Thursday, 24 August 2017

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 find it hard to believe is because it is based on efficacy, but before you start-yes I accept it appears to be very good for some people, so I think it is based on 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 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....Do they see the big picture?

CoI: None.

Wednesday, 23 August 2017

Effect of DMF is colourblind

Efficacy and Tolerability of Delayed-release Dimethyl Fumarate in Black, Hispanic, and Asian Patients with Relapsing-Remitting Multiple Sclerosis: Post Hoc Integrated Analysis of DEFINE and CONFIRM.Fox RJ, Gold R, Phillips JT, Okwuokenye M, Zhang A, Marantz JL.Neurol Ther. 2017 . doi: 10.1007/s40120-017-0077-5. [Epub ahead of print]

INTRODUCTION:Clinical course and treatment response may vary according to race/ethnicity in multiple sclerosis (MS) patients. Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated significant efficacy and a favorable benefit-risk profile in relapsing-remitting MS (RRMS) patients in the 2-year phase III DEFINE/CONFIRM studies.
METHODS:In this post hoc analysis of integrated data from DEFINE/CONFIRM, we assessed clinical efficacy and safety/tolerability in black, Hispanic, and Asian patients treated with DMF 240 mg twice daily (approved dosage) or placebo. Eligible patients were 18-55 years of age with an Expanded Disability Status Scale score of 0-5.0. In the integrated intention-to-treat population, 769 and 771 patients were treated with DMF or placebo, respectively, of whom 10 and 19 were black, 31 and 23 were Hispanic, and 66 and 70 were Asian.
RESULTS:In the black, Hispanic, and Asian subgroups, DMF was associated with lower annualized relapse rates at 2 years compared with placebo [rate ratio (95% confidence interval (CI)), 0.05 (0.00-1.07); 0.31 (0.10-0.95); and 0.64 (0.30-1.34), respectively]. The percentage of black, Hispanic, and Asian patients with 12-week confirmed disability progression was lower with DMF (43%, 8%, and 20%, respectively) compared with placebo [57%, 30%, and 25%, respectively; hazard ratio (95% CI), 0.53 (0.02-1.39); 0.17 (0.00-0.60); and 0.71 (0.32-1.58), respectively]. The safety/tolerability profile of DMF was generally consistent with that in the overall population of DEFINE/CONFIRM. The incidence of adverse events leading to treatment discontinuation in black, Hispanic, and Asian patients was 2/10, 2/31, and 3/66, respectively, with DMF, and 2/19, 1/23, and 8/70, respectively, with placebo.
CONCLUSION:DMF may be an efficacious treatment with a favorable benefit-risk profile in black, Hispanic, and Asian patients with RRMS. Further clinical studies are needed to characterize differences in MS presentation and treatment outcomes across ethnic and racial groups.

You can all read the conclusions that DMF is effective in people irrespective of their skin colour.. Strange study to do but there you go.

Tuesday, 22 August 2017

A bygone era: AZA, MTX, CYC increase cancer risk in MS

BMC Neurol. 2017 Aug 8;17(1):155. doi: 10.1186/s12883-017-0932-0.

Association between multiple sclerosis, cancer risk, and immunosuppressant treatment: a cohort study.

Ragonese P, Aridon P, Vazzoler G, Mazzola MA, Lo Re V, Lo Re M, Realmuto S, Alessi S, D'Amelio M, Savettieri G, Salemi G.



The association between multiple sclerosis (MS) and cancer has long been investigated with conflicting results. Several reports suggest an increased cancer risk among MS patients treated with immunosuppressant (IS) drugs.


We performed a cohort study including MS patients recruited at the Neurological Department of the University of Palermo. Mean follow-up period was ten years for the whole cohort. We calculated cancer incidence among patients treated with IS. Incidence rates were compared in the cohort by calculating the relative risk according to length and dose of exposure to IS. Cancer incidence among MS patients was compared to cancer incidence in the general population of Sicily in similar age groups.


On an overall cohort of 531 MS patients (346 women and 185 men) exposed to IS, we estimated a crude incidence rate for cancer of 2.26% (2.02% in women, 2.7% in men). Cancer risk was higher compared to rates observed among an equal number of patients not exposed to IS, and to the risk in the general population in Sicily at similar age groups (adjusted HR: 11.05; CI 1.67-73.3; p = 0.013).


The present study showed a higher cancer risk in MS patients associated only to previous IS exposure. Studies on long-term outcomes are essential to evaluate the possibility that treatment options that need to be considered for a long time-period may modify risk for life threatening diseases.

The association between MS therapies and cancer risk is neither simple nor clear cut. However, context is all, and cancer is undoubtedly the single most important thing in a person's life - not too banal to be buried under some statistic or to exercise tolerance over...And yet our understanding of it has not improved. A work in progress.

