Genetic variation in the HLA region is associated with susceptibility to herpes zoster

Crosslin, David R.; Carrell, David; Burt, Amber; Kim, Daniel S.; Underwood, Jason G.; Hanna, D.; Comstock, Bryan A.; Baldwin, Eric; Andrade, Mariza de; Kullo, Iftikhar J.; Tromp, Gerard; Kuivaniemi, Helena; Borthwick, Kenneth M.; McCarty, Catherine A.; Peissig, Peggy L.; Doheny, Kim; Pugh, Elizabeth; Kho, Abel N.; Pacheco, Jennifer A.; Hayes, M. Geoffrey; Ritchie, Marylyn D.; Verma, Shefali S.; Armstrong, G.; Stallings, Sarah; Denny, Joshua C.; Carroll, Robert J.; Crawford, Dana C.; Crane, Paul K.; Mukherjee, Shubhabrata; Böttinger, Erwin P.; Li, R.; Keating, Brendan J.; Mirel, Daniel B.; Carlson, Chris; Harley, John B.; Larson, Eric B.; Jarvik, Gail P.

doi:10.1038/gene.2014.51

Cited by 58 publications

(44 citation statements)

References 27 publications

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“…This gene is an endogenous retrovirus that likely suppresses viral activity through regulatory functions. Variants in this genetic region are also known to be associated with delay in development of AIDS in people infected by HIV [200].…”

Section: Infectious Diseasesmentioning

confidence: 99%

Molecular functions of human endogenous retroviruses in health and disease

Suntsova

Garazha

Ivanova

et al. 2015

Cell. Mol. Life Sci.

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Human endogenous retroviruses (HERVs) and related genetic elements form 504 distinct families and occupy ~8% of human genome. Recent success of high-throughput experimental technologies facilitated understanding functional impact of HERVs for molecular machinery of human cells. HERVs encode active retroviral proteins, which may exert important physiological functions in the body, but also may be involved in the progression of cancer and numerous human autoimmune, neurological and infectious diseases. The spectrum of related malignancies includes, but not limits to, multiple sclerosis, psoriasis, lupus, schizophrenia, multiple cancer types and HIV. In addition, HERVs regulate expression of the neighboring host genes and modify genomic regulatory landscape, e.g., by providing regulatory modules like transcription factor binding sites (TFBS). Indeed, recent bioinformatic profiling identified ~110,000 regulatory active HERV elements, which formed at least ~320,000 human TFBS. These and other peculiarities of HERVs might have played an important role in human evolution and speciation. In this paper, we focus on the current progress in understanding of normal and pathological molecular niches of HERVs, on their implications in human evolution, normal physiology and disease. We also review the available databases dealing with various aspects of HERV genetics.

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Section: Infectious Diseasesmentioning

confidence: 99%

Molecular functions of human endogenous retroviruses in health and disease

Suntsova

Garazha

Ivanova

et al. 2015

Cell. Mol. Life Sci.

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“…This attenuated varicella strain modestly boosts serum antibody and VZV-specific CD4 T-cells (16). It is thought to work via T-cells, as shingles risk correlates with HLA-region single nucleotide polymorphisms (17), and with age-related declines in VZV-specific CD4 T cells (18). The apparent correlation of efficacy with antibody responses could reflect CD4 T-cell help (19).…”

Section: Introductionmentioning

confidence: 99%

Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses

Jing

Laing

Dong

et al. 2016

The Journal of Immunology

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The alphaherpesvirinae subfamily includes HSV types 1 and 2 and the sequence-divergent pathogen varicella zoster virus (VZV). T cells, controlled by TCR and HLA molecules that tolerate limited epitope amino acid variation, might cross-react between these microbes. We show that memory PBMC expansion with either HSV or VZV enriches for CD4 T cell lines that recognize the other agent at the whole virus, protein, and peptide levels, consistent with bi-directional cross-reactivity. HSV-specific CD4 T cells recovered from HSV seronegative persons can be partially explained by such VZV cross-reactivity. HSV-1-reactive CD8 T cells also cross-react with VZV-infected cells, full-length VZV proteins, and VZV peptides, and kill VZV-infected dermal fibroblasts. Mono- and cross-reactive CD8 T cells use distinct TCRB CDR3 sequences. Cross-reactivity to VZV is reconstituted by cloning and expressing TCRA/TCRB receptors from T-cells that are initially isolated using HSV reagents. Overall, we define 13 novel CD4 and CD8 HSV-VZV cross-reactive epitopes and strongly imply additional cross-reactive peptide sets. Viral proteins can harbor both CD4 and CD8 HSV/VZV cross-reactive epitopes. Quantitative estimates of HSV/VZV cross-reactivity for both CD4 and CD8 T cells vary from 10-50%. Based on these findings, we hypothesize host herpesvirus immune history may influence the pathogenesis and clinical outcome of subsequent infections or vaccinations for related pathogens, and that cross-reactive epitopes and TCRs may be useful for multi-alphaherpesvirus vaccine design and adoptive cellular therapy.

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“…Using automated phenotyping algorithms, investigators have identified cases and controls for diseases of interest to replicate known phenotype-genotype associations and make novel discoveries, [12][13][14][15][16][17] potentially with decreased cost 18 and faster execution than traditional trials.…”

Section: Background and Significancementioning

confidence: 99%

Evaluating electronic health record data sources and algorithmic approaches to identify hypertensive individuals

Teixeira

Wei

Cronin

et al. 2016

Journal of the American Medical Informatics Association

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Objective: Phenotyping algorithms applied to electronic health record (EHR) data enable investigators to identify large cohorts for clinical and genomic research. Algorithm development is often iterative, depends on fallible investigator intuition, and is time-and labor-intensive. We developed and evaluated 4 types of phenotyping algorithms and categories of EHR information to identify hypertensive individuals and controls and provide a portable module for implementation at other sites. Materials and Methods: We reviewed the EHRs of 631 individuals followed at Vanderbilt for hypertension status. We developed features and phenotyping algorithms of increasing complexity. Input categories included International Classification of Diseases, Ninth Revision (ICD9) codes, medications, vital signs, narrative-text search results, and Unified Medical Language System (UMLS) concepts extracted using natural language processing (NLP). We developed a module and tested portability by replicating 10 of the best-performing algorithms at the Marshfield Clinic. Results: Random forests using billing codes, medications, vitals, and concepts had the best performance with a median area under the receiver operator characteristic curve (AUC) of 0.976. Normalized sums of all 4 categories also performed well (0.959 AUC). The best non-NLP algorithm combined normalized ICD9 codes, medications, and blood pressure readings with a median AUC of 0.948. Blood pressure cutoffs or ICD9 code counts alone had AUCs of 0.854 and 0.908, respectively. Marshfield Clinic results were similar. Conclusion: This work shows that billing codes or blood pressure readings alone yield good hypertension classification performance. However, even simple combinations of input categories improve performance. The most complex algorithms classified hypertension with excellent recall and precision.

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Genetic variation in the HLA region is associated with susceptibility to herpes zoster

Cited by 58 publications

References 27 publications

Molecular functions of human endogenous retroviruses in health and disease

Molecular functions of human endogenous retroviruses in health and disease

Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses

Evaluating electronic health record data sources and algorithmic approaches to identify hypertensive individuals

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