Immunochip analysis and replication study. Human leukocyte antigen (HLA) variant rs6903608 conferred a 2.5-fold higher risk of developing aTTP. rs6903608 and HLA-DQB1*05:03 may explain most of the HLA association signal in aTTP. Click to hear Dr Cataland's presentation on acquired thrombotic thrombocytopenic purpura SUMMARY: Background Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy associated with the development of autoantibodies against the von Willebrand factor-cleaving protease ADAMTS-13. Similarly to what has been found for other autoimmune disorders, there is evidence of a genetic contribution, including the association of the human leukocyte antigen (HLA) class II complex with disease risk. Objective To identify novel genetic risk factors in acquired TTP. Patients/Methods We undertook a case-control genetic association study in 190 European-origin TTP patients and 1255 Italian healthy controls by using the Illumina Immunochip. Replication analysis in 88 Italian cases and 456 controls was performed with single-nucleotide polymorphism (SNP) TaqMan assays. Results and conclusion We identified one common variant (rs6903608) located within the HLA class II locus that was independently associated with acquired TTP at genome-wide significance and conferred a 2.6-fold increased risk of developing a TTP episode (95% confidence interval [CI] 2.02-3.27, P = 1.64 × 10 ). We also found five non-HLA variants mapping to chromosomes 2, 6, 8 and X that were suggestively associated with the disease: rs9490550, rs115265285, rs5927472, rs7823314, and rs1334768 (nominal P-values ranging from 1.59 × 10 to 7.60 × 10 ). Replication analysis confirmed the association of HLA variant rs6903608 with acquired TTP (pooled P = 3.95 × 10 ). Imputation of classic HLA genes followed by stepwise conditional analysis revealed that the combination of rs6903608 and HLA-DQB1*05:03 may explain most of the HLA association signal in acquired TTP. Our results refined the association of the HLA class II locus with acquired TTP, confirming its importance in the etiology of this autoimmune disease.
One of the mechanisms by which viruses can evade the host’s immune system is to modify the host’s DNA methylation pattern. This work aims to investigate the DNA methylation and gene expression profile of COVID-19 patients, divided into symptomatic and asymptomatic, and healthy controls, focusing on genes involved in the immune response. In this study, changes in the methylome of COVID-19 patients’ upper airways cells, the first barrier against respiratory infections and the first cells presenting viral antigens, are shown for the first time. Our results showed alterations in the methylation pattern of genes encoding proteins implicated in the response against pathogens, in particular the HLA-C gene, also important for the T-cell mediated memory response. HLA-C expression significantly decreases in COVID-19 patients, especially in those with a more severe prognosis and without other possibly confounding co-morbidities. Moreover, our bionformatic analysis revealed that the identified methylation alteration overlaps with enhancers regulating HLA-C expression, suggesting an additional mechanism exploited by SARS-CoV-2 to inhibit this fundamental player in the host’s immune response. HLA-C could therefore represent both a prognostic marker and an excellent therapeutic target, also suggesting a preventive intervention that conjugate a virus-specific antigenic stimulation with an adjuvant increasing the T-cell mediated memory response.
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