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

A Correction to this article was published on 23 November 2020

This article has been updated

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.

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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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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