Genomic scale analysis of racial impact on response to IFN-[alpha]

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-01, Vol.107 (2), p.803
• Main Authors: Pos, Zoltan, Selleri, Silvia, Spivey, Tara L, Wang, Jeanne K, Liu, Hui, Worschech, Andrea, Sabatino, Marianna, Monaco, Alessandro, Leitman, Susan F, Falus, Andras, Wang, Ena, Alter, Harvey J, Marincola, Francesco M
• Format: Article
• Language: English
• Subjects: African Americans; Comparative analysis; Gene expression; Genomics; Hepatitis; Polymorphism; Viruses
• ISSN: 0027-8424; 1091-6490

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-a 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...) 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. (ProQuest: ... denotes formulae/symbols omitted.)