COPD: Lucky Strike Thanks Marlboro-Gene

7. December 2015
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The fact that smoking causes COPD is nothing new. However, not all smokers develop the disease - a new British study has now identified genetic differences that influence smoking behaviour and predisposition to lung disease.

For the study published in September 2015 in Lancet Respiratory Medicine Studies, the researchers led by Professor Martin Tobin from the University of Leicester and Professor Ian Hall from the University of Nottingham investigated a sample of 50,008 Britons. They chose, from the UK BiLEVE register, 10,002 samples from individuals with low FEV1, 10,000 from people with moderate FEV1 and 5,002 samples from individuals with high FEV1 – both from the group of heavy smokers as well as from the group of people who had never smoked in their lives.

The researchers identified six loci that have an impact on lung health: KANSL1, TSEN54, TET2, RBM19/TBX5, NPNT and HLA-DQB1/HLA DQA2. Several of these genes suggest that epigenetic mechanisms play a role in the pathogenesis of lung diseases such as COPD: In KANSL1 is a subunit of the NSL1 protein complex. This complex is involved in histone acetylation and so affects how accessible the DNA is for transcription. Inflammatory processes could be regulated in the lung tissue in this way. The TET2 gene encodes methylcytosine dioxygenase 2, an enzyme that controls the degree of methylation of the DNA and plays a role in the adaptive immune response by controlling the differentiation of CD4+ T cells.

Mutations with a wide variety of effects

Besides epigenetics, lung development apparently plays a role in the pathogenesis of COPD: The protein HHIP has long been known to influence lung health and growth. Now the researchers were able to confirm that HHIP also mediates susceptibility to COPD. In addition, the researchers found several genetic variants that influenced smoking behaviour: CHRNA3 and CHRNA5 concern nicotinic acetylcholine receptors – it is hardly surprising that these genes are associated with smoking behaviour. NCAM1 is a membrane-bound glycoprotein that mediates adhesion of nerve cells and has so far not been linked with nicotine addiction. Since the researchers have now identified certain NCAM1 variants as genetic markers for smoking, in the future it will be important to find out how exactly NCAM influences addictive behaviour.

The results of the study provide the first evidence of new molecules and mechanisms that affect lung health and are involved in the pathogenesis of lung disease. “Understanding how genes affect disease and tobacco addiction can help us to design and develop better and more targeted therapies, which will probably be more effective and have fewer side effects” says study leader Hall. However, it will be some time before new treatments for lung diseases like COPD are available. The first step is to confirm the results using a larger collective and elucidate the molecular mechanisms behind the newly-discovered association between certain genes and lung health and smoking behaviour.

Environment, genes, epigenetics: factors at play

Even before the study was published, there were indications that epigenetic modifications control local inflammation in the lungs. In 2005, British researchers found that the histone deacetylase activity in the lungs of COPD patients is reduced. This leads to hyperacetylation resulting in an overexpression of inflammatory genes and increased production of proinflammatory cytokines. The study by Tobin and Hall now suggests that mutations in genes that control epigenetic regulation can make the lung susceptible to harmful environmental factors such as cigarette smoke.

But cigarette smoke has also a direct effect on the epigenetic code: Many groups have shown that in the lung tissue of smokers DNA methylates and histones acetylates are abnormal. Cigarette smoke causes oxidative stress which plays a key role. Oxidative stress can, as an example, increase the expression and activity of the DNA methyltransferase 1 enzyme and thus lead to hypermethylation promotion, through which target genes can be switched off. Similarly, reduced oxidative stress causes the expression and activity of histone deacetylase 2 (HDAC2). After all, although these epigenetic changes are detected for many years after the cessation of smoking, they seem to be at least partially reversible.

Epigenetic therapies: A new hope…

Despite all the research on epigenetic issues, epigenetics is not yet part of everyday medical practice – with a few exceptions. Researchers like Dr. Heinz Linhart from the National Centre for Tumour Diseases in Germany has nevertheless already shown [Paywall] that epigenetic modifications such as methylation may be useful in diagnosis. “Since methylcytosine is very sensitive and cost-efficient, tumour-associated methylation changes are outstandingly suitable as diagnostic markers,” says Linhart.

But even in therapy, epigenetics offers new possibilities: The expression profile of genes to alter selectively, for example using histone deacetylase inhibitors, could be effective in a variety of diseases, for example, malignant tumours, neurodegenerative disease, Diabetes mellitus and cardiovascular disease. And as the study by Tobin and Hall demonstrated, this is possible in COPD, since epigenetic changes are the cellular response to cigarette smoke and other pollutants in the air.

…or is it a lot of hot air about nothing?

So far there is, however, only a handful of drugs that are based on epigenetic mechanisms. These include cytostatic azacitidine, approved since 2009 for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). The incorporation of the substance into the DNA results in the inactivation of DNA methyltransferases and thus reduces the degree of DNA methylation. Decitabine also acts as a DNA methyltransferase inhibitor; it has been approved since 2012 for the treatment of AML. Like all chemotherapeutic drugs, azacitidine and decitabine also have a number of side effects including severe haematological reactions such as thrombocytopenia, neutropenia and leucopenia.

Vorinostat is a histone deacetylase inhibitor; the NDA for the treatment of advanced cutaneous T-cell lymphoma (CTCL) has, however, been provided by the manufacturer. And the HDAC inhibitor Romidepsin ekes out a shadow existence as Orphan Drug: The EMA refused drug market approval in 2010. The manufacturer of the HDAC inhibitor Belinostat has meanwhile learned from the debacles of the competition and still not applied to the Orphan Drug EMA. In the US, however, it is the agent for the treatment of peripheral T-cell lymphoma (PTCL). Numerous other HDAC inhibitors are currently being investigated in clinical studies; indications are hematologic and solid tumours such as lung, breast and bladder cancers.

One reason for the rather disappointing results might be that pharmacological manipulation of such important epigenetic regulators such methylases and acetyltransferases always influences an entire network of genes. If such a central switch is removed as part of epigenetic therapy, “then you will also trigger very unspecific activations or shutdowns of genes,” says Professor Thomas Tuschl from Rockefeller University in New York. “The simultaneous change in many of the components does not have predictable consequences. But therein lies precisely the fascination and sometimes the secret of new drugs”.

Original publication:

Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): a genetic association study in UK Biobank
Ian P. Hall et al.; Lancet Respiratory Medicine, doi: 10.1016/S2213-2600(15)00283-0; 2015

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Professor Jacques De Grève
Professor Jacques De Grève

Indeed, manipulation of epigenetics is sofar not able to address specific genes.
Better not to smoke.

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