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Genome-wide association study (GWAS) of human host factors influencing viral severity of herpes simplex virus type 2 (HSV-2)

Genes & Immunity volume 20, pages 112–120 (2019)Cite this article

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Abstract

Herpes simplex virus type 2 (HSV-2) is an incurable viral infection with severity ranging from asymptomatic to frequent recurrences. The viral shedding rate has been shown as a reproducible HSV-2 severity end point that correlates with lesion rates. We used a genome-wide association study (GWAS) to investigate the role of common human genetic variation in HSV-2 severity. We performed a GWAS on 223 HSV-2-positive participants of European ancestry. Severity was measured by viral shedding rate, as defined by the percent of days PCR+ for HSV-2 DNA over at least 30 days. Analyses were performed under linear regression models, adjusted for age, sex, and ancestry. There were no genome-wide significant (p < 5E-08) associations with HSV-2 viral shedding rate. The top nonsignificant SNP (rs75932292, p = 6.77E-08) associated with HSV-2 viral shedding was intergenic, with the nearest known biologically interesting gene (ABCA1) ~130 kbp downstream. Several other SNPs approaching significance were in or near genes with viral or neurological associations, including four SNPs in KIF1B. The current study is the first comprehensive genome-wide investigation of human genetic variation in virologic severity of established HSV-2 infection. However, no significant associations were observed with HSV-2 virologic severity, leaving the exact role of human variation in HSV-2 severity unclear.

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References

  1. Looker KJ, Magaret AS, Turner KME, Vickerman P, Gottlieb SL, Newman LM. Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. PLoS ONE. 2015;10:e114989

    Article  Google Scholar 

  2. Bradley H, Markowitz LE, Gibson T, McQuillan GM. Seroprevalence of herpes simplex virus types 1 and 2-United States, 1999-2010. J Infect Dis. 2013;209:325–33.

    Article  Google Scholar 

  3. Johnston C, Gottlieb SL, Wald A. Status of vaccine research and development of vaccines for herpes simplex virus. Vaccine . 2016;34:2948–52.

    Article  CAS  Google Scholar 

  4. Wald A, Zeh J, Selke S, Warren T, Ryncarz AJ, Ashley R, et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med. 2000;342:844–50.

    Article  CAS  Google Scholar 

  5. Kimberlin DW, Rouse DJ. Clinical practice. Genit herpes. N Engl J Med. 2004;350:1970–7.

    Article  CAS  Google Scholar 

  6. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep. 2002;51:1–78.

    Google Scholar 

  7. STD facts - genital herpes [Internet] [cited 31 Oct 2013]. http://www.cdc.gov/std/herpes/STDFact-herpes.html. Accessed 13 Jul 2016.

  8. Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350:11–20.

    Article  CAS  Google Scholar 

  9. Ross K, Johnston C, Wald A. Herpes simplex virus type 2 serological testing and psychosocial harm: a systematic review. Sex Transm Infect. 2011;87:594–600.

    Article  Google Scholar 

  10. Carney O, Ross E, Bunker C, Ikkos G, Mindel A. A prospective study of the psychological impact on patients with a first episode of genital herpes. Genitourin Med. 1994;70:40–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Sacks SL, Griffiths PD, Corey L, Cohen C, Cunningham A, Dusheiko GM, et al. HSV-2 transmission. Antivir Res. 2004;63 Suppl 1:S27–35.

    Article  CAS  Google Scholar 

  12. Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS Lond Engl. 2006;20:73–83.

    Article  Google Scholar 

  13. Gray RH, Li X, Wawer MJ, Serwadda D, Sewankambo NK, Wabwire-Mangen F, et al. Determinants of HIV-1 load in subjects with early and later HIV infections, in a general-population cohort of Rakai, Uganda. J Infect Dis. 2004;189:1209–15.

    Article  Google Scholar 

  14. Martin ET, Krantz E, Gottlieb SL, Magaret AS, Langenberg A, Stanberry L, et al. A pooled analysis of the effect of condoms in preventing HSV-2 acquisition. Arch Intern Med. 2009;169:1233–40.

    Article  Google Scholar 

  15. Magaret AS, Mujugira A, Hughes JP, Lingappa J, Bukusi EA, DeBruyn G, et al. Effect of condom use on per-act HSV-2 transmission risk in HIV-1, HSV-2-discordant couples. Clin Infect Dis Publ Infect Dis Soc Am. 2016;62:456–61.

    Google Scholar 

  16. Tronstein E, Johnston C, Huang M-L, Selke S, Magaret A, Warren T, et al. Genital shedding of herpes simplex virus among symptomatic and asymptomatic persons with HSV-2 infection. JAMA. 2011;305:1441–9.

