Open Access Research article

Meta-analysis: implications of interleukin-28B polymorphisms in spontaneous and treatment-related clearance for patients with hepatitis C

María A Jiménez-Sousa*, Amanda Fernández-Rodríguez, María Guzmán-Fulgencio, Mónica García-Álvarez and Salvador Resino*

Author Affiliations

Unit of HIV/Hepatitis Coinfection, National Center for Microbiology, Health Institute Carlos III (ISCIII), 28220 Majadahonda, Madrid, Spain

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BMC Medicine 2013, 11:6  doi:10.1186/1741-7015-11-6

Published: 8 January 2013

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Additional file 1:

Figure S1, Search terms. Relevant studies were identified by a literature search of PubMed without imposing study period restrictions.

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Additional file 2:

Table S1, Summary of characteristics of all studies included for pegylated interferon-α plus ribavirin (PEG-IFN/RBV) treatment outcome and spontaneous clearance. * Data belongs to original sample size, not to the genotyped subpopulation. Abbreviations: A, African; AA, African American; As, Asian; C, Caucasian; H, Hispanic; NA, North African; ND, no data; RCT, randomized controlled trial.

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Additional file 3:

Table S2, Quality appraisal for meta-analysis of sustained virologic response (SVR). 1) Source population well described? 2) Population well described and appropriate? 3) Did participants represent those eligible? 4) Was information on previous hepatitis C virus (HCV) treatment information reported? 5) Inclusion/exclusion criteria reported? 6) Type of treatment well described? 7) Outcome measures well described and without incongruencies? 8) Outcome measurement complete? (That is, all genotype counts reported?) 9) Assessment of Hardy-Weinberg equilibrium? 10) Description of what genetic model was assumed? 11) Consideration of genotyping errors and confirmation of results? 12) Information of linkage disequilibrium? 13) Information on haplotypes? 14) Responder and non-responder groups comparison at baseline? 15) Raw data given or calculable? 16) Study sufficiently powered? 17) Statistical methods appropriate? 18) Study results internally valid (that is, unbiased)? (Summary of items 5 to 8 and 14 to 17)? 19) Genetic study reliable? (Summary of items 9 to 13). 20) Results generalizable to the source population (that is, external validity)? (Summary of items 1 to 4). 21) Overall study quality? Abbreviations: NA, not applicable; NR, not reported.

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Additional file 4:

Table S3, Quality appraisal for SC meta-analysis. 1) Source population well described? 2) Population well described and appropriate? 3) Did participants represent those eligible? 4)? Was information on previous hepatitis C virus (HCV) reported? 5) Inclusion/exclusion criteria reported? 6) Type of treatment well described? 7) Outcome measures well described and without incongruencies? 8) Outcome measurement complete? (That is, all genotype counts reported?) 9) Assessment of Hardy-Weinberg equilibrium? 1) Description of what genetic model was assumed? 11) Consideration of genotyping errors and confirmation of results? 12) Information on linkage disequilibrium? 13) Information on haplotypes? 14) Spontaneous responder and non-responder groups comparison at baseline? 15? Raw data given or calculable? 16) Study sufficiently powered? 17) Statistical methods appropriate? 18) Study results internally valid (that is, unbiased)? (summary of items 5 to 8 and 14 to 17.) 19) Genetic study reliable? (summary of items 9 to 13.) 20) Results generalizable to the source population (that is, external validity)? (summary of items 1 to 4.) 21) Overall study quality? Abbreviations: NA, not applicable; NR, not reported.

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Additional file 5:

Figure S2, The location of the studied single-nucleotide polymorphisms (SNPs) in the genome. * SNPs most studied in recent years.

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Additional file 6:

Table S4, Identification of all subgroups available for each study.

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Additional file 7:

Table S5, Egger test result bias for rs12979860 and rs8099917 for sustained virologic response (SVR). No., number of studies; Coef., asymmetry regression coefficient; Std. Err., standard error; t, statistic; P > |t|, significance; and 95% CI, confidence interval. Coef. corresponds to the intercept value in the regression equation, which estimates the asymmetry of the funnel plot. Positive values (Coef. > 0) indicate higher levels of effect size in studies with smaller sample sizes.

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Additional file 8:

Table S6, Genotype and allele frequencies stratified by ethnicity for all the polymorphisms included in the meta-analysis. (a) Sustained virologic response (SVR) and (b) spontaneous clearance (SC).Abbreviations: A, African; AA, African American; As, Asian; C, Caucasian; H, Hispanic; NA, North African; n.d., no data available. Favorable genotypes: rs12979860 (CC), rs8099917 (TT), rs12980275 (AA), rs8105790 (TT), rs11881222 (AA), rs8103142 (TT), rs7248668 (GG). There is conflicting information for rs10853728.

