Multi-ancestry fine mapping of interferon lambda and the outcome of acute hepatitis C virus infection
GENES AND IMMUNITY
Authors: Vergara, Candelaria; Duggal, Priya; Thio, Chloe L.; Valencia, Ana; O' Brien, Thomas R.; Latanich, Rachel; Timp, Winston; Johnson, Eric O.; Kral, Alex H.; Mangia, Alessandra; Goedert, James J.; Piazzola, Valeria; Mehta, Shruti H.; Kirk, Gregory D.; Peters, Marion G.; Donfield, Sharyne M.; Edlin, Brian R.; Busch, Michael P.; Alexander, Graeme; Murphy, Edward L.; Kim, Arthur Y.; Lauer, Georg M.; Chung, Raymond T.; Cramp, Matthew E.; Cox, Andrea L.; Khakoo, Salim, I; Rosen, Hugo R.; Alric, Laurent; Wheelan, Sarah J.; Wojcik, Genevieve L.; Thomas, David L.; Taub, Margaret A.
Abstract
Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/Delta G) 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 Delta G/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and Delta G/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 x 10(-04)) and rs8099917 (P value = 5.5 x 10(-04)). In the European ancestry group, individuals with the haplotype rs368234815 Delta G/rs4803221C were 1.7x more likely to clear than those with the rs368234815 Delta G/rs4803221G haplotype (P value = 3.6 x 10(-05)). For another nearby SNP, the haplotype of rs368234815 Delta G/rs8099917T was associated with HCV clearance compared to rs368234815 Delta G/rs8099917G (OR: 1.6, P value = 1.8 x 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.
Influenza-Induced Interferon Lambda Response Is Associated With Longer Time to Delivery Among Pregnant Kenyan Women
FRONTIERS IN IMMUNOLOGY
Authors: Seiler, Christof; Bayless, Nicholas L.; Vergara, Rosemary; Pintye, Jillian; Kinuthia, John; Osborn, Lusi; Matemo, Daniel; Richardson, Barbra A.; John-Stewart, Grace; Holmes, Susan; Blish, Catherine A.
Abstract
Specific causes of preterm birth remain unclear. Several recent studies have suggested that immune changes during pregnancy are associated with the timing of delivery, yet few studies have been performed in low-income country settings where the rates of preterm birth are the highest. We conducted a retrospective nested case-control evaluation within a longitudinal study among HIV-uninfected pregnant Kenyan women. To characterize immune function in these women, we evaluated unstimulated and stimulated peripheral blood mononuclear cells in vitro with the A/California/2009 strain of influenza to understand the influenza-induced immune response. We then evaluated transcript expression profiles using the Affymetrix Human GeneChip Transcriptome Array 2.0. Transcriptional profiles of sufficient quality for analysis were obtained from 54 women; 19 of these women delivered 37 weeks. The median time to birth from sample collection was 13 weeks. No transcripts were significantly associated with preterm birth in a case-control study of matched term and preterm birth (n = 42 women). In the influenza-stimulated samples, expression of IFNL1 was associated with longer time to delivery-the amount of time between sample collection and delivery (n = 54 women). A qPCR analysis confirmed that influenza-induced IFNL expression was associated with longer time to delivery. These data indicate that during pregnancy, ex vivo influenza stimulation results in altered transcriptional response and is associated with time to delivery in cohort of women residing in an area with high preterm birth prevalence.