1. Genetics and Genomics
  2. Microbiology and Infectious Disease
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Adaptation of hepatitis C virus to interferon lambda polymorphism across multiple viral genotypes

  1. Nimisha Chaturvedi  Is a corresponding author
  2. Evguenia S Svarovskaia
  3. Hongmei Mo
  4. Anu O Osinusi
  5. Diana M Brainard
  6. G Mani Subramanian
  7. John G McHutchison
  8. Stefan Zeuzem
  9. Jacques Fellay  Is a corresponding author
  1. École Polytechnique Fédérale de Lausanne, Switzerland
  2. Swiss Institute of Bioinformatics, Switzerland
  3. Gilead Sciences Inc, United States
  4. Goethe University Hospital, Germany
  5. Lausanne University Hospital, Switzerland
Research Article
Cite this article as: eLife 2019;8:e42542 doi: 10.7554/eLife.42542
3 figures, 2 tables and 6 additional files

Figures

Figure 1 with 2 supplements
Per genotype integrated association analysis results.

Manhattan plot for associations between human SNP rs12979860 and HCV amino acid variants. The dotted line shows the Bonferroni-corrected significance threshold.

https://doi.org/10.7554/eLife.42542.003
Figure 1—figure supplement 1
Per genotype integrated association analysis results corrected for HCV viral load.

Manhattan plot for associations between human SNP rs12979860 and HCV amino acid variants, with (filled dots) and without HCV (filled triangles) viral load. The dotted line shows the Bonferroni-corrected significance threshold.

https://doi.org/10.7554/eLife.42542.004
Figure 1—figure supplement 2
Boxplot of transformed viral load stratified by rs12979860 genotypes (CC, CT, TT).

The association p-values, together with r-squared and beta values, given in the brackets are for associations between rs12979860 and transformed HCV viral load.

https://doi.org/10.7554/eLife.42542.005
Per genotype viral load GWAS analysis results.

Manhattan plot for associations between human Box-Cox transformed pre-treatment viral load and HCV amino acid variants. The dotted line shows the Bonferroni-corrected significance threshold.

https://doi.org/10.7554/eLife.42542.007
Figure 3 with 5 supplements
Associations between amino acid variables at position 2224 of NS5A, rs12979860 genotypes and HCV viral load in the group of patients infected with HCV genotype 1b.

(A) Boxplot of transformed viral load stratified by amino acids present at position 2224 of NS5A. (B): Boxplot of transformed viral load stratified by rs12979860 genotypes (CC, CT, TT) and by presence or absence of leucine at position 2224 of NS5A.

https://doi.org/10.7554/eLife.42542.008
Figure 3—figure supplement 1
Boxplot of transformed viral load stratified by rs12979860 genotypes (CC, CT, TT) in samples infected with viral genotype 3a, whose virus carries Serine at position 2414.
https://doi.org/10.7554/eLife.42542.009
Figure 3—figure supplement 2
Per genotype viral load residual analysis results.

Manhattan plot for associations between viral load residual and HCV amino acid variants. The dotted line shows the Bonferroni-corrected significance threshold.

https://doi.org/10.7554/eLife.42542.010
Figure 3—figure supplement 3
Per genotype integrated association analysis results in the European subgroup.

Manhattan plot for associations between human SNP rs12979860 and HCV amino acid variants. The dotted line shows the Bonferroni-corrected significance threshold.

https://doi.org/10.7554/eLife.42542.011
Figure 3—figure supplement 4
European per genotype viral load GWAS analysis results.

Manhattan plot for associations between human Box-Cox transformed pre-treatment viral load and HCV amino acid variants. The dotted line shows the Bonferroni-corrected significance threshold.

https://doi.org/10.7554/eLife.42542.012
Figure 3—figure supplement 5
European per genotype viral load residual GWAS analysis results.

