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German Team Finds Smoking-Related Methylation Change in Cardiovascular Gene

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Smoking behavior is linked to shifts in the methylation patterns for at least one cardiovascular-related gene, a new study suggests.

German researchers used microarrays to gauge methylation patterns in blood samples from nearly 200 individuals who smoke, have been smokers in the past, or have never smoked. The study, which appears online today in the American Journal of Human Genetics, suggests smokers have lower than usual methylation in a region of the genome falling in coagulation factor II receptor-like 3, or F2RL3 — a blood clotting gene that is thought to have additional roles in the cardiovascular system.

Those involved in the study argue that the previously unappreciated link may help explain how smoking affects the cardiovascular system and might ultimately lead to new strategies for treating individuals who can't kick the habit.

"Our results show that the gene coding for a potential drug target of cardiovascular importance features altered methylation patterns in smokers," corresponding author Lutz Breitling, a clinical epidemiology and aging researcher at the German Cancer Research Center, said in a statement.

Because smoking has previously been tied to methylation shifts across the genome and at cancer-related genes, the researchers reasoned that it might be possible to learn more about the pathogenic mechanisms of smoking by comparing epigenetic marks in individuals who smoke and those who don't. In particular, Breitling and his colleagues focused on CpG methylation, methylation occurring in situations where cytosine and guanine nucleotides neighbor one another.

"Given the recent accessibility of genome-wide locus-specific methylation methodology and previous support for a role of methylation changes in smoking-related pathologies, we conducted a genome-wide screen for CpG sites that are differentially methylated by tobacco-smoking status in peripheral-blood DNA," they explained.

Using the Illumina HumanMethylation 27K BeadChip array, they assessed CpG methylation patterns at nearly 27,600 sites in the genomes of 177 smokers, non-smokers, or former smokers. The participants ranged in age from 50 to 60 years old and were recruited through the ESTHER project, a population-based epidemiological study centered in southwest Germany.

Overall, the researchers' methylation array data pointed to decreased CpG methylation in smokers compared to non-smokers. When they looked for regions in the genome with statistically significant methylation changes, though, they found a lone site that reached genome-wide significance: a region within the F2RL3 gene.

This F2RL3 locus showed substantially lower methylation levels in smokers compared to both non-smokers and former smokers, the team found — findings they verified in a subset of samples from the initial cohort and in more than 300 more individuals using a Sequenom MALDI-TOF mass spectrometry MassArray assay.

Because the F2RL3 gene is known to participate in blood clotting, a process that seems to be negatively affected in smokers, the researchers speculated that this methylation difference might be a harbinger of smoking-related damage to the cardiovascular system.

Though they noted that more research is needed to explore that possibility and determine the functional consequences of these methylation differences, if any, the study authors argued that the gene may eventually serve as an attractive target for smoking-related drug development.

"Intriguing perspectives lie in the possibility that variants in this gene could be causally involved at a very initial stage of smoking-related cardiovascular pathology through the gene's role in endothelial physiology and platelet activation," they concluded. "In this case, better understanding of its role might open up avenues for preventing the development of associated disease in subjects unable to give up smoking."

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