title: Genetic variation in the HLA region is associated with susceptibility to herpes zoster.
abstract: Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.
authors.affiliation: 1] Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA [2] Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Crosslin
authors.affiliation: Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Carrell
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Burt
authors.affiliation: 1] Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA [2] Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Underwood
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Hanna
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Comstock
authors.affiliation: Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Baldwin
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
authors.forename: M
authors.initials: M
authors.lastname: de Andrade
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
authors.forename: I J
authors.initials: IJ
authors.lastname: Kullo
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Tromp
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kuivaniemi
authors.affiliation: The Sigfried and Janet Weis Center for Research, Geisinger Health System, Danville, PA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Borthwick
authors.affiliation: 1] Essentia Institute of Rural Health, Duluth, MN, USA [2] Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: McCarty
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA.
authors.forename: P L
authors.initials: PL
authors.lastname: Peissig
authors.affiliation: Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: K F
authors.initials: KF
authors.lastname: Doheny
authors.affiliation: Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Pugh
authors.affiliation: Divisions of General Internal Medicine and Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kho
authors.affiliation: Divisions of General Internal Medicine and Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pacheco
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Hayes
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, Pennsylvania State University, Pennsylvania, PA, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, Pennsylvania State University, Pennsylvania, PA, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Verma
authors.affiliation: Center for Systems Genomics, Department of Biochemistry and Molecular Biology, Pennsylvania State University, Pennsylvania, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Armstrong
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Stallings
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Carroll
authors.affiliation: 1] Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA [2] Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Crawford
authors.affiliation: Division of General Internal Medicine, University of Washington, Seattle, WA, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: Division of General Internal Medicine, University of Washington, Seattle, WA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine, New York, NY, USA.
authors.forename: E
authors.initials: E
authors.lastname: Bottinger
authors.affiliation: Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Li
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Keating
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Mirel
authors.affiliation: Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Carlson
authors.affiliation: Cincinnati Children's Hospital Medical Center/Boston's Children's Hospital (CCHMC/BCH), Boston, MA, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
authors.forename: E B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: 1] Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA [2] Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: G P
authors.initials: GP
authors.lastname: Jarvik
mesh_terms: D017668:Age of Onset; D000368:Aged; D000465:Algorithms; D015331:Cohort Studies; D057286:Electronic Health Records; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006562:Herpes Zoster / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D014645:Herpesvirus 3, Human / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D012189:Retrospective Studies; D014481:United States / Q000453:epidemiology / Q000208:ethnology
chemical_list: C080521:HCP5 long noncoding RNA, human; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated