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Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):803-8. doi: 10.1073/pnas.0913491107. Epub 2009 Dec 22.

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

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  • 1Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, and Center for Human Immunology, National Institutes of Health, Bethesda, MD 20892, USA.


Limited responsiveness to IFN-alpha 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-alpha is determined directly by race. We compared baseline and IFN-alpha-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-alpha-stimulated gene expression compared to EAs. Although >200 genes reacted to IFN-alpha 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-alpha and bears no known relationship to IFN-alpha 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-alpha 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-alpha are unrelated to inherent racial differences in IFN-alpha 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.

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