Genomic scale analysis of racial impact on response to IFN-α

Z Pos, S Selleri, TL Spivey, JK Wang… - Proceedings of the …, 2010 - National Acad Sciences
Z Pos, S Selleri, TL Spivey, JK Wang, H Liu, A Worschech, M Sabatino, A Monaco
Proceedings of the National Academy of Sciences, 2010National Acad Sciences
Limited responsiveness to IFN-α in hepatitis C virus (HCV)-infected African-Americans
compared to European Americans (AAs vs. EAs) hinders the management of HCV. Here, we
studied healthy non-HCV-infected AA and EA subjects to test whether immune cell response
to IFN-α is determined directly by race. We compared baseline and IFN-α-induced signal
transducer and activator of transcription (STAT)-1, STAT-2, STAT-3, STAT-4, and STAT-5
protein and phosphorylation levels in purified T cells, global transcription, and a …
Limited responsiveness to IFN-α in hepatitis C virus (HCV)-infected African-Americans compared to European Americans (AAs vs. EAs) hinders the management of HCV. Here, we studied healthy non-HCV-infected AA and EA subjects to test whether immune cell response to IFN-α is determined directly by race. We compared baseline and IFN-α-induced signal transducer and activator of transcription (STAT)-1, STAT-2, STAT-3, STAT-4, and STAT-5 protein and phosphorylation levels in purified T cells, global transcription, and a genomewide single-nucleotide polymorphism (SNP) profile of healthy AA and EA blood donors. In contrast to HCV-infected individuals, healthy AAs displayed no evidence of reduced STAT activation or IFN-α-stimulated gene expression compared to EAs. Although >200 genes reacted to IFN-α treatment, race had no impact on any of them. The only gene differentially expressed by the two races (NUDT3, P < 10−7) was not affected by IFN-α and bears no known relationship to IFN-α signaling or HCV pathogenesis. Genomewide analysis confirmed the self-proclaimed racial attribution of most donors, and numerous race-associated SNPs were identified within loci involved in IFN-α signaling, although they clearly did not affect responsiveness in the absence of HCV. We conclude that racial differences observed in HCV-infected patients in the responsiveness to IFN-α are unrelated to inherent racial differences in IFN-α signaling and more likely due to polymorphisms affecting the hosts’ response to HCV, which in turn may lead to a distinct disease pathophysiology responsible for altered IFN signaling and treatment response.
National Acad Sciences