Gender-dependent association of CTLA4 polymorphisms with resolution of hepatitis C virus infection.
OBJECTIVE
A vigorous T-cell response is essential for the resolution of HCV infection. It is modified by co-stimulatory molecules that attenuate T-lymphocyte responses by binding to CTLA4. We investigated whether CTLA4 single nucleotide polymorphisms are associated with the resolution of infection or with the course of disease.


METHODS
We enrolled 127 individuals with self-limited and 947 patients with chronic HCV infection, of whom 560 were treated with interferon-alpha-based therapies, and 200 healthy controls. We analyzed CTLA4 polymorphisms -318C>T and +49A>G by melting curve analysis and reconstructed haplotypes.


RESULTS
CTLA4 haplotypes were distributed differently between men but not women with self-limited and chronic infection (p=0.043) but were not predictive of the stage of fibrosis in chronic carriers. Haplotypes were distributed differently between male but not female end-of-treatment responders and non-responders (p=0.025). The influence of CTLA4 haplotypes was more pronounced in "hard-to-treat" situations, i.e., treatment with interferon-alpha monotherapy or infection with HCV genotypes 1/4. Logistic regression analysis confirmed gender-specific risk factors for a virological non-response.


CONCLUSIONS
CTLA4 polymorphisms are associated with the resolution of HCV infection. This study underlines the role of an efficient T-cell response in the clearance of HCV and sheds light on a gender-dependent difference of immune regulation.
Schott
Eckart
E
Department of Hepatology and Gastroenterology, CVK, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Witt
Heiko
H
Hinrichsen
Holger
H
Neumann
Konrad
K
Weich
Viola
V
Bergk
Alexandra
A
Halangk
Juliane
J
Müller
Tobias
T
Tinjala
Sebastian
S
Puhl
Gero
G
Neuhaus
Peter
P
Wiedenmann
Bertram
B
Berg
Thomas
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics*; D000943:Antigens, Differentiation / Q000235:genetics*; D000998:Antiviral Agents / Q000627:therapeutic use*; D060908:CTLA-4 Antigen; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D008103:Liver Cirrhosis / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use; D012727:Sex Characteristics; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology; D016896:Treatment Outcome
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000998:Antiviral Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a