Priya Duggal, PhD; Chloe L. Thio, MD; Genevieve L. Wojcik, MHS; James J. Goedert, MD; Alessandra Mangia, MD; Rachel Latanich, BS; Arthur Y. Kim, MD; Georg M. Lauer, PhD; Raymond T. Chung, MD; Marion G. Peters, MD; Gregory D. Kirk, MD, PhD; Shruti H. Mehta, PhD; Andrea L. Cox, MD, PhD; Salim I. Khakoo, MD; Laurent Alric, MD, PhD; Matthew E. Cramp, MD; Sharyne M. Donfield, PhD; Brian R. Edlin, MD; Leslie H. Tobler, DrPH; Michael P. Busch, MD, PhD; Graeme Alexander, MD; Hugo R. Rosen, MD; Xiaojiang Gao, PhD; Mohamed Abdel-Hamid, MD, PhD; Richard Apps, PhD; Mary Carrington, PhD; David L. Thomas, MD
Disclaimer: This content does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.
Grant Support: This project was funded in whole or in part by the Office of AIDS Research through the Center for Inherited Diseases at Johns Hopkins University, the National Institute on Drug Abuse (R01013324, DA033541, DA12568, and DA04334), the National Institute of Allergy and Infectious Diseases (U19AI088791 and AI082630), and the Frederick National Laboratory for Cancer Research (contract HHSN261200800001E). This research was supported in part by the Intramural Research Programs of the National Institutes of Health and the Frederick National Laboratory for Cancer Research. The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (UO1-AI-35042, UL1-RR025005, UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, and UO1-AI-35041). The WIHS is funded by the National Institute of Allery and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the National Institute of Child Health and Human Development (UO1-HD-32632). The REVELL cohort was funded by R01HL076902. Swann cohort was funded by R01-DA16159, R01-DA21550, and UL1-RR024996.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1353.
Reproducible Research Statement: Study protocol: Not available. Statistical code: Available from Dr. Duggal (e-mail, email@example.com). Data set: Available from the central National Institutes of Health genome-wide association study data repository at the National Center for Biotechnology Information, National Library of Medicine (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).
Requests for Single Reprints: David L. Thomas, MD, Johns Hopkins School of Medicine, 1830 East Monument Street, Suite 437, Baltimore, MD 21287; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Duggal: Johns Hopkins University School of Public Health, 615 North Wolfe Street, E6539, Baltimore, MD 21205.
Dr. Thio: Johns Hopkins University School of Medicine, 855 North Wolfe Street, Suite 530, Baltimore, MD 21205.
Ms. Wojcik: Johns Hopkins University School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205.
Dr. Goedert: Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Room 7068, Rockville, MD 20852.
Dr. Mangia: Casa Sollievo della Sofferenza Hospital, Viale Cappuccini 1, 71013 San Giovanni Rotondo, Province of Foggia, Italy.
Ms. Latanich: Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205.
Drs. Kim, Lauer, and Chung: Massachusetts General Hospital, Harvard Medical School, Warren 1019A, 55 Fruit Street, Boston, MA 02114.
Dr. Peters: University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, Department of Medicine, 513 Parnassus Avenue, Suite 357, PO Box 0538, San Francisco, CA 94143-0538.
Dr. Kirk: Johns Hopkins University, Bloomberg School of Public Health, 615 North Wolfe Street, E6535, Baltimore, MD 21205.
Dr. Mehta: Johns Hopkins University, Bloomberg School of Public Health, 615 North Wolfe Street, Suite E6537, Baltimore, MD 21205.
Dr. Cox: Johns Hopkins University School of Medicine, 855 North Wolfe Street, Suite 536, Baltimore, MD 21205.
Dr. Khakoo: Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom.
Dr. Alric: Department of Medicine, Purpan Hospital, UMR 152, IRD, Toulouse III University, Toulouse, France.
Dr. Cramp: Gastroenterology Unit, Plymouth Hospitals, Derriford Road, Crownhill, Plymouth, Devon PL6 8DH, United Kingdom.
Dr. Donfield: Rho, Rho Building, 6330 Quadrangle Drive, Chapel Hill, NC 27517.
Dr. Edlin: Weill Cornell Medical College, 402 East 67th Street, Floor Concourse 2, New York, NY 10065.
