Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection
Candelaria Vergara
(1)
,
Priya Duggal
(1)
,
Chloe Thio
(1)
,
Ana Valencia
(1, 2)
,
Thomas O’brien
(3)
,
Rachel Latanich
(1)
,
Winston Timp
(1)
,
Eric Johnson
(4)
,
Alex Kral
(4)
,
Alessandra Mangia
(5)
,
James Goedert
(3)
,
Valeria Piazzola
(5)
,
Shruti Mehta
(1)
,
Gregory Kirk
(1)
,
Marion Peters
(6)
,
Sharyne Donfield
(7)
,
Brian Edlin
(8)
,
Michael Busch
(6)
,
Graeme Alexander
(9)
,
Edward Murphy
(6)
,
Arthur Kim
(10)
,
Georg Lauer
(10)
,
Raymond Chung
(10)
,
Matthew Cramp
,
Andrea Cox
(1)
,
Salim Khakoo
(11)
,
Hugo Rosen
(12)
,
Laurent Alric
(13)
,
Sarah Wheelan
(1)
,
Genevieve Wojcik
(1)
,
David Thomas
(1)
,
Margaret Taub
(1)
1
JHU -
Johns Hopkins University
2 UPB - Universidad Pontificia Bolivariana
3 NIH - National Institutes of Health [Bethesda, MD, USA]
4 RTI International - Research Triangle Institute International
5 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo]
6 UC San Francisco - University of California [San Francisco]
7 UNC - University of North Carolina [Chapel Hill]
8 CDC - Centers for Disease Control and Prevention [Atlanta]
9 Royal Free Hospital [London, UK]
10 Massachusetts General Hospital [Boston]
11 University of Southampton
12 University of Colorado [Colorado Springs]
13 PHARMA-DEV - Pharmacochimie et Biologie pour le Développement
2 UPB - Universidad Pontificia Bolivariana
3 NIH - National Institutes of Health [Bethesda, MD, USA]
4 RTI International - Research Triangle Institute International
5 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo]
6 UC San Francisco - University of California [San Francisco]
7 UNC - University of North Carolina [Chapel Hill]
8 CDC - Centers for Disease Control and Prevention [Atlanta]
9 Royal Free Hospital [London, UK]
10 Massachusetts General Hospital [Boston]
11 University of Southampton
12 University of Colorado [Colorado Springs]
13 PHARMA-DEV - Pharmacochimie et Biologie pour le Développement
Candelaria Vergara
- Fonction : Auteur
- PersonId : 795289
- ORCID : 0000-0003-3297-8057
Priya Duggal
- Fonction : Auteur
- PersonId : 817631
- ORCID : 0000-0001-5809-2081
Ana Valencia
- Fonction : Auteur
- PersonId : 817630
- ORCID : 0000-0001-9133-218X
Winston Timp
- Fonction : Auteur
- PersonId : 821700
- ORCID : 0000-0003-2083-6027
Eric Johnson
- Fonction : Auteur
- PersonId : 776958
- ORCID : 0000-0002-8870-1949
Alessandra Mangia
- Fonction : Auteur
- PersonId : 817627
- ORCID : 0000-0002-2600-3555
Michael Busch
- Fonction : Auteur
- PersonId : 764686
- ORCID : 0000-0002-1446-125X
Graeme Alexander
- Fonction : Auteur
- PersonId : 817629
- ORCID : 0000-0002-9713-1394
Georg Lauer
- Fonction : Auteur
- PersonId : 807198
- ORCID : 0000-0002-9792-4271
- IdRef : 223399175
Matthew Cramp
- Fonction : Auteur
Genevieve Wojcik
- Fonction : Auteur
- PersonId : 795288
- ORCID : 0000-0001-7206-8088
Résumé
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.