Manhattan plot for associations between viral load residual and HCV amino acid variants. The dotted line shows the Bonferroni-corrected significance threshold.

https://doi.org/10.7554/eLife.42542.013

Tables

Table 1
Characteristics of study participants, by HCV genotype group.
https://doi.org/10.7554/eLife.42542.002
HCV genotypeAll1a1b2a2b3a4aOthers
N87293548 (41)1924 (22)304 (3)472 (5)1839 (21)193 (2)449 (5)
Europeans
Asians
Africans
Others
6704 (77)
1103 (13)
723 (8)
199 (2)
2987 (84)
59 (2)
421 (12)
81 (2)
1133 (59)
577 (30)
192 (10)
22 (1)
100 (33)
197 (65)
7 (2)
0 (0)
421 (89)
15 (3)
25 (5)
11 (2)
1635 (89)
111 (6)
19 (1)
74 (4)
178 (92)
2 (1)
8 (4)
5 (3)
250 (56)
142 (32)
51 (11)
6 (1)
Cirrhosis2410 (28)978 (28)536 (28)35 (12)77 (16)629 (34)60 (31)95 (21)
Male sex5605 (64)2434 (69)1096 (57)141 (46)301 (64)1230 (67)143 (74)260 (58)
SVR7702 (88)3240 (91)1773 (92)273 (90)426 (90)1452 (79)153 (79)385 (86)
  1. Data are indicated as number (percent); SVR: sustained virological response after treatment.

Table 2
Genome-to-genome analysis results per genotype.

The table shows significant p-values (<4.7×10−6), NA representing non-significant associations. We also give odds ratio (OR) and 97% confidence interval for each significant association.

