IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European cohort: A cross-sectional study

Vijay Suppiah, Silvana Gaudieri, Nicola J. Armstrong, Kate S. O'Connor, Thomas Berg, Martin Weltman, Maria Lorena Abate, Ulrich Spengler, Margaret Bassendine, Gregory J. Dore, William L. Irving, Elizabeth Powell, Margaret Hellard, Stephen Riordan, Gail Matthews, David Sheridan, Jacob Nattermann, Antonina Smedile, Tobias Müller, Emma Hammond & 8 others David Dunn, Francesco Negro, Pierre Yves Bochud, Simon Mallal, Golo Ahlenstiel, Graeme J. Stewart, Jacob George, David R. Booth

Research output: Contribution to journalArticle

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Abstract

Background: To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%-50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control. Methods and Findings: We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 "G" was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10-8, 1.67-2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10-14, 2.67-5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05-2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10-6, 2.03-7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B. Conclusions: Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B.

LanguageEnglish
Article numbere1001092
JournalPLoS Medicine
Volume8
Issue number9
DOIs
Publication statusPublished - 1 Jan 2011

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Suppiah, Vijay ; Gaudieri, Silvana ; Armstrong, Nicola J. ; O'Connor, Kate S. ; Berg, Thomas ; Weltman, Martin ; Abate, Maria Lorena ; Spengler, Ulrich ; Bassendine, Margaret ; Dore, Gregory J. ; Irving, William L. ; Powell, Elizabeth ; Hellard, Margaret ; Riordan, Stephen ; Matthews, Gail ; Sheridan, David ; Nattermann, Jacob ; Smedile, Antonina ; Müller, Tobias ; Hammond, Emma ; Dunn, David ; Negro, Francesco ; Bochud, Pierre Yves ; Mallal, Simon ; Ahlenstiel, Golo ; Stewart, Graeme J. ; George, Jacob ; Booth, David R. / IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European cohort : A cross-sectional study. In: PLoS Medicine. 2011 ; Vol. 8, No. 9.
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title = "IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European cohort: A cross-sectional study",
abstract = "Background: To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40{\%}-50{\%} of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control. Methods and Findings: We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 {"}G{"} was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10-8, 1.67-2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10-14, 2.67-5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05-2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66{\%} with IL28B to 80{\%} using both genes in this cohort (OR 3.78, p = 8.83×10-6, 2.03-7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B. Conclusions: Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B.",
author = "Vijay Suppiah and Silvana Gaudieri and Armstrong, {Nicola J.} and O'Connor, {Kate S.} and Thomas Berg and Martin Weltman and Abate, {Maria Lorena} and Ulrich Spengler and Margaret Bassendine and Dore, {Gregory J.} and Irving, {William L.} and Elizabeth Powell and Margaret Hellard and Stephen Riordan and Gail Matthews and David Sheridan and Jacob Nattermann and Antonina Smedile and Tobias M{\"u}ller and Emma Hammond and David Dunn and Francesco Negro and Bochud, {Pierre Yves} and Simon Mallal and Golo Ahlenstiel and Stewart, {Graeme J.} and Jacob George and Booth, {David R.}",
year = "2011",
month = "1",
day = "1",
doi = "10.1371/journal.pmed.1001092",
language = "English",
volume = "8",
journal = "Nature Methods",
issn = "1549-1277",
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Suppiah, V, Gaudieri, S, Armstrong, NJ, O'Connor, KS, Berg, T, Weltman, M, Abate, ML, Spengler, U, Bassendine, M, Dore, GJ, Irving, WL, Powell, E, Hellard, M, Riordan, S, Matthews, G, Sheridan, D, Nattermann, J, Smedile, A, Müller, T, Hammond, E, Dunn, D, Negro, F, Bochud, PY, Mallal, S, Ahlenstiel, G, Stewart, GJ, George, J & Booth, DR 2011, 'IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European cohort: A cross-sectional study', PLoS Medicine, vol. 8, no. 9, e1001092. https://doi.org/10.1371/journal.pmed.1001092

IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European cohort : A cross-sectional study. / Suppiah, Vijay; Gaudieri, Silvana; Armstrong, Nicola J.; O'Connor, Kate S.; Berg, Thomas; Weltman, Martin; Abate, Maria Lorena; Spengler, Ulrich; Bassendine, Margaret; Dore, Gregory J.; Irving, William L.; Powell, Elizabeth; Hellard, Margaret; Riordan, Stephen; Matthews, Gail; Sheridan, David; Nattermann, Jacob; Smedile, Antonina; Müller, Tobias; Hammond, Emma; Dunn, David; Negro, Francesco; Bochud, Pierre Yves; Mallal, Simon; Ahlenstiel, Golo; Stewart, Graeme J.; George, Jacob; Booth, David R.

In: PLoS Medicine, Vol. 8, No. 9, e1001092, 01.01.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European cohort

T2 - Nature Methods

AU - Suppiah, Vijay

AU - Gaudieri, Silvana

AU - Armstrong, Nicola J.

AU - O'Connor, Kate S.

AU - Berg, Thomas

AU - Weltman, Martin

AU - Abate, Maria Lorena

AU - Spengler, Ulrich

AU - Bassendine, Margaret

AU - Dore, Gregory J.

AU - Irving, William L.

AU - Powell, Elizabeth

AU - Hellard, Margaret

AU - Riordan, Stephen

AU - Matthews, Gail

AU - Sheridan, David

AU - Nattermann, Jacob

AU - Smedile, Antonina

AU - Müller, Tobias

AU - Hammond, Emma

AU - Dunn, David

AU - Negro, Francesco

AU - Bochud, Pierre Yves

AU - Mallal, Simon

AU - Ahlenstiel, Golo

AU - Stewart, Graeme J.

AU - George, Jacob

AU - Booth, David R.

PY - 2011/1/1

Y1 - 2011/1/1

N2 - Background: To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%-50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control. Methods and Findings: We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 "G" was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10-8, 1.67-2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10-14, 2.67-5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05-2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10-6, 2.03-7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B. Conclusions: Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B.

AB - Background: To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%-50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control. Methods and Findings: We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 "G" was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10-8, 1.67-2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10-14, 2.67-5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05-2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10-6, 2.03-7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B. Conclusions: Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B.

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U2 - 10.1371/journal.pmed.1001092

DO - 10.1371/journal.pmed.1001092

M3 - Article

VL - 8

JO - Nature Methods

JF - Nature Methods

SN - 1549-1277

IS - 9

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ER -