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Coupling germline genetics to interferon-alpha responses in polycythemia vera treatment

Sep 22, 2020

Pegylated interferon alfa-2 (PEG-IFN) induces high response rates in many patients with polycythemia vera (PV), while some patients do not respond well. In order to identify specific genetic predictors, a new study by Jaeger and colleagues in Bloodinvestigated specific germline diplotypes of the interferon lambda 4 ( IFNL4) gene locus and their correlation with PEG-IFN treatment outcome. 1

Methods

Samples from 122 patients treated with PEG-IFN in the PROUD-PV and CONTINUATION-PV trials were used for the primary analysis, while samples from 27 patients treated in the PEGINVERA trial ( NCT01193699) were used to replicate results. 1,2The samples were analyzed with Affymetrix SNP 6.0 microarrays at 12, 18, 24, 30, and 36 months of follow-up. IFNL4variants were sequenced and phased with SHAPEIT. 3

Results

Using a genome-wide association study analysis tagging single nucleotide polymorphism (SNP) and correlating allelic differences with hematologic response (HR) or molecular response (MR) in PEG-IFN-treated patients did not reveal any significant genome-wide associations. However, in a hypothesis-driven approach investigating the role of the IFNL4gene locus variants, the authors demonstrated a significant genomic correlation between non-functional IFNL4variants and improved MR (not HR).

The IFNL4gene is a polymorphic pseudogene, which translates into the functional IFNL4 protein only in some humans. The gene is polymorphic in humans, and the TT allele for the variants rs368234815 and rs8099917 produces a frameshift in the coding region leading to a non-coding mRNA. Similarly, for the rs12979860 variant, a CC allele leads to lack of IFNL4 expression. In contrast, the rs117648444 variant can come with a G allele leading to the expression of an impaired IFNL4-S70 protein, while the non-G allele produces the fully functional IFNL4-P70 protein. Interestingly, non-coding IFNL4SNPs (rs12979860, rs8099917) have previously shown to be associated with response to PEG-IFN and viral clearance during hepatitis C virus infection.

In accordance with results for hepatitis C virus treatment, the investigated PV population showed a significant genotypic association of the non-coding alleles of rs368234815 (OR, 6.10; 95% CI, 1.49–36.64; p = 0.00065), rs8099917 (OR, 4.60; 95% CI, 1.39–16.69; p = 0.0071), and rs12979860 (OR, 6.10; 95% CI, 1.49–36.64; p = 0.0065) for MR at 36 months follow-up.

Based on that finding, the authors investigated diplotypes of these variants in patients, which comprises three functional classes: no IFNL4, nonfunctional IFNL4-S70, and active IFNL4-P70. As was expected, MR (but not HR) was strongly associated with the absence of IFNL4 (89.3%) versusa completely functional IFNL4-P70 (43.3%) protein. Interestingly, the impaired IFNL4-S70 induced similar responses to no IFNL4 ( Table 1)

Table 1. Influence of IFNL4diplotypes on the molecular response in PEG-IFN treatment of PV 1

CI, confidence interval; IFNL4, interferon lambda 4; n, number of patients; NR, non-responders; N (no IFNL4); OR, odds ratio; P, IFNL4-P70; R, responders; S, IFNL4-S70.

Variant/
diplotype

Diploid
status

n

NR, n

R, n

R, %

OR, 95% CI

P value

Contribution of IFNL4-S70 and no-IFNL4 compared with IFNL4-P70 alone

IFNL4-P70 alone

P/N and P/P

26

15

11

42.3

Reference

 

IFNL4-S70 and S70/P70

N/S and P/S

15

3

12

80.0

5.23, 1.06 35.87

0.0254

no IFNL4

N/N

28

3

25

89.3

10.80, 2.39 69.97

0.000391

Contribution of IFNL4-S70 compared with no-IFNL4

no IFNL4

N/N

28

3

25

89.3

Reference

 

IFNL4-S70 and S70/P70

N/S and

P/S

15

3

12

80.0

0.49, 0.06 4.20

0.6474

These results were confirmed in 27 patients treated in the PEGINVERA trial, where a consistent trend for a better MR after PEG-IFN treatment was observed in patients lacking functional IFNL4 at 24 months follow-up (p = 0.068).

Conclusions

In patients with PV treated with PEG-IFN, lack of functional IFNL4 expression status confers a significantly better MR indicating deeper responses which the potential for cure. In contrast, no differences were observed for HR. These data may have implications for optimizing patient management during PEG-IFN treatment, warranting further confirmation in bigger patient cohorts.

  1. Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7(3):e196-e208. DOI: 10.1016/S2352-3026(19)30236-4

  2. Gisslinger H, Zagrijtschuk O, Buxhofer-Ausch V, et al. Ropeginterferon alfa-2b, a novel IFNalpha-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood. 2015;126(15):1762-1769. DOI: 10.1182/blood-2015-04-637280

  3. Delaneau O, Zagury JF, Marchini J. Improved whole-chromosome phasing for disease and population genetic studies. Nat Methods. 2013;10(1):5–6. DOI:  10.1038/nmeth.2307