Genetics of spontaneous clearance of hepatitis C virus infection: A complex topic with much to learn
Authors: Jason Grebely, Gregory J. Dore, Arthur Y. Kim, Andrew Lloyd, Naglaa H. Shoukry, Maria Prins, Kimberly Page
Journal: Hepatology (2014)

We appreciate the insightful comments by Alric et al.1, 2 highlighting the role of the DQB1*0301 allele of the major histocompatibility complex class II (HLA class II) and spontaneous hepatitis C virus (HCV) clearance. The demonstration that the DQB1*0301 allele is associated with spontaneous HCV clearance, independent of the interferon-λ3 (IFNL3) genotype, is an important advance in our understanding of host factors important in control of HCV infection.2 Up until recently, the International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC3) Study has relied on the availability of data that has already been collected from the contributing cohorts.3, 4 Many of the cohorts have not performed HLA-DQ or DR locus genotyping, so this could not be included in this analysis. However, the Laboratory Steering Committee of the InC3 study (chaired by Andrew Lloyd from UNSW Australia and Naglaa Shoukry from the Université de Montréal) has initiated a protocol for the collection of DNA samples from each cohort which will be available for future genetic research (led by Arthur Kim from Harvard Medical School). As such, it will be possible to assess the association of the DQB1*0301 allele with spontaneous HCV clearance within our cohort in the near future. Interestingly, in the large genome-wide association study, only 15% of the variance of spontaneous clearance was attributed to the two single nucleotide polymorphisms (SNPs) related to DQB1*0301,2 suggesting that other host, environmental, and viral factors are likely involved in spontaneous HCV clearance. This also highlights the complexity of trying to understand factors important in the control of HCV infection. Host polymorphisms related to genes encoding proteins associated with innate or adaptive immunity such as HLA class I and II, tapasin, natural-killer-cell receptors, chemokine receptors, interleukins, Toll-like receptors, and interferon-stimulated genes have been associated with control of HCV.5-7 However, often the identified genetic associations have not been confirmed in independent cohorts, differ in diverse populations, and the studies are limited by small sample size or varying definitions of HCV outcome; moreover, little is known about their functional basis.5-7 The large genome-wide association study performed by Duggal et al.2 has helped advance our knowledge in this area and highlights the importance of the genetic role of HLA Class II and IFNL3 genotype in spontaneous HCV clearance. Additional research is needed to ascertain the mechanisms through which these genes and others affect the outcome of HCV infection. While the hypothesis posed by the authors that the association of DQB1*0301 and IFNL3 genotype may abolish the observed effect of female sex is interesting, there are no data yet to support this hypothesis and answering this question should be a focus of future studies. In the study by Duggal et al.,2 the HLA class II association was detected in both men and women. The availability from the well-defined cases of acute HCV with spontaneous HCV clearance from the InC3 Study will form a valuable tool for future research to assess novel genetic markers associated with spontaneous HCV clearance. It is hoped that this information will assist with HCV vaccine design and lead to better global control of HCV infection. The InC3 Study is supported by the National Institute on Drug Abuse Award Number R01DA031056. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health. The Kirby Institute is funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian Government. J.G. is supported by a National Health and Medical Research Council (NHMRC) Career Development Fellowship. G.D. is supported by an NHMRC Practitioner Research Fellowship. Jason Grebely, Ph.D.1 Gregory J. Dore, B.Sc., MBBS, MPH, Ph.D.1 Arthur Y. Kim, M.D.2 Andrew Lloyd, MBBS, M.D., FRACPC3 Naglaa H. Shoukry, Ph.D.4 Maria Prins, Ph.D.5 Kimberly Page, Ph.D.6 1Kirby Institute UNSW Australia, Sydney, Australia 2Harvard Medical School Boston, MA, USA 3Inflammation and Infection Research Centre School of Medical Sciences UNSW Australia, Sydney, Australia 4CRCHUM, Université de Montréal Montreal, QC, Canada 5GGD Public Health Service of Amsterdam Amsterdam, The Netherlands 6Department of Epidemiology and Biostatistics University of California San Francisco, San Francisco, CA, USA