The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Drug Allergy: A 2022 Practice Parameter Update.

Pharmacogenomics: current status and future perspectives

Drug-Induced Hypersensitivity Syndrome (DIHS)/ Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS): Clinical Features and Pathogenesis.

After over a billion of vaccinations with messenger RNA-lipid nanoparticle (mRNA-LNP) based SARS-CoV-2 vaccines, anaphylaxis and other manifestations of hypersensitivity can be considered as very rare adverse events. Although current recommendations include avoiding a second dose in those with first-dose anaphylaxis, the underlying mechanisms are unknown; therefore, the risk of a future reaction cannot be predicted. Given how important new mRNA constructs will be to address the emergence of new viral variants and viruses, there is an urgent need for clinical approaches that would allow a safe repeated immunization of high-risk individuals and for reliable predictive tools of adverse reactions to mRNA vaccines. In many aspects, anaphylaxis symptoms experienced by the affected vaccine recipients resemble those of infusion reactions to nanomedicines. Here we share lessons learned over a decade of nanomedicine research and discuss the current knowledge about several factors that individually or collectively contribute to infusion reactions to nanomedicines. We aim to use this knowledge to inform the SARS-CoV-2 lipid-nanoparticle-based mRNA vaccine field. 

/pdf/applying-lessons-learned-from-nanomedicines-to-understand-2hepd0wx.pdf

Applying lessons learned from nanomedicines to understand rare hypersensitivity reactions to mRNA-based SARS-CoV-2 vaccines

Background Hypersensitivity reactions to drugs are often unpredictable and can be life-threatening, underscoring a need for understanding the underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. Methods We extracted data from the electronic health records of 52,000 Estonian and 500,000 UK biobank participants to study the role of genetic variation in the occurrence of penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from up to 22,554 and 488,377 individuals from the Estonian and UK cohorts, respectively, to further fine-map the human leukocyte antigen (HLA) association and replicated our results in two additional cohorts involving a total of 1.14 million individuals. Results Genome-wide meta-analysis of penicillin allergy revealed a significant association located in the HLA region on chromosome 6. The signal was further fine-mapped to the HLA-B*55:01 allele (OR 1.47 95% CI 1.37-1.58, P-value 4.63×10−26) and confirmed by independent replication in two cohorts. The meta-analysis of all four cohorts in the study revealed a strong association of HLA-B*55:01 allele with self-reported penicillin allergy (OR 1.33 95% CI 1.29-1.37, P-value 2.23×10−72). In silico follow-up suggests a potential effect on T lymphocytes at HLA-B*55:01. Conclusion We present the first robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.

https://www.biorxiv.org/content/biorxiv/early/2020/02/28/2020.02.27.967497.full.pdf

Genome-wide study identifies association between HLA-B*55:01 and penicillin allergy

Summary Hypersensitivity reactions to drugs are often unpredictable and can be life threatening, underscoring a need for understanding their underlying mechanisms and risk factors. The extent to which germline genetic variation influences the risk of commonly reported drug allergies such as penicillin allergy remains largely unknown. We extracted data from the electronic health records of more than 600,000 participants from the UK, Estonian, and Vanderbilt University Medical Center’s BioVU biobanks to study the role of genetic variation in the occurrence of self-reported penicillin hypersensitivity reactions. We used imputed SNP to HLA typing data from these cohorts to further fine map the human leukocyte antigen (HLA) association and replicated our results in 23andMe’s research cohort involving a total of 1.12 million individuals. Genome-wide meta-analysis of penicillin allergy revealed two loci, including one located in the HLA region on chromosome 6. This signal was further fine-mapped to the HLA-B∗55:01 allele (OR 1.41 95% CI 1.33–1.49, p value 2.04 × 10−31) and confirmed by independent replication in 23andMe’s research cohort (OR 1.30 95% CI 1.25–1.34, p value 1.00 × 10−47). The lead SNP was also associated with lower lymphocyte counts and in silico follow-up suggests a potential effect on T-lymphocytes at HLA-B∗55:01. We also observed a significant hit in PTPN22 and the GWAS results correlated with the genetics of rheumatoid arthritis and psoriasis. We present robust evidence for the role of an allele of the major histocompatibility complex (MHC) I gene HLA-B in the occurrence of penicillin allergy.

Genome-wide Study Identifies Association between HLA-B∗55:01 and Self-Reported Penicillin Allergy.

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Genome-wide study identifies association between HLA-B*55:01 and penicillin allergy

Genome-wide Study Identifies Association between HLA-B∗55:01 and Self-Reported Penicillin Allergy.