    Article  CAS  Google Scholar 

  17. Magaret AS, Johnston C, Wald A. Use of the designation “shedder” in mucosal detection of herpes simplex virus DNA involving repeated sampling. Sex Transm Infect. 2009;85:270–5.

    Article  CAS  Google Scholar 

  18. Szpara ML, Gatherer D, Ochoa A, Greenbaum B, Dolan A, Bowden RJ, et al. Evolution and diversity in human herpes simplex virus genomes. J Virol. 2013;88:1209–27.

    Article  Google Scholar 

  19. Koelle DM, Magaret A, Warren T, Schellenberg GD, Wald A. APOE genotype is associated with oral herpetic lesions but not genital or oral herpes simplex virus shedding. Sex Transm Infect. 2010;86:202–6.

    Article  Google Scholar 

  20. Bochud P-Y, Magaret AS, Koelle DM, Aderem A, Wald A. Polymorphisms in TLR2 are associated with increased viral shedding and lesional rate in patients with genital herpes simplex virus Type 2 infection. J Infect Dis. 2007;196:505–9.

    Article  CAS  Google Scholar 

  21. Magaret A, Dong L, John M, Mallal SA, James I, Warren T, et al. HLA class I and II alleles, heterozygosity and HLA-KIR interactions are associated with rates of genital HSV shedding and lesions. Genes Immun. 2016;17:412–8.

    Article  CAS  Google Scholar 

  22. Zhang S-Y, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317:1522–7.

    Article  CAS  Google Scholar 

  23. Zhang S-Y, Casanova J-L. Inborn errors underlying herpes simplex encephalitis: from TLR3 to IRF3. J Exp Med. 2015;212:1342–3.

    Article  CAS  Google Scholar 

  24. Lafaille FG, Pessach IM, Zhang S-Y, Ciancanelli MJ, Herman M, Abhyankar A, et al. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature. 2012;491:769–73.

    Article  CAS  Google Scholar 

  25. Svensson A, Tunback P, Nordstrom I, Padyukov L, Eriksson K. Polymorphisms in Toll-like receptor 3 confer natural resistance to human herpes simplex virus type 2 infection. J Gen Virol. 2012;93(Pt_8):1717–24.

    Article  CAS  Google Scholar 

  26. Svensson A, Bergin A-MH, Löwhagen G-B, Tunbäck P, Bellner L, Padyukov L, et al. A 3′-untranslated region polymorphism in the TBX21 gene encoding T-bet is a risk factor for genital herpes simplex virus type 2 infection in humans. J Gen Virol. 2008;89:2262–8.

    Article  CAS  Google Scholar 

  27. Seppänen M, Lokki M-L, Lappalainen M, Hiltunen-Back E, Rovio AT, Kares S, et al. Mannose-binding lectin 2 gene polymorphism in recurrent herpes simplex virus 2 infection. Hum Immunol. 2009;70:218–21.

    Article  Google Scholar 

  28. Chatterjee K, Dandara C, Gyllensten U, van der Merwe L, Galal U, Hoffman M, et al. A fas gene polymorphism influences herpes simplex virus type 2 infection in South African women. J Med Virol. 2010;82:2082–6.

    Article  CAS  Google Scholar 

  29. Crosslin DR, Carrell DS, Burt A, Kim DS, Underwood JG, Hanna DS, et al. Genetic variation in the HLA region is associated with susceptibility to herpes zoster. Genes Immun. 2015;16:1–7.

    Article  CAS  Google Scholar 

  30. Hobbs MR, Jones BB, Otterud BE, Leppert M, Kriesel JD. Identification of a herpes simplex labialis susceptibility region on human chromosome 21. J Infect Dis. 2008;197:340–6.

    Article  Google Scholar 

  31. Kriesel JD, Jones BB, Matsunami N, Patel MK, St. Pierre CA, Kurt-Jones EA, et al. C21orf91 genotypes correlate with herpes simplex labialis (cold sore) frequency: description of a cold sore susceptibility gene. J Infect Dis. 2011;204:1654–62.

    Article  CAS  Google Scholar 

  32. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401.

    Article  CAS  Google Scholar 

  33. Fellay J, Ge D, Shianna KV, Colombo S, Ledergerber B, Cirulli ET, et al. Common genetic variation and the control of HIV-1 in humans. PLoS Genet. 2009;5:e1000791.

    Article  Google Scholar 

  34. Lingappa JR, Petrovski S, Kahle E, Fellay J, Shianna K, McElrath MJ. et al. Genomewide association study for determinants of HIV-1 acquisition and viral set point in HIV-1 serodiscordant couples with quantified virus exposure. PLoS ONE. 2011;6:e28632

    Article  CAS  Google Scholar 

  35. Petrovski S, Fellay J, Shianna KV, Carpenetti N, Kumwenda J, Kamanga G, et al. Common human genetic variants and HIV-1 susceptibility: a genome-wide survey in a homogeneous African population. AIDS Lond Engl. 2011;25:513–8.

