Abstract
The immune response to hepatitis B vaccination differs greatly among individuals, with 5–10% of healthy people failing to produce protective levels of antibodies. Several factors have been implicated in determining this response, chiefly individual genetic variation and age. Aiming to identify genes involved in the response to hepatitis B vaccination, a two-stage investigation of 6091 single-nucleotide polymorphisms (SNPs) in 914 immune genes was performed in an Indonesian cohort of 981 individuals showing normal levels of anti-HBs versus 665 individuals displaying undetectable levels of anti-HBs 18 months after initial dose of the vaccine. Of 275 SNPs identified in the first stage (476 normal/372 nonresponders) with P<0.05, significant associations were replicated for 25 polymorphisms in 15 genes (503 normal/295 nonresponders). We validated previous findings (HLA-DRA, rs5000563, P-value combined=5.57 × 10−10; OR (95%CI)=0.61 (0.52–0.71)). In addition, we detected a new association outside of the human leukocyte antigen loci region that passed correction for multiple testing. This SNP is in the 3′ downstream region of FOXP1, a transcription factor involved in B-cell development (P-value combined=9.2 × 10−6; OR (95%CI)=1.38 (1.2–1.6)).These findings might help to understand the biological reasons behind vaccine failure and other aspects of variation in the immune responses of healthy individuals.
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References
The World Health Organization (2008). Hepatitis B. Fact sheet no. 204. Fact Sheet Revised August. World Health Organization: Geneva.
Lavanchy D . Worldwide epidemiology of HBV infection, disease burden, and vaccine prevention. J Clin Virol 2005; 34 (Suppl 1) 1: S1–S3.
Zuckerman JN . Protective efficacy, immunotherapeutic potential, and safety of hepatitis B vaccines. J Med Virol 2006; 78: 169–177.
Boland GJ, van Bommel T, Rulos-van den Berg A, van den Berg JP, van Loon AM, van Hattum J . The efficacy of a two-dose hepatitis B vaccination scheme. Adv Exp Med Biol 2003; 531: 185–190.
Hollinger FB . Factors influencing the immune response to hepatitis B vaccine, booster dose guidelines, and vaccine protocol recommendations. Am J Med 1989; 87: 36S–40S.
Alper CA, Kruskall MS, Marcus-Bagley D, Craven DE, Katz AJ, Brink SJ et al. Genetic prediction of nonresponse to hepatitis B vaccine. N Engl J Med 1989; 321: 708–712.
Hohler T, Reuss E, Evers N, Dietrich E, Rittner C, Freitag CM et al. Differential genetic determination of immune responsiveness to hepatitis B surface antigen and to hepatitis A virus: a vaccination study in twins. Lancet 2002; 360: 991–995.
Milich DR, Leroux-Roels GG . Immunogenetics of the response to HBsAg vaccination. Autoimmun Rev 2003; 2: 248–257.
Newport MJ, Goetghebuer T, Weiss HA, Whittle H, Siegrist CA, Marchant A . Genetic regulation of immune responses to vaccines in early life. Genes Immun 2004; 5: 122–129.
McDermott AB, Zuckerman JN, Sabin CA, Marsh SG, Madrigal JA . Contribution of human leukocyte antigens to the antibody response to hepatitis B vaccination. Tissue Antigens 1997; 50: 8–14.
Desombere I, Willems A, Leroux-Roels G . Response to hepatitis B vaccine: multiple HLA genes are involved. Tissue Antigens 1998; 51: 593–604.
Yucesoy B, Sleijffers A, Kashon M, Garssen J, de Gruijl FR, Boland GJ et al. IL-1beta gene polymorphisms influence hepatitis B vaccination. Vaccine 2002; 20: 3193–3196.
Frodsham AJ, Zhang L, Dumpis U, Taib NA, Best S, Durham A et al. Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence. Proc Natl Acad Sci USA 2006; 103: 9148–9153.
Thomas HC, Foster GR, Sumiya M, McIntosh D, Jack DL, Turner MW et al. Mutation of gene of mannose-binding protein associated with chronic hepatitis B viral infection. Lancet 1996; 348: 1417–1419.
Hohler T, Wunschel M, Gerken G, Schneider PM, Meyer zum Buschenfelde KH, Rittner C . No association between mannose-binding lectin alleles and susceptibility to chronic hepatitis B virus infection in German patients. Exp Clin Immunogenet 1998; 15: 130–133.
Thio CL, Mosbruger T, Astemborski J, Greer S, Kirk GD, O′Brien SJ et al. Mannose binding lectin genotypes influence recovery from hepatitis B virus infection. J Virol 2005; 79: 9192–9196.
Hennig BJ, Fielding K, Broxholme J, Diatta M, Mendy M, Moore C et al. Host genetic factors and vaccine-induced immunity to hepatitis B virus infection. PLoS ONE 2008; 3: e1898.
Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E, Ballinger DG et al. Whole-genome patterns of common DNA variation in three human populations. Science 2005; 307: 1072–1079.
McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 2008; 9: 356–369.
Balding DJ . A tutorial on statistical methods for population association studies. Nat Rev Genet 2006; 7: 781–791.
