Glatiramer acetate affected gene linked to heart disease gene: A shaggy dog story

Brænne I, Zeng L, Willenborg C, Tragante V, Kessler T; CARDIoGRAM Consortium; CARDIoGRAMplusC4D Consortium, Willer CJ, Laakso M, Wallentin L, Franks PW, Salomaa V, Dehghan A, Meitinger T, Samani NJ, Asselbergs FW, Erdmann J, Schunkert H. Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk. PLoS One. 2017 Aug 22;12(8):e0182999

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.

Copaxone is currently the number one best selling MS drug, which I think it is based on its safety.

As a non-medic I don't pay much attention to the side effects of the MS drugs, as I have other things I have to bother about, so was surprised to see this paper surface.

The cardiotoxic effects of mitoxantrone are well known and is a reason why the dosing is limited.

Fingolimod is associated with heart arrhythmias on first use, but heart disease and copaxone?

Post injection changes in heart rate after use of GA is known and easily found and this can lead to hypertension...but artery disease. This made me look at this one.

In the study they looked at genes affected by copaxone

These were a chemokine CCR5, immune response gene (HLA-DR)m interferon alpha and transforming growth factor which are immunomodulatory genes. They looked at the adverse events on websites plucked out heart attack and then did a genome of coronary heart disease and found that Transforming growth factor was a risk factor. The variants associated with CAD are influenced by copaxone.

So do I take it that copaxone causes heart attack....em.

If you look at risks in the post trial marketing experience and you look under cardiovascular risks yo can see:

thrombosis; peripheral vascular disease; pericardial effusion; myocardial infarct; deep thrombophlebitis; coronary occlusion; congestive heart failure; cardiomyopathy; cardiomegaly; arrhythmia; angina pectoris

However, this may, not be causal.  Companies give this information to mitigate risk to themselves.  When an adverse event occurs they have to record and report it. Alot may occur and then you can see a link to a drug, but if you do a literature search of heart disease and copaxone you don't find anything. So I would not be unduly worried.

A quick look and the SNP rs12459996 is associated with myopia...does this mean that people taking copaxone are short-sighted...Em..

CoI: None.