    Article  Google Scholar 

  36. The 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015;526:68–74.

    Article  Google Scholar 

  37. Hook LM, Lubinski JM, Jiang M, Pangburn MK, Friedman HM. Herpes simplex virus type 1 and 2 glycoprotein C prevents complement-mediated neutralization induced by natural immunoglobulin M antibody. J Virol. 2006;80:4038–46.

    Article  CAS  Google Scholar 

  38. Bodzioch M, Orsó E, Klucken J, Langmann T, Böttcher A, Diederich W, et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet. 1999;22:347–51.

    Article  CAS  Google Scholar 

  39. Marcil M, Yu L, Krimbou L, Boucher B, Oram JF, Cohn JS, et al. Cellular cholesterol transport and efflux in fibroblasts are abnormal in subjects with familial HDL deficiency. Arterioscler Thromb Vasc Biol. 1999;19:159–69.

    Article  CAS  Google Scholar 

  40. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999;22:336–45.

    Article  CAS  Google Scholar 

  41. Zwarts KY, Clee SM, Zwinderman AH, Engert JC, Singaraja R, Loubser O, et al. ABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels. Clin Genet. 2002;61:115–25.

    Article  CAS  Google Scholar 

  42. Mujawar Z, Tamehiro N, Grant A, Sviridov D, Bukrinsky M, Fitzgerald ML. Mutation of the ATP cassette binding transporter A1 (ABCA1) C-terminus disrupts HIV-1 Nef binding but does not block the Nef enhancement of ABCA1 protein degradation. Biochemistry. 2010;49:8338–49.

    Article  CAS  Google Scholar 

  43. Cui HL, Grant A, Mukhamedova N, Pushkarsky T, Jennelle L, Dubrovsky L, et al. HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux. J Lipid Res. 2012;53:696–708.

    Article  CAS  Google Scholar 

  44. Jacob D, Hunegnaw R, Sabyrzyanova TA, Pushkarsky T, Chekhov VO, Adzhubei AA, et al. The ABCA1 domain responsible for interaction with HIV-1 Nef is conformational and not linear. Biochem Biophys Res Commun. 2014;444:19–23.

    Article  CAS  Google Scholar 

  45. Jennelle L, Hunegnaw R, Dubrovsky L, Pushkarsky T, Fitzgerald ML, Sviridov D, et al. HIV-1 protein Nef inhibits activity of ATP-binding cassette transporter A1 by targeting endoplasmic reticulum chaperone calnexin. J Biol Chem. 2014;289:28870–84.

    Article  CAS  Google Scholar 

  46. Sheng X-X, Sun Y-J, Zhan Y, Qu Y-R, Wang H-X, Luo M, et al. The LXR ligand GW3965 inhibits Newcastle disease virus infection by affecting cholesterol homeostasis. Arch Virol. 2016;161:2491–501.

    Article  CAS  Google Scholar 

  47. Bocchetta S, Maillard P, Yamamoto M, Gondeau C, Douam F, Lebreton S, et al. Up-regulation of the ATP-binding cassette transporter A1 inhibits hepatitis C virus infection. PLoS ONE. 2014;9:e92140.

    Article  Google Scholar 

  48. Matsuura K, Isogawa M, Tanaka Y. Host genetic variants influencing the clinical course of hepatitis B virus infection. J Med Virol. 2016;88:371–9.

    Article  CAS  Google Scholar 

  49. Malikov V, da Silva ES, Jovasevic V, Bennett G, de Souza Aranha Vieira DA, Schulte B, et al. HIV-1 capsids bind and exploit the kinesin-1 adaptor FEZ1 for inward movement to the nucleus. Nat Commun. 2015;6:6660.

    Article  CAS  Google Scholar 

  50. Wisner TW, Sugimoto K, Howard PW, Kawaguchi Y, Johnson DC. Anterograde transport of herpes simplex virus capsids in neurons by both separate and married mechanisms. J Virol. 2011;85:5919–28.

    Article  CAS  Google Scholar 

  51. Land A, Braakman I. Folding of the human immunodeficiency virus type 1 envelope glycoprotein in the endoplasmic reticulum. Biochimie. 2001;83:783–90.

    Article  CAS  Google Scholar 

  52. Miyakawa K, Sawasaki T, Matsunaga S, Tokarev A, Quinn G, Kimura H, et al. Interferon-induced SCYL2 limits release of HIV-1 by triggering PP2A-mediated dephosphorylation of the viral protein Vpu. Sci Signal. 2012;5:ra73.

