0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Original Research |

Genome-Wide Association Study of Spontaneous Resolution of Hepatitis C Virus Infection: Data From Multiple Cohorts

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; and David L. Thomas, MD
[+] Article and Author Information

From Johns Hopkins University Bloomberg School of Public Health and Johns Hopkins University School of Medicine, Baltimore, Maryland; National Cancer Institute, Rockville, Maryland; IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy; Massachusetts General Hospital, Harvard Medical School, and Ragon Institute of Harvard, Boston, Massachusetts; University of California, San Francisco, and Viral Reference Laboratory and Repository Core at the Blood Systems Research Institute, San Francisco, California; University of Southampton and Southampton General Hospital, Southampton, United Kingdom; University of Toulouse III, Toulouse, France; South West Liver Unit, Plymouth Hospitals NHS Trust, Plymouth, United Kingdom; Rho, Chapel Hill, North Carolina; State University of New York Downstate College of Medicine, Brooklyn, New York; Cambridge University Hospitals NHS Foundation Trust and Addenbrooke's Hospital, Cambridge, United Kingdom; University of Colorado, Denver, Colorado; Minia University, Minia, and Viral Hepatitis Research Laboratory, National Hepatology and Tropical Disease Research Institute, Cairo, Egypt; and Cancer and Inflammation Program, Laboratory of Experimental Immunology, Science Applications International Corporation–Frederick, Frederick National Laboratory for Cancer Research, Frederick, Maryland.

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, pduggal@jhsph.edu). 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, dthomas@jhmi.edu.

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.


Ann Intern Med. 2013;158(4):235-245. doi:10.7326/0003-4819-158-4-201302190-00003
Text Size: A A A

Chinese translation

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 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).

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.

Figures

Grahic Jump Location
Figure 1.

Manhattan plot summarizing the genome-wide association results in 919 persons with spontaneous resolution of hepatitis C virus infection and 1482 persons with chronic hepatitis C virus infection.

Each point corresponds to a P value from a test of association for a single nucleotide polymorphism. The −log10 P values are plotted by location of the person's single nucleotide polymorphism across the genome. The dashed line represents an accepted level of genome-wide significance (P = 5 × 10−8). Single nucleotide polymorphisms in the HLA and IL-28B region on chromosomes 6 and 19, respectively, exceed this threshold. IL-28B = interleukin-28B.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Conditional analyses of HLA class II and IL-28B regions.

The top plot shows the genome-wide association results for hepatitis C virus clearance and persistence conditioned on rs4273729 in the HLA class II region. The middle plot is conditioned on rs12979860 in the IL-28B region. The bottom plot is conditioned on both single nucleotide polymorphisms. The dashed line represents P = 5 × 10−8, an accepted level of genome-wide significance. IL-28B = interleukin-28B.

Grahic Jump Location
Grahic Jump Location
Figure 3.

Genotyped and imputed single nucleotide polymorphisms for IL-28B and HLA class II regions.

Each point corresponds to a P value from a test of association for a single nucleotide polymorphism. The −log10 P values are plotted by location of the person's single nucleotide polymorphism in these regions. Genotyped single nucleotide polymorphisms are in dark gray, and 1000 genomes imputed single nucleotide polymorphisms are in light gray. The dashed green line is P = 5 × 10−8, an accepted level of genome-wide significance. IL-28B = interleukin-28B.

Grahic Jump Location
Grahic Jump Location
Figure 4.

Additive relationship for hepatitis C virus clearance for HLA class II and IL-28B single nucleotide polymorphisms.

Among 919 persons with spontaneous clearance and 1482 with viral persistence, the proportions with viral clearance are shown for rs12979860 in the IL-28B region by ethnicity, rs4273729 in the HLA class II region by ethnicity, and both rs4273729 and rs12979860 by ethnicity. Because these results are from case–control studies, the absolute effects may not be generally representative because they will vary by the ratio of clearance to persistence in the study population. See Figure S16 of Supplement 3 for a similar plot of the relative effects (odds ratio). IL-28B = interleukin-28B.

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
Submit a Comment

Summary for Patients

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Related Point of Care
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)