Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence

^†The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom;
^§Medical Research Council Laboratories, Fajara, The Gambia;
^¶Imperial College School of Medicine, St Mary’s Hospital, Praed Street, London W2 1PG, United Kingdom;
**Roche Discovery Welwyn, Welwyn Garden City, Herts AL7 3AY, United Kingdom; and
^‖Universita degli Studi dell’Aquila, 67100 L’Aquila, Italy

Communicated by Baruch S. Blumberg, Fox Chase Cancer Center, Philadelphia, PA, April 18, 2006
↵ ^‡A.J.F. and L.Z. contributed equally to this work.
↵ ^††M.R.T. and A.V.S.H. contributed equally to this work. (received for review June 21, 2005)

Abstract

Persistent hepatitis B virus infection is a major risk factor for hepatocellular carcinoma, the most frequent cancer in some developing countries. Up to 95% of those infected at birth and 15% of those infected after the neonatal period fail to clear hepatitis B virus, together resulting in ≈350 million persistent carriers worldwide. Via a whole genome scan in Gambian families, we have identified a major susceptibility locus as a cluster of class II cytokine receptor genes on chromosome 21q22. Coding changes in two of these genes, the type I IFN receptor gene, IFN-AR2, and the IL-10RB gene that encodes a receptor chain for IL-10-related cytokines including the IFN-λs, are associated with viral clearance (haplotype P value = 0.0003), and in vitro assays support functional roles for these variants in receptor signaling.

Footnotes

^‡‡To whom correspondence should be addressed at:
Faculty of Medicine, Imperial College, Saint Mary’s Campus, Norfolk Place, London W2 1NY, United Kingdom.
E-mail: m.thursz{at}imperial.ac.uk
Author contributions: A.J.F., L.Z., B.J.W.H., M.C., J.I.B., M.G., H.C.W., H.C.T., M.R.T., and A.V.S.H. designed research; A.J.F., L.Z., U.D., N.A.M.T., S.B., A.D., B.J.W.H., S.H., S.K., M.W., M.C., H.C.W., M.R.T., and A.V.S.H. performed research; M.G. contributed new reagents/analytic tools; A.J.F., L.Z., U.D., N.A.M.T., S.B., A.D., B.J.W.H., S.H., S.K., M.W., M.G., H.C.T., M.R.T., and A.V.S.H. analyzed data; and A.J.F., M.R.T., and A.V.S.H. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

E,

acidic glutamate;

EBV,

Epstein–Barr virus;

F,

phenylalanine;

HBV,

hepatitis B virus;

K,

basic lysine;

PDT,

pedigree disequilibrium test;

S,

serine.