    Article  Google Scholar 

  53. Ferreira M, Massano J. An updated review of Parkinson’s disease genetics and clinicopathological correlations. Acta Neurol Scand. 2016;135:273–84.

    Article  Google Scholar 

  54. Hara Y, Yanatori I, Ikeda M, Kiyokage E, Nishina S, Tomiyama Y, et al. Hepatitis C virus core protein suppresses mitophagy by interacting with parkin in the context of mitochondrial depolarization. Am J Pathol. 2014;184:3026–39.

    Article  CAS  Google Scholar 

  55. Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet. 2010;11:415–25.

    Article  CAS  Google Scholar 

  56. Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012;49:353–61.

    Article  CAS  Google Scholar 

  57. Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015;347:1436–41.

    Article  CAS  Google Scholar 

  58. Mujugira A, Huang M-L, Selke S, Drolette L, Magaret AS, Wald A. High rate of β-globin dna detection validates self-sampling in herpes simplex virus shedding studies. Sex Transm Dis. 2015;42:705–9.

    Article  CAS  Google Scholar 

  59. Siontis KCM, Patsopoulos NA, Ioannidis JPA. Replication of past candidate loci for common diseases and phenotypes in 100 genome-wide association studies. Eur J Hum Genet. 2010;18:832–7.

    Article  CAS  Google Scholar 

  60. Phipps W, Saracino M, Magaret A, Selke S, Remington M, Huang M-L, et al. Persistent genital herpes simplex virus-2 shedding years following the first clinical episode. J Infect Dis. 2011;203:180–7.

    Article  Google Scholar 

  61. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.

    Article  CAS  Google Scholar 

  62. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–9.

    Article  CAS  Google Scholar 

  63. Sham PC, Purcell SM. Statistical power and significance testing in large-scale genetic studies. Nat Rev Genet. 2014;15:335–46.

    Article  CAS  Google Scholar 

  64. Li M-X, Yeung JMY, Cherny SS, Sham PC. Evaluating the effective numbers of independent tests and significant p-value thresholds in commercial genotyping arrays and public imputation reference datasets. Hum Genet. 2012;131:747–56.

    Article  CAS  Google Scholar 

  65. Pe’er I, Yelensky R, Altshuler D, Daly MJ. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol. 2008;32:381–5.

    Article  Google Scholar 

  66. Purcell S, Cherny SS, Sham PC. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics. 2003;19:149–50.

    Article  CAS  Google Scholar 

  67. Shiina T, Hosomichi K, Inoko H, Kulski JK. The HLA genomic loci map: expression, interaction, diversity and disease. J Hum Genet. 2009;54:15–39.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Dr. Amalia Magaret for her statistical input. This work was supported by NIH grants P01 AI030731 (AW and DMK) and R01 AI094019 (DMK).

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Authors and Affiliations

  1. Institute for Genomic Medicine, Columbia University, New York, NY, 10032, USA

    Sarah E. Kleinstein, Patrick R. Shea & David B. Goldstein

  2. Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, 27708, USA

    Sarah E. Kleinstein

  3. Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, 27708, USA

    Andrew S. Allen

  4. Department of Medicine, University of Washington, Seattle, WA, 98195, USA

    David M. Koelle & Anna Wald

  5. Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

    David M. Koelle & Anna Wald

  6. Benaroya Research Institute, Seattle, WA, 98101, USA

    David M. Koelle

  7. Department of Laboratory Medicine, University of Washington, Seattle, WA, 98195, USA

    David M. Koelle

  8. Department of Global Health, University of Washington, Seattle, WA, 98195, USA

    David M. Koelle

  9. Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA

    Anna Wald

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  1. Sarah E. Kleinstein
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Correspondence to David B. Goldstein.

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Conflict of interest

SEK, PRS, and ASA declare that they have no conflict of interest. DMK is a consultant to Glaxo SmithKline and has research grants or contracts from Immune Design Corporation, Admedus Vaccines, Merck, and Sanofi Pasteur. DMK and AW are co-inventors on patents owned by the University of Washington. AW receives research funding from Genocea and Vical and is a consultant for Aicuris. DBG receives research funding from Janssen, AstraZeneca, Gilead, Biogen, and UCB, is a consultant for AstraZeneca, and holds a patent for IL28B findings.

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Kleinstein, S.E., Shea, P.R., Allen, A.S. et al. Genome-wide association study (GWAS) of human host factors influencing viral severity of herpes simplex virus type 2 (HSV-2). Genes Immun 20, 112–120 (2019). https://doi.org/10.1038/s41435-018-0013-4

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