Parkinson's disease: the protective role of cigarette smoking is based on interactions with certain genes

Science

The reduced risk of Parkinson's disease observed in smokers can be explained by the interaction of several genes with the tobacco. The underlying mechanisms and cigarette smoke compounds implicated remain to be elucidated.

According to epidemiological data, smokers have a 40% lower risk of developing Parkinson's disease in relation to non-smokers. What? Tobacco - good for health? A provocative enough observation to pique the interest of the researchers. Are we talking about a genuine protective effect of the tobacco related to a biological mechanism? Or rather interpretation bias? To try to answer this question, a team headed by Alexis Elbaz* has recently studied the interactions between tobacco and genetics. Its research suggests that two genes – RXRA and SLC17A6 – could be responsible for modulating the relationship between tobacco and Parkinson's disease. Since the two proteins coded by these genes play a role in neurotransmission, this research supports the idea of protection conferred by the tobacco in connection with an underlying biological mechanism. "Obviously, the idea isn't to encourage people to smoke, insists the researcher, but rather to identify the compounds in tobacco smoke which would be responsible for this interaction, as well as the biological mechanisms involved". This would make it possible, in the longer term, to envisage prevention or even treatment approaches in Parkinson's disease, were these results to be confirmed.

Parkinson's disease is a neurodegenerative disease characterized by the gradual destruction of the dopaminergic neurons located in the substantia nigra, a region of the brain implicated in motricity. Its onset is based on both genetic and environmental factors. A number of genes have been identified as being able to favor the onset of the disease but, for the most part, they have low penetrance: in other words, only a minority of the carriers of one or other of these genes develops Parkinson's disease. In reality, these genetic particularities constitute a first step towards the disease, but only their interaction with one or more environmental factors – such as exposure to pesticides - would lead to its development. Conversely, the epidemiological data which describe fewer smokers or ex-smokers with Parkinson's would suggest that certain interactions can be protective.

Two genes among others...

To investigate the potential interaction of tobacco with genes, the team of researchers adopted an approach devoid of preconceptions: it chose to examine 298 genes involved in susceptibility -absorption, transport, breakdown, elimination- to xenobiotics (substances foreign to the body) in order to observe whether some of these were distributed differently in sufferers in comparison with healthy subjects, and this according to their smoking habits -current or former smokers versus non-smokers.

Based on a French study on 513 sufferers compared with 1147 controls, genetic analysis revealed 9 single nucleotide polymorphisms (SNP) implicated in interaction with tobacco. Two of these were then confirmed on the basis of analyses conducted on a US cohort of 1,200 subjects, including both patients and controls. Interestingly, explains Alexis Elbaz, “the genes carrying these SNPs – RXRA and SLC17A6 – respectively code for a retinoic acid receptor implicated in the dopaminergic system, and for a glutamate transporter whose transmission is disrupted in the disease”.

Now, we must conduct the same analysis within a larger patient cohort in order to fully validate these results. This research has now been scheduled and over the coming months will gather data from 25,000 European patients, he envisages. Furthermore, we have since then revealed an interaction of other genes with tobacco. Indeed, by taking a different approach, the team has identified another interaction between tobacco and the HLA-DRBA1 gene in Parkinson’s disease. "These results make it possible to identify the biological mechanisms to be studied: indeed, if these genes influence the relationship between cigarette smoking and disease onset, they constitute just as many avenues to explore in order to fully elucidate the initial pathophysiological mechanisms”.

Note :

*unit 1018 Inserm/Versailles Saint-Quentin-en-Yvelines University/Paris-Sud University, Center for Research in Epidemiology and Population Health, Epidemiology of aging and age-related diseases team, Villejuif

Source

  • Lee PC et coll. Smoking and Parkinson disease Evidence for gene-by-smoking interactions. Neurology 2018, 90:e1-e10. doi:10.1212/WNL.0000000000004953
  • Chuang YH et coll. Pooled Analysis of the HLA-DRB1 by Smoking Interaction in Parkinson Disease. Ann Neurol. 2017 Nov, 82(5):655-664. doi: 10.1002/ana.25065

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