Genomic scale analysis of racial impact on response to IFN-alpha.
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.
Pos
Zoltan
Z
Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, and Center for Human Immunology, National Institutes of Health, Bethesda, MD 20892, USA. posz@cc.nih.gov
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
D000328:Adult; D044383:Black People / Q000235:genetics; D017124:Conserved Sequence; D005260:Female; D005434:Flow Cytometry; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015894:Genome, Human; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology; D006526:Hepatitis C / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012367:RNA, Viral / Q000235:genetics; D044469:Racial Groups / Q000235:genetics*; D012016:Reference Values; D015398:Signal Transduction / Q000235:genetics; D044465:White People / Q000235:genetics; D001741:Black or African American
D016898:Interferon-alpha; D012367:RNA, Viral