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Additional file 9:

Figure S3, Overall forest plot showing the association of rs12979860 with sustained virologic response (SVR). The vertical continuous line indicates no difference for SVR regarding IL28B genotype. The size of each square denotes the proportion of information provided by each trial. Pooled odds ratios were calculated from random-effects models with the DerSimonian-Laird method. (a) The number of patients with the favorable genotype (CC) who achieved SVR with respect to the total number of patients having the favorable genotype. (b) The number of patients with the unfavorable genotype (CT+TT) who achieved SVR with respect to the total number of patients having the unfavorable genotype. The dashed vertical red line represents overall OR.

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Additional file 10:

Figure S4, Forest plot showing the association between rs12979860 and sustained virologic response (SVR) stratified by ethnicity. See description in Figure S3.

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Additional file 11:

Figure S5, Forest plot showing the association between rs12979860 and sustained virologic response (SVR) stratified by hepatitis C virus (HCV) genotype. See description in Figure S3.

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Additional file 12:

Table S7, Subgroup analysis by ethnicity and hepatitis C virus (HCV) genotype (pooled odds ratio and 95% confidence interval). ‡Data from only one study. * P < 0.05; ** P < 0.001. Abbreviations: A, African; AA, African American; As, Asian; C, Caucasian; H, Hispanic; n.d., no data available.

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Additional file 13:

Figure S6, Forest plot showing the association between rs12979860 and sustained virologic response (SVR), stratified by type of infection: hepatitis C virus (HCV) mono-infection and HCV/HIV co-infection. For details, see main description in Figure S3.

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Additional file 14:

Figure S7, Overall forest plot showing the association between rs8099917 and sustained virologic response (SVR). Superscripts: number of patients with (a) favorable genotype (TT) or (b) unfavorable genotype (TG+GG) who achieved SVR, with respect to the total number of patients with the favorable or unfavorable genotype, respectively. For extended details, see main description in Figure S3.

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Additional file 15:

Figure S8, Forest plot showing the association between rs8099917 and sustained virologic response (SVR), stratified by ethnicity. Superscripts: number of patients with (a) favorable genotype (TT) or (b) unfavorable genotype (TG+GG) who achieved SVR, with respect to the total number of patients having the favorable or unfavorable genotype, respectively. For complete details, see main description in Figure S3.

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Additional file 16:

Figure S9, Forest plot showing the association between rs8099917 and sustained virologic response (SVR) stratified by hepatitis C virus (HCV) genotype. Superscripts: number of patients with (a) favorable genotype (TT) or (b) unfavorable genotype (TG+GG) who achieved SVR with respect to the total number of patients having the favorable or unfavorable genotype, respectively. For complete details, see main description in Figure S3.

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Additional file 17:

Figure S10, Overall forest plot showing the association between rs8099917 and sustained virologic response (SVR) stratified by type of infection: hepatitis C virus (HCV) mono-infection and HCV/HIV co-infection. Superscripts: number of patients with (a) favorable genotype (TT) or (b) unfavorable genotype (TG+GG) who achieved SVR, with respect to the total number of patients having the favorable or unfavorable genotype, respectively. For extended details, see main description in Figure S3.

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Additional file 18:

Figure S11, Overall forest plot showing the association between rs12980275 and sustained virologic response (SVR). Superscripts: number of patients with (a) favorable genotype (AA) or (b) unfavorable genotype (AG+GG) who achieved SVR, with respect to the total number of patients having the favorable or unfavorable genotype, respectively. For extended details, see main description in Figure S3.

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Additional file 19:

Figure S12, Forest plot showing the association between rs12980275 and sustained virologic response (SVR), stratified by ethnicity. Superscripts: number of patients with (a) favorable genotype (AA) or (b) unfavorable genotype (AG+GG) who achieved SVR, with respect to the total number of patients having the favorable or unfavorable genotype, respectively. For extended details, see main description in Figure S3.

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Additional file 20:

Figure S13, Forest plot showing the association between rs12980275 and sustained virologic response (SVR) stratified by hepatitis C virus (HCV) genotype. Superscripts: number of patients with (a) favorable genotype (AA) or (b) unfavorable genotype (AG+GG) who achieved SVR, with respect to the total number of patients having the favorable or unfavorable genotype, respectively. For extended details, see main description in Figure S3.

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Additional file 21:

Figure S14, Overall forest plot showing the association between rs11881222 and sustained virologic response (SVR). Pooled odds ratios were calculated from fixed-effects models with the Mantel-Haenszel method. Superscripts: number of patients with (a) favorable genotype (AA) or (b) unfavorable genotype (AG+GG) who achieved SVR, with respect to the total number of patients having the favorable or unfavorable genotype, respectively. For extended details, see main description in Figure S3.

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Additional file 22:

Figure S15, Overall forest plot showing the association between rs7248668 and sustained virologic response (SVR). Pooled odds ratios were calculated from fixed-effect models with the Mantel-Haenszel method. Superscripts: number of patients with (a) favorable genotype (GG) or (b) unfavorable genotype (GA+AA) who achieved SVR, with respect to the total number of patients having the favorable or unfavorable genotype, respectively For extended details, see main description in Figure S3.

