Genes and response to interferons

Bertoli D, Serana F, Sottini A, Cordioli C, Maimone D, Amato MP, Centonze D, Florio C, Puma E, Capra R, Imberti L.Less Frequent and Less Severe Flu-Like Syndrome in Interferon Beta-1a Treated Multiple Sclerosis Patients with at Least One Allele Bearing the G&C Polymorphism at Position -174 of the IL-6 Promoter Gene.
PLoS One. 2015;10(8):e0135441

One of the most common adverse event of interferon beta (IFNβ) therapy for multiple sclerosis is flu-like syndrome (FLS), which has been reportedly related to increased levels of cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Average cytokine levels can be affected by single nucleotide polymorphism in the gene promoter regions. To investigate whether IL-6 -174 G>C and TNF-α -376 G>A polymorphisms could be correlated to the incidence of FLS, and whether an anti-inflammatory/antipyretic therapy may influence FLS development, a prospective observational study was performed in 190 treatment naïve, multiple sclerosis patients who started IM IFNβ-1a 30mcg once weekly. The identification of IL-6 -174 G>C and TNF-α -376 G>A polymorphisms was achieved by performing an amplification-refractory mutation system. Serum IL-6 levels were measured using enzyme-linked immunosorbent assay in blood samples taken before therapy and then after the first and last IFNβ-1a injection of the follow-up. FLS-related symptoms were recorded by patients once per week during the first 12 weeks of therapy into a self-reported diary. We found that patients carrying at least one copy of the C allele at position -174 in the promoter of IL-6 gene produced lower levels of IL-6 and were less prone to develop FLS, which was also less severe. On the contrary, the polymorphism of TNF-α had no effect on FLS. Patients taking the first dose of anti-inflammatory/antipyretic therapy in the peri-injection period (within 1 hour) experienced a reduced FLS severity. In conclusion, the study of IL-6 -174 G>C polymorphism would allow the identification of patients lacking the C nucleotide on both alleles who are at risk of a more severe FLS, and may be addressed to a timely and stronger anti-inflammatory/anti-pyretic therapy for a more effective FLS prevention.

The promoter region of a gene contains regulatory elements that influence secretion of a protein. In this study they found that if you have a certain gene variant in the interleukin 6 gene that you were less likely to have flu like symptoms after beta interferon injection. Interleukin 6 is produced in response to infection and is known as an endogenous pyrogen (heat) and can induce fever, as heat can help destroy some bacteria. In this study they found that one gene variant was associated with more IL-6.

So now you say you are full of mushroom food MD, because if  you were genotyped it could tell you if you were going to get flu-like symptoms and explain why this is happening. While this may be part of the explanation, some one with the associated gene variant may make less IL-6 than someone without the gene variant because there is overlap as can be seen in figure B above and people without the variant get flu like symptoms. So at present it is a small piece of a bigger jigsaw.

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  • It is known that for some people IFN-B-1A can make some or all of your MS symptoms worse, despite the intention being that the drug will reduce relapse rates. I wonder if there is a relationship between people who experience this problem and the level of flu-like side effects experienced.

    I know that Rebif made everything worse for me, and I also never stopped suffering the flu-like side effects in the year that I was on Rebif. The NSAIDS taken to counter the flu-like side effects also caused other problems after such long term use.
    (maybe I just put my genes on back to front………..)

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