TY - JOUR
T1 - Genome-wide association study of spontaneous resolution of hepatitis C virus infection
T2 - Data from multiple cohorts
AU - Duggal, Priya
AU - Thio, Chloe L.
AU - Wojcik, Genevieve L.
AU - Goedert, James J.
AU - Mangia, Alessandra
AU - Latanich, Rachel
AU - Kim, Arthur Y.
AU - Lauer, Georg M.
AU - Chung, Raymond T.
AU - Peters, Marion G.
AU - Kirk, Gregory D.
AU - Mehta, Shruti H.
AU - Cox, Andrea L.
AU - Khakoo, Salim I.
AU - Alric, Laurent
AU - Cramp, Matthew E.
AU - Donfield, Sharyne M.
AU - Edlin, Brian R.
AU - Tobler, Leslie H.
AU - Busch, Michael P.
AU - Alexander, Graeme
AU - Rosen, Hugo R.
AU - Gao, Xiaojiang
AU - Abdel-Hamid, Mohamed
AU - Apps, Richard
AU - Carrington, Mary
AU - Thomas, David L.
PY - 2013/2/19
Y1 - 2013/2/19
N2 - Background: Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person's lifetime risk for cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and persons with genetic variants near interleukin-28B (IL-28B), the genetic basis is not well-understood. Objective: To evaluate the host genetic basis for spontaneous resolution of HCV infection. Design: 2-stage, genome-wide association study. Setting: 13 international multicenter study sites. Patients: 919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence). Measurements: Frequencies of 792 721 single nucleotide polymorphisms (SNPs). Results: Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL-28B and included rs12979860 (overall per-allele OR, 0.45; P = 2.17×10 30) and 10 additional SNPs spanning 55 000 base pairs. On chromosome 6, allele frequency differences localized near genes for HLA class II and included rs4273729 (overall perallele OR, 0.59; P = 1.71×10 16) near DQB1*03:01 and an additional 116 SNPs spanning 1 090 000 base pairs. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% (95% CI, 8.5% to 22.6%) and 15.8% (CI, 4.4% to 31.0%) of the variation in HCV resolution in persons of European and African ancestry, respectively. Replication of the chromosome 6 SNP, rs4272729, in an additional 745 persons confirmed the findings (P = 0.015). Limitation: Epigenetic effects were not studied. Conclusion: IL-28B and HLA class II are independently associated with spontaneous resolution of HCV infection, and SNPs marking IL-28B and DQB1*03:01 may explain approximately 15% of spontaneous resolution of HCV infection. Primary Funding Source: Office of AIDS Research, National Institutes of Health, and Frederick National Laboratory for Cancer Research.
AB - Background: Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person's lifetime risk for cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and persons with genetic variants near interleukin-28B (IL-28B), the genetic basis is not well-understood. Objective: To evaluate the host genetic basis for spontaneous resolution of HCV infection. Design: 2-stage, genome-wide association study. Setting: 13 international multicenter study sites. Patients: 919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence). Measurements: Frequencies of 792 721 single nucleotide polymorphisms (SNPs). Results: Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL-28B and included rs12979860 (overall per-allele OR, 0.45; P = 2.17×10 30) and 10 additional SNPs spanning 55 000 base pairs. On chromosome 6, allele frequency differences localized near genes for HLA class II and included rs4273729 (overall perallele OR, 0.59; P = 1.71×10 16) near DQB1*03:01 and an additional 116 SNPs spanning 1 090 000 base pairs. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% (95% CI, 8.5% to 22.6%) and 15.8% (CI, 4.4% to 31.0%) of the variation in HCV resolution in persons of European and African ancestry, respectively. Replication of the chromosome 6 SNP, rs4272729, in an additional 745 persons confirmed the findings (P = 0.015). Limitation: Epigenetic effects were not studied. Conclusion: IL-28B and HLA class II are independently associated with spontaneous resolution of HCV infection, and SNPs marking IL-28B and DQB1*03:01 may explain approximately 15% of spontaneous resolution of HCV infection. Primary Funding Source: Office of AIDS Research, National Institutes of Health, and Frederick National Laboratory for Cancer Research.
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U2 - 10.7326/0003-4819-158-4-201302190-00003
DO - 10.7326/0003-4819-158-4-201302190-00003
M3 - Article
C2 - 23420232
AN - SCOPUS:84874606648
SN - 0003-4819
VL - 158
SP - 235
EP - 245
JO - Annals of internal medicine
JF - Annals of internal medicine
IS - 4
ER -