Genetic variation associated with the susceptibility to herpes zoster in the eMERGE Network. D. Crosslin1,2, D. Carrell3, E. Baldwin3, M. de Andrade4, I. Kullo5, G. Tromp6, H. Kuivaniemi6, K. Doheny7, E. Pugh7, A. Kho8, M. Hayes9, M. Ritchie10, S. Verma10, G. Armstrong10, A. Saip11, J. Denny11, D. Crawford12,13, P. Crane14, S. Mukherjee14, E. Bottinger15, T. Manolio16, R. Li16, A. Burt1, D. Kim1,2, B. Keating17, D. Mirel18, E. Larson3, C. Carlson19, G. Jarvik1,2, The electronic Medical Records and Genomics (eMERGE) Network 1) Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA; 2) Department of Genome Sciences, University of Washington, Seattle, WA; 3) Group Health Research Institute, Center for Health Studies, Seattle, WA; 4) Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN; 5) Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN; 6) Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA; 7) Center for Inherited Disease Research, Johns Hopkins University, Baltimore, MD; 8) Divisions of General Internal Medicine and Preventive Medicine, Northwestern University, Chicago, IL; 9) Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL; 10) Center for Systems Genomics, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA; 11) Department of Biomedical Informatics, Vanderbilt University, Nashville, TN; 12) Center for Human Genetics Research, Vanderbilt University, Nashville, TN; 13) Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN; 14) Division of General Internal Medicine, University of Washington, Seattle, WA; 15) The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine Mount Sinai, New York, NY; 16) Office of Population Genomics, National Human Genome Research Institute, Bethesda, MD; 17) Center for Applied Genomics. Children's Hospital of Philadelphia, Philadelphia, PA; 18) Program in Medical & Population Genetics, Broad Institute of Harvard & MIT, Cambridge, MA; 19) Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA.

   Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox in youth, but can remain latent in nerve tissues for many years and reemerge as shingles for unknown reasons. Two-thirds of shingles cases are older than 60 years. Shingles presents as painful, usual unilateral vesicular skin infection leaving 10%-18% of those affected with chronic post-herpetic neuralgia. Annual U.S. costs of incident infections are $1.1 billion. Assessment of genetic variation has the potential to inform inter-individual variation in susceptibility to VZV reemergence. While a vaccine is now available, it is only 50% effective and is not widely used. Polymorphisms of the immune system that predicts risk of VZV re-activation could suggest the basis for latency and aid clinical decision-making as well as informing insight into the immune biological process of infection and clearance. We performed a joint and site-stratified genome-wide association analyses to identify variants associated with infection susceptibility to VZV in subjects from the electronic Medical Records and Genomics (eMERGE) Network. The eMERGE Network comprises a multi-ethnic cohort of roughly 50,000 individuals linked to electronic medical records for phenotype mining from nine participating sites in the US. Early joint association results using logistic regression from four eMERGE sites (1,684 cases, 12,088 controls) suggest two genomic regions of interest reaching genome-wide significance (P-value = 1.0x10-8). One region on chromosome 14 represents variants found in the gene encoding signal recognition particle 54kDa (SRP54). This signal recognition particle binds to the signal sequence of presecretory proteins as they emerge from the ribosome. On chromosome 18, there are variants found in the region representing the gene zinc finger and BTB domain containing 7C (ZBTB7C). The relationship of its function as a tumor suppressor gene with VZV infection susceptibility is not clear, but is currently being assessed. More data are pending from the remaining eMERGE sites, which will enhance power. We will also assess genomic association using survival analysis with endpoints of loss to follow-up, date of death, or first zoster reactivation for unvaccinated subjects. We aim to robustly identify variants associated with infection susceptibility to VZV.

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