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Additional file 23:

Figure S16, Overall forest plot showing the association between rs8103142 and sustained virologic response (SVR). Pooled odds ratios were calculated from fixed-effect models with the Mantel-Haenszel method. Superscripts: number of patients with (a) favorable genotype (TT) or (b) unfavorable genotype (TC+CC) who achieved SVR, with respect to the total number of patients having the favorable or unfavorable genotype, respectively. For extended details, see main description in Figure S3.

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Additional file 24:

Figure S17, Overall forest plot showing the association between rs8105790 and sustained virologic response (SVR). Pooled odds ratios were calculated from fixed-effect models with the Mantel-Haenszel method. Superscripts: number of patients with (a) favorable genotype (TT) or (b) unfavorable genotype (TC+CC) who achieved SVR, with respect to the total number of patients having the favorable or unfavorable genotype, respectively. For extended details, see main description in Figure S3.

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Additional file 25:

Figure S18, Overall forest plot showing the association between rs10853728 and sustained virologic response (SVR). Superscripts: number of patients with (a) favorable genotype (CC) or (b) unfavorable genotype (CG+GG) who achieved SVR, with respect to the total number of patients having the favorable or unfavorable genotype, respectively. For extended details, see main description in Figure S3.

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Additional file 26:

Figure S19, Forest plot showing the associations between interleukin 28B (IL28B) gene polymorphisms reported in only one study and sustained virologic response (SVR). Superscripts: number of patients with (a) favorable genotype (CC) or (b) unfavorable genotype (CG+GG) who achieved SVR with respect to the total number of patients having the favorable or unfavorable genotype, respectively. * Single-nucleotide polymorphisms (SNPs) from Smith et al article; † SNPs from Chen et al article.

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Additional file 27:

Figure S20, Overall forest plot showing the association between rs12979860 and spontaneous clearance (SC). The vertical continuous line indicates no difference in SC for the interleukin 28B (IL28B) genotype. Pooled odds ratios were calculated from random-effects models with the DerSimonian-Laird method. (a) The number of patients with favorable genotype who achieved SC, with respect to the total number of patients having the favorable genotype. (b) The number of patients with unfavorable genotype who achieved SC, with respect to the total number of patients having the unfavorable genotype. For complete details, see main description in Figure S3.

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Additional file 28:

Figure S21, Forest plot showing the association between rs12979860 and spontaneous clearance (SC) stratified by ethnicity. The vertical continuous line indicates no difference in SC for the interleukin 28B (IL28B) genotype. Pooled odds ratios were calculated from random-effects models with the DerSimonian-Laird method. (a) The number of patients with the favorable genotype who achieved SC, with respect to the total number of patients having the favorable genotype. (b) The number of patients with unfavorable genotype who achieved SC, with respect to the total number of patients having the unfavorable genotype. For complete details, see main description in Figure S3.

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Additional file 29:

Figure S22, Forest plot showing the association between rs12979860 and spontaneous clearance (SC) stratified by hepatitis C virus (HCV) genotype. The vertical continuous line indicates no difference in SC for interleukin 28B (IL28B) gene genotype. Pooled odds ratios were calculated from random-effects models with the DerSimonian-Laird method. (a) The number of patients with favorable genotype who achieved SC, with respect to the total number of patients having the favorable genotype. (b) The number of patients with unfavorable genotype who achieved SC, with respect to the total number of patients having the unfavorable genotype. For complete details, see main description in Figure S3.

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Additional file 30:

Figure S23, Forest plot showing the association between rs8099917 and spontaneous clearance (SC). The vertical continuous line indicates no difference in SC for the interleukin 28B (IL28B) genotype. Pooled odds ratios were calculated from fixed-effect models with the Mantel-Haenszel method. (a) The number of patients with the favorable genotype who achieved SC, with respect to the total number of patients having the favorable genotype. (b) The number of patients with the unfavorable genotype who achieved SC, with respect to the total number of patients having the unfavorable genotype. For complete details, see main description in Figure 3.

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Additional file 31:

Figure S24, Forest plot showing the association between rs12980275 and spontaneous clearance (SC). The vertical continuous line indicates no difference in SC for the interleukin 28B IL28B) genotype. Pooled odds ratios were calculated from random-effects models with the DerSimonian-Laird method. (a) The number of patients with the favorable genotype who achieved SC, with respect to the total number of patients having the favorable genotype. (b) The number of patients with the unfavorable genotype who achieved SC, with respect to the total number of patients having the unfavorable genotype. For complete details, see main description in Figure 3.

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Additional file 32:

Figure S25, Forest plot showing the associations between interleukin 28B (IL28B) gene polymorphisms reported in only one study and spontaneous clearance (SC). For extended details, see main description in Figure S3.

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