https://doi.org/10.7554/eLife.42542.006
HCV genePosition
(amino acid)
Genotype 1a
N = 3548
Genotype 1b
N = 1924
Genotype 2a
N = 304
Genotype 2b
N = 472
Genotype 3a
N = 1839
Genotype 4a
N = 193
 NS31332(A)1.02e-10
(OR 1.06; 1.04–1.08)
NANANANANA
 NS31355(I)3.14e-07
(OR 1.1; 1.06–1.14)
NANANANANA
 NS31370(I)NA1.09e-08
(OR 0.83; 0.78–0.88)
NANANANA
 NS31370(T)NA4.87e-08
(OR 1.2; 1.12–1.28)
NANANANA
 NS31473(D)3.82e-07
(OR 1.03 1.02–1.04)
NANANANANA
 NS31516(I)3.51e-07
(OR 1.06; 1.04–1.09)
NANANANANA
 NS31598(R)2.26e-07
(OR 1.04; 1.02–1.05)
NANANANANA
 NS31612(I)7.88e-16
(OR 0.86; 0.83–0.89)
NANANANANA
 NS31612(N)1.54e-11
(OR 1.09; 1.06–1.11)
NANANANANA
 NS31612(T)1.54e-08
(OR 1.11; 1.07–1.15)
NANANANANA
 NS31635(I)7e-07
(OR 1.1; 1.06–1.14)
NANANANANA
 NS4A1671(T)1.83e-07
(OR 1.03; 1.02–1.04)
NANANANANA
 NS4A1703(R)NA6.94e-07
(OR 1.19; 1.11–1.27)
NANANANA
 NS5A1996(R)7.87e-07
(OR 1.01; 1.01–1.02)
NANANANANA
 NS5A2009(F)NA1.04e-08
(OR 1.11; 1.07–1.15)
NANANANA
 NS5A2009(I)2.01e-06
(OR 1.02; 1.01–1.02)
NANANANANA
 NS5A2024(V)5.81e-09
(OR 1.04; 1.03–1.05)
NANANANANA
 NS5A2034(D)1.75e-07
(OR 1.03; 1.02–1.04)
NANANANANA
 NS5A2034(T)NANANANA1.61e-07
(OR 0.91; 0.87–0.94)
NA
 NS5A2040(K)3.05e-06
(OR 0.98; 0.97–0.99)
NANANANANA
 NS5A2040(R)2.54e-07
(OR 1.03; 1.02–1.04)
NANANANANA
 NS5A2047(A)9.8e-20
(OR 1.07; 1.06–1.09)
NANANANANA
 NS5A2065(H)9.81e-07
(OR 1.01; 1.01–1.02)
1.38e-07
(OR 1.06; 1.04–1.09)
NANANANA
 NS5A2080(K)NA2.9e-18
(OR 1.12; 1.09–1.14)
NANANANA
 NS5A2080(R)NA1.39e-06
(OR 0.95; 0.93–0.97)
NANANANA
 NS5A2187(R)NA1.07e-06
(OR 1.07; 1.04–1.09)
NANANANA
 NS5A2211(L)2.84e-06
(OR 0.99; 0.98–0.99)
NANANANANA
 NS5A2220(R)NA2.65e-06
(OR 1.03; 1.02–1.04)
NANANANA
 NS5A2224(L)NA1.6e-12
(OR 1.05; 1.04–1.07)
NANANANA
 NS5A2234(W)NA1.46e-07
(OR 1.06; 1.03–1.08)
NANANANA
 NS5A2237(K)NA2.6e-12
(OR 1.06; 1.04–1.08)
NANANANA
 NS5A2251(I)NA2.05e-11
(OR 1.07; 1.05–1.09)
NANANANA
 NS5A2252(I)1.29e-25
(OR 1.12; 1.1–1.15)
NANANA8.68e-07
(OR 1.05; 1.03–1.07)
NA
 NS5A2252(V)1.72e-22
(OR 0.89; 0.87–0.91)
NANANA5.5e-07
(OR 0.95; 0.92–0.97)
NA
 NS5A2287(I)1.54e-14
(OR 1.09; 1.07–1.12)
6.24e-07
(OR 1.08; 1.05–1.11)
NANANANA
 NS5A2287(V)1.82e-10
(OR 0.92; 0.90–0.95)
NANANANANA
 NS5A2298(I)1.56e-06
(OR 1.05; 1.03–1.08)
NANANANANA
 NS5A2298(V)1.66e-14
(OR 0.92; 0.90–0.94)
NANANANANA
 NS5A2300(P)NA2.7e-15
(OR 1.12; 1.09–1.15)
NANANANA
 NS5A2300(S)NA9.41e-08
(OR 0.94; 0.91–0.96)
NANANANA
 NS5A2320(Q)5.01e-09
(OR 1.08; 1.05–1.11)
NANANANANA
 NS5A2330(R)NA1.26e-06
(OR 1.03; 1.02–1.04)
NANANANA
 NS5A2360(A)NA1.46e-12
(OR 1.12; 1.09–1.16)
NANANANA
 NS5A2371(S)2.03e-07
(OR 1.03; 1.02–1.04)
NANANANANA
 NS5A2372(A)2.44e-06
(OR 0.96; 0.94–0.97)
NANANANANA
 NS5A2372(S)1.63e-14
(OR 1.06; 1.04–1.07)
NANANANANA
 NS5A2385(C)3.24e-14
(OR 1.09; 1.07–1.11)
4.35e-07
(OR 1.04; 1.03–1.06)
NANANANA
 NS5A2385(Y)2.7e-13
(OR 0.93; 0.91–0.94)
NANANANANA
 NS5A2411(G)NA4.61e-08
(OR 1.11; 1.07–1.15)
NANANANA
 NS5A2411(S)NA9.02e-07
(OR 0.92; 0.89–0.95)
NANANANA
 NS5A2412(K)5.74e-09
(OR 1.03; 1.02–1.05)
NANANANANA
 NS5A2412(T)7.87e-10
(OR 0.93; 0.91–0.95)
NANANANANA
 NS5A2414(D)2.43e-07
(OR 0.97; 0.96–0.98)
NANANANANA
 NS5A2416(G)NANANANA5.21e-07
(OR 1.06; 1.04–1.09)
NA
 NS5A2416(N)NANANANA2.5e-07
(OR 1.09; 1.05–1.12)
NA
 NS5A2416(S)NANANANA1.04e-11
(OR 0.89; 0.86–0.92)
NA
 NS5A2420(N)NANANANA3.39e-09
(OR 1.08; 1.05–1.11)
NA
 NS5A2420(S)NANANANA7.1e-07
(OR 0.95; 0.93–0.97)
NA
 NS5B2510(N)2.25e-06
(OR 1.02; 1.01–1.03)
NANANANANA
 NS5B2567(I)1.73e-13
(OR 1.02; 1.02–1.03)
5.73e-08
(OR 1.07; 1.04–1.09)
NANANANA
 NS5B2570(A)NANANANA2.63e-07
(OR 1.11; 1.06–1.15)
NA
 NS5B2570(T)NANANANA8.87e-15
(OR 1.11; 1.08–1.14)
NA
 NS5B2570(V)NANANANA5.57e-20
(OR 0.84; 0.81–0.87)
NA
 NS5B2576(A)1.21e-11
(OR 1.02; 1.01–1.02)
NA3.84e-06
(OR 1.27; 1.15–1.4)
4.02e-08
(OR 1.2; 1.13–1.28)
1.04e-14
OR 1.07; 1.05–1.08)
NA
 NS5B2576(P)1.53e-10
(OR 0.98; 0.98–0.99)
NANA5.41e-15
(OR 0.77; 0.72–0.82)
8.39e-12
(OR 0.95; 0.94–0.96)
1.13e-07
(OR 0.83; 0.77–0.88)
 NS5B2633(S)NA2.33e-09
(OR 1.08; 1.06–1.11)
NANANANA
 NS5B2729(Q)1.19e-12
(OR 0.91; 0.89–0.94)
1.38e-07
(OR 0.94; 0.92–0.96)
NANANANA
 NS5B2729(R)9.13e-12
(OR 1.09; 1.06–1.12)
2.22e-09
(OR 1.08; 1.05–1.11)
NANANANA
 NS5B2755(N)2.98e-06
(OR 1.04; 1.02–1.06)
NANANANANA
 NS5B2758(A)NA2.3e-06
(OR 1.05; 1.03–1.07)
NANANANA
 NS5B2794(Q)NANANANA3.56e-10
(OR 1.08; 1.05–1.1)
NA
 NS5B2860(G)NA4.63e-12
(OR 1.07; 1.05–1.09)
NANANANA
 NS5B2937(K)8.23e-07
(OR 0.95; 0.93–0.97)
NANANANANA
 NS5B2937(R)NANANANA4.4e-08
(OR 1.08; 1.05–1.11)
NA
 NS5B2986(H)NANANANA1.03e-06
(OR 0.95; 0.93–0.97)
NA
 NS5B2986(R)NANANANA2.9e-07
(OR 1.05; 1.03–1.07)
NA
 NS5B2991(H)NANANANA4.66e-12
(OR 0.88; 0.85–0.91)
NA
 NS5B2991(Y)NANANANA1.86e-17
(OR 1.17; 1.13–1.22)
NA
 NS5B3008(F)7.47e-08
(OR 1.01; 1.01–1.02)
NANANANANA