Drs. Tobler and Busch: Blood Systems Research Institute, 270 Masonic Avenue, San Francisco, CA 94118.
Dr. Alexander: Academic Department of Medical Genetics, University of Cambridge, Addenbrooke's Hospital, Hill's Road, Cambridge CB2 0QQ, United Kingdom.
Dr. Rosen: University of Colorado, Anschutz Medical Campus, Building 500–13001 East 17th Place, Campus Box C290, Room E1354, Aurora, CO 80045.
Drs. Gao and Apps: National Cancer Institute at Frederick, Building 560, Room 21-75, PO Box B, Frederick, MD 21702.
Dr. Abdel-Hamid: Faculty of Medicine, Department of Microbiology and Immunology, Minia University, Minia, Egypt.
Dr. Carrington: National Cancer Institute at Frederick, Building 560, Room 21-89, Frederick, MD 21702-1201.
Dr. Thomas: Johns Hopkins School of Medicine, 1830 East Monument Street, Suite 437, Baltimore, MD 21287.
Author Contributions: Conception and design: P. Duggal, C.L. Thio, L. Alric, H.R. Rosen, R. Apps.
Analysis and interpretation of the data: P. Duggal, C.L. Thio, G.L. Wojcik, J.J. Goedert, A.Y. Kim, M.G. Peters, G.D. Kirk, L. Alric, B.R. Edlin, H.R. Rosen, X. Gao, R. Apps, M. Carrington, D.L. Thomas.
Drafting of the article: P. Duggal, C.L. Thio, G.L. Wojcik, G.M. Lauer, M.P. Busch, H.R. Rosen.
Critical revision of the article for important intellectual content: P. Duggal, C.L. Thio, J.J. Goedert, A. Mangia, A.Y. Kim, R.T. Chung, M.G. Peters, A.L. Cox, L. Alric, M.E. Cramp, B.R. Edlin, G. Alexander, H.R. Rosen, X. Gao, M. Carrington, D.L. Thomas.
Final approval of the article: P. Duggal, C.L. Thio, G.L. Wojcik, J.J. Goedert, A. Mangia, G.M. Lauer, M.G. Peters, G.D. Kirk, S.H. Mehta, L. Alric, M.E. Cramp, B.R. Edlin, M.P. Busch, G. Alexander, H.R. Rosen, M. Abdel-Hamid, R. Apps, M. Carrington, D.L. Thomas.
Provision of study materials or patients: C.L. Thio, J.J. Goedert, A. Mangia, A.Y. Kim, G.M. Lauer, R.T. Chung, M.G. Peters, S.H. Mehta, A.L. Cox, S.I. Khakoo, L. Alric, M.E. Cramp, S.M. Donfield, B.R. Edlin, L.H. Tobler, G. Alexander, M. Abdel-Hamid.
Statistical expertise: P. Duggal, G.L. Wojcik, M.P. Busch.
Obtaining of funding: J.J. Goedert, G.M. Lauer, G.D. Kirk, B.R. Edlin.
Administrative, technical, or logistic support: R. Latanich, M. Abdel-Hamid.
Collection and assembly of data: C.L. Thio, A. Mangia, R. Latanich, A.Y. Kim, G.M. Lauer, G.D. Kirk, S.H. Mehta, L. Alric, B.R. Edlin, L.H. Tobler, R. Apps, M. Carrington.
Duggal P, Thio CL, Wojcik GL, Goedert JJ, Mangia A, Latanich R, et al. Genome-Wide Association Study of Spontaneous Resolution of Hepatitis C Virus Infection: Data From Multiple Cohorts. Ann Intern Med. 2013;158:235-245. doi: 10.7326/0003-4819-158-4-201302190-00003
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Published: Ann Intern Med. 2013;158(4):235-245.
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.
To evaluate the host genetic basis for spontaneous resolution of HCV infection.
2-stage, genome-wide association study.
13 international multicenter study sites.
919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence).
Frequencies of 792 721 single nucleotide polymorphisms (SNPs).
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 per-allele 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).
Epigenetic effects were not studied.
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.
Office of AIDS Research, National Institutes of Health, and Frederick National Laboratory for Cancer Research.
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Gastroenterology/Hepatology, Infectious Disease, Viral Hepatitis.
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