Here, Ragonese et al., report that simply having MS does not increase your cancer risk. Although, other epidemiological research have alluded to a link based on the type of cancer. The authors, however did note an increase cancer risk in those who took the older immunosuppressant drugs - azathioprine (AZA), mitoxantrone (MTX) and cyclophosphamide (CYC); compared to age-adjusted controls (hazard ratio 11.05; 95% CI 1.67-73.3). This risk appears to be largely driven by AZA and MTX, rather than CYC where no cancers were observed (although the group receiving CYC was small and the follow up was not as long as for the other drugs). The average treatment period was 5y for AZA and 1y for MTX, but this alone led to a 4-fold increase in cancer. With MTX, the association was with leukaemia, which is a known risk of the drug. We no longer use AZA/MTX in MS, but continue to do so in neuromyelitis optica, sarcoidosis, for example, and as such should be more cautious over their long-term use. Improved surveillance programmes may be the answer.

Unfortunatly, this work does not look at the newer agents (Copaxone, Interferons, and monoclonal antibody therapies). Again, the data on this from other studies are conflicting, and it's not certain whether these drugs are exposing an intrinsic cancer susceptibility in MS.

In summary, cancer risk from immunosuppressant use is a realistic one. It is a debate worth having. Make it your agenda for this year and the next.

Monday, 21 August 2017

In Top 50 MS blogs

Got Email to say we are in top 50 MS blogs.....Ta.....However no links to their website even from the picture..So you'll have to guess who ;-)

Gene expression is controlled in MS the effect of Carbon and hydrogen

Pinto-Medel MJ, Oliver-Martos B, Urbaneja-Romero P, Hurtado-Guerrero I, Ortega-Pinazo J, Serrano-Castro P, Fernández Ó, Leyva L.Global methylation correlates with clinical status in multiple sclerosis patients in the first year of IFNbeta treatment.
Sci Rep. 2017;7(1):8727.

The alteration of DNA methylation patterns are a key component of disease onset and/or progression. Our objective was to evaluate the differences in Long Interspersed Nuclear Element-1 (LINE-1) methylation levels, as a surrogate marker of global DNA methylation, between multiple sclerosis (MS) patients and healthy controls. In addition, we assessed the association of LINE-1 methylation with clinical disease activity in patients treated with IFNbeta (IFNβ). We found that individuals with high levels of LINE-1 methylation showed 6-fold increased risk of suffering MS. Additionally, treated MS patients who bear high LINE-1 methylation levels had an 11-fold increased risk of clinical activity. Moreover, a negative correlation between treatment duration and percentage of LINE-1 methylation, that was statistically significant exclusively in the group of patients without clinical activity, was observed. Our data suggest that in MS patients, a slight global DNA hypermethylation occurs that may be related to the pathophysiology of the disease. In addition, global DNA methylation levels could play a role as a biomarker for the differential clinical response to IFNβ.

So in this study it implicates hypermethylation as a problemChomyk AM, Volsko C, Tripathi A, Deckard SA, Trapp BD, Fox RJ, Dutta R.DNA methylation in demyelinated multiple sclerosis hippocampus.Sci Rep. 2017 ;7(1):8696

Multiple Sclerosis (MS) is an immune-mediated demyelinating disease of the human central nervous system (CNS). Memory impairments and hippocampal demyelination are common features in MS patients. Our previous data have shown that demyelination alters neuronal gene expression in the hippocampus. DNA methylation is a common epigenetic modifier of gene expression. In this study, we investigated whether DNA methylation is altered in MS hippocampus following demyelination. Our results show that mRNA levels of DNA methyltransferase were increased in demyelinated MS hippocampus, while de-methylation enzymes were decreased. Comparative methylation profiling identify hypo-methylation within upstream sequences of 6 genes and hyper-methylation of 10 genes in demyelinated MS hippocampus. Genes identified in the current study were also validated in an independent microarray dataset generated from MS hippocampus. Independent validation using RT-PCR revealed that DNA methylation inversely correlated with mRNA levels of the candidate genes. Queries across cell-specific databases revealed that a majority of the candidate genes are expressed by astrocytes and neurons in mouse and human CNS. Taken together, our results expands the list of genes previously identified in MS hippocampus and establish DNA methylation as a mechanism of altered gene expression in MS hippocampus.

In this study some genes are methylated others are not

Methylation is the addition of a methyl group which is one carbon atom and three hydrogen atoms

DNA contains combinations of four nucleotides which include cytosine, guanine, thymine and adenine. DNA methylation refers to the addition of a methyl (CH3) group to the DNA strand itself, often to the fifth carbon atom of a cytosine ring. This conversion of cytosine bases to 5-methylcytosine is catalysed by DNA methyltransferases (DNMTs). These modified cytosine residues usually lie next to a guanine base (CpG methylation) and the result is two methylated cytosines positioned diagonally to each other on opposite strands of DNA.

Different DNMTs work together either as nw DNMTs, establishing the methyl group pattern on a sequence of DNA or as maintenance DNMTs that copy the methylation pattern on an existing strand of DNA to its new partner following replication. Methylation is sparse but global in mammals, found in CpG sequences across the entire genome, aside from certain stretches (of around one kilobase) where the content of CpG is high (CpG islands). When those sequences are methylated, the result can be silencing of gene.
This also enables the expression of retroviral genes to be suppressed, 

What does it all mean, i don't know at present but this is a way that gene function can be altered.