Additional files

Supplementary file 1

HCV amino acid positions with significant association p-values from genome-to-genome analysis (column 3), viral load GWAS analysis (column 4) and viral load residual GWAS analysis (column 5) for viral genotype 1a.

HCV genes and positions on the HCV proteome are given in the first and the second column of the table. Amino acid residuals on the associated positions are given in the second column.

https://doi.org/10.7554/eLife.42542.014
Supplementary file 2

HCV amino acid positions with significant association p-values from genome-to-genome analysis (column 3), viral load GWAS analysis (column 4) and viral load residual GWAS analysis (column 5) for viral genotype 1b.

HCV genes and positions on the HCV proteome are given in the first and the second column of the table. Amino acid residuals on the associated positions are given in the second column.

https://doi.org/10.7554/eLife.42542.015
Supplementary file 3

Genome to genome analysis results for Asians and Europeans.

The table consists of significant p-values and NA represents non-significant p-values.

https://doi.org/10.7554/eLife.42542.016
Supplementary file 4

Genome to genome analysis results per genotype in European samples.

The table consists of significant p-values and NA represents non-significant p-values.

https://doi.org/10.7554/eLife.42542.017
Supplementary file 5

HCV amino acid positions with significant association p-values from genome-to-genome analysis (column 3), viral load GWAS analysis (column 4) and viral load residual GWAS analysis (column 5), for European samples infected with viral genotype 1a.

HCV genes and positions on the HCV proteome are given in the first and the second column of the table. Amino acid residuals on the associated positions are given in the second column.

https://doi.org/10.7554/eLife.42542.018
Transparent reporting form
https://doi.org/10.7554/eLife.42542.019

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