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

ABSTRACT: 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.

SUBMITTER: Pos Z

PROVIDER: S-EPMC2818915 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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

Pos Zoltan Z Selleri Silvia S Spivey Tara L TL Wang Jeanne K JK Liu Hui H Worschech Andrea A Sabatino Marianna M Monaco Alessandro A Leitman Susan F SF Falus Andras A Wang Ena E Alter Harvey J HJ Marincola Francesco M FM

Proceedings of the National Academy of Sciences of the United States of America 20091222 2

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 ...[more]

PMID: 20080756

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Project description:Abstract Objectives Viral respiratory infections cause considerable morbidity and economic loss. While rhinoviruses (RV) typically cause little more than the common cold, they can produce severe infections and disease exacerbations in susceptible individuals, such as those with asthma. Variations in the regulation of key antiviral cytokines, particularly type I interferon (IFN‐α and IFN‐β), may contribute to RV susceptibility. To understand this variability, we compared the transcriptomes of high and low type I IFN producers. Methods Blood mononuclear cells from 238 individuals with or without asthma were cultured in the presence or absence of RV. Those samples demonstrating high or low RV‐stimulated IFN‐α production (N = 75) underwent RNA‐sequencing. Results Gene expression patterns were similar in samples from healthy participants and those with asthma. At baseline, the high IFN‐α producer group showed higher expression of genes associated with plasmacytoid dendritic cells, the innate immune response and vitamin D activation, but lower expression of oxidative stress pathways than the low IFN‐α producer group. After RV stimulation, the high IFN‐α producer group showed higher expression of genes found in immune response biological pathways and lower expression of genes linked to developmental and catabolic processes when compared to the low IFN‐α producer group. Conclusions These differences suggest that the high IFN‐α group has a higher level of immune system readiness, resulting in a more intense and perhaps more focussed pathogen‐specific immune response. These results contribute to a better understanding of the variability in type I IFN production between individuals. For this study on variation in IFN‐α production, samples from high and low IFN‐α producers were selected and their transcriptomes were compared before and after rhinovirus stimulation. Differential gene expression analysis revealed immunological differences at baseline prior to stimulus and differences in antiviral response and expression of genes related to cellular functions.

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

Publications

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

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