Myxovirus-1 and protein kinase haplotypes and fibrosis in chronic hepatitis C virus.
Candidate genes, including myxovirus resistance-1 (Mx1), protein kinase (PKR), transforming growth factor-beta1 (TGF-beta), interleukin-10 (IL-10), and interferon-gamma (IFN-gamma), were evaluated for associations with liver fibrosis in 374 treatment-naive patients with genotype-1 chronic HCV infection [194 Caucasian Americans (CAs) and 180 African Americans (AAs)], using a genetic haplotype approach. Among the 18 haplotypes that occurred with a frequency >or=5% in the cohort overall, the Mx1-(-123C)-(+6886A)-(+19820G(379V))-(+38645T) (abbreviated Mx1-CAGT), and PKR-(+110T)-(+7949G)-(+13846A)-(+22937T)-(+40342T) (abbreviated PKR-TGATT) haplotypes were independently associated with less severe hepatic fibrosis (Ishak >or= 3 versus <3). These associations persisted after adjustment for potential confounders such as alcohol use, sex, age (which is strongly correlated with the estimated duration of HCV infection [Spearman's correlation coefficient (r(s)) = 0.6)], and race (for Mx1-CAGT: OR = 0.33; 95% CI: 0.16-0.68; P = 0.0027; and for PKR-TGATT: OR = 0.56; 95% CI: 0.32-0.98; P = 0.0405). Population structure was evaluated using the structured association method using data from 161 ancestry-informative markers and did not affect our findings. We used an independent cohort of 34 AA and 160 CA in an attempt to validate our findings, although notable differences were found in the characteristics of the two patient groups. Although we observed a similar protective trend for the Mx1-CAGT haplotype in the validation set, the association was not statistically significant.


CONCLUSIONS
In addition to other factors, polymorphisms in cytokine genes may play a role in the progression of HCV-related fibrosis; however, further studies are needed.
Yee
Leland J
LJ
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. YeeL@edc.pitt.edu
Tang
Yong-Ming
YM
Kleiner
David E
DE
Wang
Dai
D
Im
KyungAh
K
Wahed
Abdus
A
Tong
Xiaomei
X
Rhodes
Shannon
S
Su
Xiaowen
X
Whelan
R Margaret
RM
Fontana
Robert J
RJ
Ghany
Marc G
MG
Borg
Brian
B
Liang
T Jake
TJ
Yang
Huiying
H
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D044383:Black People; D002874:Chromosome Mapping; D017931:DNA Primers; D004351:Drug Resistance; D024882:Drug Resistance, Viral; D005260:Female; D019698:Hepatitis C, Chronic / Q000201:enzymology* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D009975:Orthomyxoviridae / Q000235:genetics / Q000302:isolation & purification*; D011110:Polymorphism, Genetic; D011494:Protein Kinases / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics; D014481:United States; D044465:White People; D001741:Black or African American
D000998:Antiviral Agents; D017931:DNA Primers; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma; D011494:Protein Kinases