Wang C, Tang J, Song W, Lobashevsky E, Wilson CM, Kaslow RA . HLA and cytokine gene polymorphisms are independently associated with responses to hepatitis B vaccination. Hepatology 2004; 39: 978–988.
Hohler T, Meyer CU, Notghi A, Stradmann-Bellinghausen B, Schneider PM, Starke R et al. The influence of major histocompatibility complex class II genes and T-cell Vbeta repertoire on response to immunization with HBsAg. Hum Immunol 1998; 59: 212–218.
Hsu HY, Chang MH, Ho HN, Hsieh RP, Lee SD, Chen DS et al. Association of HLA-DR14-DR52 with low responsiveness to hepatitis B vaccine in Chinese residents in Taiwan. Vaccine 1993; 11: 1437–1440.
Stenzel A, Lu T, Koch WA, Hampe J, Guenther SM, De La Vega FM et al. Patterns of linkage disequilibrium in the MHC region on human chromosome 6p. Hum Genet 2004; 114: 377–385.
Kamatani Y, Wattanapokayakit S, Ochi H, Kawaguchi T, Takahashi A, Hosono N et al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet 2009; 41: 591–595.
Hu H, Wang B, Borde M, Nardone J, Maika S, Allred L et al. Foxp1 is an essential transcriptional regulator of B cell development. Nat Immunol 2006; 7: 819–826.
Cella M, Dohring C, Samaridis J, Dessing M, Brockhaus M, Lanzavecchia A et al. A novel inhibitory receptor (ILT3) expressed on monocytes, macrophages, and dendritic cells involved in antigen processing. J Exp Med 1997; 185: 1743–1751.
Colonna M, Nakajima H, Cella M . A family of inhibitory and activating Ig-like receptors that modulate function of lymphoid and myeloid cells. Semin Immunol 2000; 12: 121–127.
Daheshia M, Friend DS, Grusby MJ, Austen KF, Katz HR . Increased severity of local and systemic anaphylactic reactions in gp49B1-deficient mice. J Exp Med 2001; 194: 227–234.
Chang CC, Ciubotariu R, Manavalan JS, Yuan J, Colovai AI, Piazza F et al. Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol 2002; 3: 237–243.
Bissell DM . Chronic liver injury, TGF-beta, and cancer. Exp Mol Med 2001; 33: 179–190.
Hashimoto K, Mori N, Tamesa T, Okada T, Kawauchi S, Oga A et al. Analysis of DNA copy number aberrations in hepatitis C virus-associated hepatocellular carcinomas by conventional CGH and array CGH. Mod Pathol 2004; 17: 617–622.
Plenge RM, Seielstad M, Padyukov L, Lee AT, Remmers EF, Ding B et al. TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide study. N Engl J Med 2007; 357: 1199–1209.
European Consensus Group on hepatitis B immunity. Are booster immunizations needed for lifelong hepatitis B immunity? Lancet 2000; 355: 561–565.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
Patterson N, Price AL, Reich D . Population structure and eigenanalysis. PLoS Genet 2006; 2: e190.
Langmore JP . Rubicon Genomics Inc. Pharmacogenomics 2002; 3: 557–560.
Elston RC, Lin D, Zheng G . Multistage sampling for genetic studies. Annu Rev Genomics Hum Genet 2007; 8: 327–342.
Skol AD, Scott LJ, Abecasis GR, Boehnke M . Optimal designs for two-stage genome-wide association studies. Genet Epidemiol 2007; 31: 776–788.
Thomas PD, Campbell MJ, Kejariwal A, Mi H, Karlak B, Daverman R et al. PANTHER: a library of protein families and subfamilies indexed by function. Genome Res 2003; 13: 2129–2141.
Oliphant A, Barker DL, Stuelpnagel JR, Chee MS . BeadArray technology: enabling an accurate, cost-effective approach to high-throughput genotyping. Biotechniques 2002 (Suppl 56–58, 60–61), PMID: 12083399.
Skipper L, Li Y, Bonnard C, Pavanni R, Yih Y, Chua E et al. Comprehensive evaluation of common genetic variation within LRRK2 reveals evidence for association with sporadic Parkinson's disease. Hum Mol Genet 2005; 14: 3549–3556.
Acknowledgements
We are grateful to our colleagues at the Genome Institute of Singapore, Heng Khai Koon and Jason Ong for genotyping, Boon Yeong Goh for sample management and Frans Verhoef for maintaining the GISSNP database. We also thank Dr Jan van Hattum, Jan and Annemarie van den Berg for their dedication and enthusiasm in arranging and performing all the vaccinations. Finally, we thank Dr Sangkot Marzuki, Dr Herawati Sudoyo and Dr David Mulyono of the Eijkman Institute for Molecular Biology in Jakarta, Indonesia, for their invaluable advice, insights and assistance with this project. This work was supported by funding from the Agency for Science & Technology and Research of Singapore (A*STAR) and the US Defense Advanced Research Projects Agency Contract Number W911QY-06-C-0085. FEMF was supported by a Dr Saal van Zwanenberg fellowship.
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Davila, S., Froeling, F., Tan, A. et al. New genetic associations detected in a host response study to hepatitis B vaccine. Genes Immun 11, 232–238 (2010). https://doi.org/10.1038/gene.2010.1
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DOI: https://doi.org/10.1038/gene.2010.1
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