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Associations between two SNPs (rs12979860, rs12980275) and complete early virological response for peginterferon alfa-2a (40KD) - based treatment in naive patients and previous non-responders
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"Among treatment-naive patients, the cEVR rate was 49.6% overall, 65.5% in those with an rs12979860 C/C genotype and 19.2% in those with a T/T genotype (Figure 3a)."
Reported by Jules Levin
Presented at The 21st Conference of the Asian Pacific Association for the Study of the Liver (APASL), February 17Đ20, 2011, Bangkok, Thailand
T. Asselah,1 P. Marcellin,1 M.W. Fried,2 D.M. Jensen,3 S. Germer,4 R. Benayed,5 F. Tatsch,5 T. Chu,6 N. Shulman,6 M. Laughlin,6 J. Thommes,7 D. Chin,6 L. Essioux5
1H™pital Beaujon, Clichy, University Diderot-Paris, France; 2University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 3Center for Liver Diseases, Chicago, IL, USA; 4Roche, Nutley, NJ, USA; 5Roche, Basel, Switzerland; 6Roche, Palo Alto, 7Genentech, San Francisco, CA, USA
RESULTS
We found a series of SNPs associated with SVR and EVR in genotype 1 patients that were located in a predicted promoter region of IL28B on chromosome 19. The top two SNPs for SVR and EVR were rs12979860 (p=3.09x10-20 and p=7.64x10-24, respectively) and rs12980275 (p=5.28x10-17 and p=3.03x10-21, respectively).
These results confirmed the findings of previous GWAS analyses.
The results of logistic regression analysis for SVR after adjustment of the GWAS for rs12979860 revealed that an additional 10 SNPs were found
to be associated with SVR (at p<10-5), but not EVR. The most prominent of these were located on chromosome 4 (rs10009948, p=2.96 x 10-7;
rs10023606, p=2.34 x 10-6; and rs7673763, p=3.93 x 10-6 respectively). There were no SNPs which achieved genome wide significance (p<10-7).
Association between SNPs on chromosome 19 (rs12979860 and rs8099917) and virological response in genotype 1 patients
Analyses of associations between two SNPs on chromosome 19 (rs12979860 and rs8099917) and three separate categories of virological response (EVR, cEVR and SVR) demonstrated stronger associations in treatment-naive patients (Figure 2a) than in previous non-responders to peginterferon alfa-2b (12KD) plus ribavirin (Figure 2b).
Figure 2. Association between SNPs on chromosome 19 (rs12979860 and rs8099917) and virological response in treatment-naive patients and non-responders to previous treatment with pegylated interferon alfa-2b (12KD) plus ribavirin.
After adjusting for the effect of rs12979860, rs8099917 was no longer significantly associated with SVR, EVR or cEVR. Conversely, after adjusting for the effect of rs8099917, rs12979860 remained significantly associated with all three categories of virological response, suggesting that it is rs12979860 that drives virological response.
Association between rs12979860 and rs8099917
genotypes and cEVR in genotype 1 patients
Among treatment-naive patients, the cEVR rate was 49.6% overall, 65.5% in those with an rs12979860 C/C genotype and 19.2% in those with a T/T genotype (Figure 3a).
Although the cEVR rate was lower among previous non-responders (13.1%), the same trend is observed: 34.6% in patients with the C/C
genotype and 8.3% in patients with the T/T genotype (Figure 3b).
In treatment-naive patients (Figure 3c) the cEVR rate was 59.4% in those with an rs8099917 T/T genotype and 28.6% in those with a G/G genotype.
Figure 3. Association between rs12979860 and rs8099917 genotype and cEVR in treatment-naive patients and non-responders to previous treatment with pegylated interferon alfa-2b (12KD) plus ribavirin.
In previous non-responders (Figure 3d) the cEVR rate was 20.9% in
patients with the rs8099917 T/T genotype and 5.6% in patients with the G/G genotype.
This research was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland Support for third-party writing assistance for this presentation was provided by F. Hoffmann-La Roche Ltd.
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