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Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection

Genes & Immunity volume 21, pages 348–359 (2020)Cite this article

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Abstract

Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/ΔG) polymorphism. We fine-mapped this region to detect possible causal variants that may contribute to HCV clearance. First, we performed sequencing of IFNL1-IFNL4 region in 64 individuals sampled according to rs368234815 genotype: TT/clearance (N = 16) and ΔG/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and ΔG/clearance (N = 14) (discordant). 25 SNPs had a difference in counts of alternative allele >5 between clearance and persistence individuals. Then, we evaluated those markers in an association analysis of HCV clearance conditioning on rs368234815 in two groups of European (692 clearance/1 025 persistence) and African ancestry (320 clearance/1 515 persistence) individuals. 10/25 variants were associated (P < 0.05) in the conditioned analysis leaded by rs4803221 (P value = 4.9 × 10−04) and rs8099917 (P value = 5.5 × 10−04). In the European ancestry group, individuals with the haplotype rs368234815ΔG/rs4803221C were 1.7× more likely to clear than those with the rs368234815ΔG/rs4803221G haplotype (P value = 3.6 × 10−05). For another nearby SNP, the haplotype of rs368234815ΔG/rs8099917T was associated with HCV clearance compared to rs368234815ΔG/rs8099917G (OR: 1.6, P value = 1.8 × 10−04). We identified four possible causal variants: rs368234815, rs12982533, rs10612351 and rs4803221. Our results suggest a main signal of association represented by rs368234815, with contributions from rs4803221, and/or nearby SNPs including rs8099917.

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Fig. 1: HCV clearance and rs368234815 marker.
Fig. 2: Schematic representation of the fine mapping analysis performed in this study.
Fig. 3: Genetic structure of the IFNL locus, amplified fragments used for targeted sequencing, and two main variants associated in prior GWAS studies with HCV clearance (rs12979860 and rs368234815).
Fig. 4: Results of the analysis conditioned on rs368234815 and LD patterns of the top associated variants from that analysis.

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Change history

  • 12 November 2020

    The original version of this Article contained an error in the author name for Thomas R. O’Brien. The family name contained a space and incorrectly appeared as O’ Brien. This has now been corrected in both the PDF and HTML versions of the Article.

  • 23 November 2020

    A Correction to this paper has been published: https://doi.org/10.1038/s41435-020-00119-z

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Acknowledgements

We thank the participants of the study. We also thank Cristian Velarde for the graphic design of the figures.

Funding

R01-013324, 2R01-AI148049, DA-04334, U19-AI088791, HHSN261200800001E, U01-AI35042, U01-AI35043, U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35004, U01-AI31834, U01-AI34994, U01-AI34989, U01-AI34993, U01-AI42590, U01-HD32632, R01-HL076902, R01-HD-41224, R01-AI148049-21, R21AI139012, U19-AI082630, U01-AI131314, R01-DA033541, U19-AI066345, DA12568, DA036297, R01-DA09532, R01-DA11860, N02CP91027, H79TI12103, R01-DA16159, R01-DA21550, UL1 RR024996.

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Authors and Affiliations

  1. Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA

    Candelaria Vergara, Priya Duggal, Shruti H. Mehta, Gregory D. Kirk, Sarah J. Wheelan, Genevieve L. Wojcik & Margaret A. Taub

  2. Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    Chloe L. Thio, Ana Valencia, Rachel Latanich, Winston Timp, Andrea L. Cox, Sarah J. Wheelan & David L. Thomas

  3. Universidad Pontificia Bolivariana, Medellin, Colombia

    Ana Valencia

  4. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Thomas R. O’Brien & James J. Goedert

  5. RTI International, Research Triangle Park, NC, USA

    Eric O. Johnson & Alex H. Kral

  6. Liver Unit IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy

    Alessandra Mangia & Valeria Piazzola

  7. Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Francisco, CA, USA

    Marion G. Peters

  8. Rho, Inc., Chapel Hill, NC, USA

    Sharyne M. Donfield

  9. Centers for Disease Control and Prevention, Atlanta, GA, USA

    Brian R. Edlin

  10. University of California San Francisco and Vitalant Research Institute, San Francisco, CA, USA

    Michael P. Busch & Edward L. Murphy

  11. University College London Institute for Liver and Digestive Health, The Royal Free Hospital, London, UK

    Graeme Alexander

  12. Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Arthur Y. Kim

  13. Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Georg M. Lauer & Raymond T. Chung

  14. South West Liver Unit, Plymouth, PL6 8DH, UK

    Matthew E. Cramp

  15. University of Southampton, Southampton General Hospital, Southampton, UK

    Salim I. Khakoo

  16. University of Colorado, Aurora, CO, USA

    Hugo R. Rosen

  17. Department of Internal Medicine and Digestive Diseases, Centre Hospitalier Universitaire Rangueil, UMR 152, Institut de Recherche pour le Développement Toulouse 3 University, Toulouse, France

    Laurent Alric

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  1. Candelaria Vergara
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Correspondence to Candelaria Vergara.

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Vergara, C., Duggal, P., Thio, C.L. et al. Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection. Genes Immun 21, 348–359 (2020). https://doi.org/10.1038/s41435-020-00115-3

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