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Epigenetic Study of Twins Shows Methylation Status Affects Sensitivity to Pain

NEW YORK (GenomeWeb News) – A genome-wide epigenetic analysis has linked the methylation status of a number of regions, including the gene TRPA1, to heat pain sensitivity, according to a study appearing today in Nature Communications.

Using a epigenome-wide association study-based approach drawing on 25 sets of identical twins discordant for heat pain sensitivity and 50 other, unrelated individuals, researchers led by Tim Spector at Kings College London found that DNA methylation changes to both novel and known genes is associated with sensitivity to pain.

"Our approach identifies epigenetic changes in both novel and established candidate genes that provide molecular insights into pain and may generalize to other complex traits," Spector and his colleagues wrote.

According to the US Institute of Medicine, acute and chronic pain affects a wide swath of Americans, with chronic pain in particular affecting about 100 million adults in the US, at a cost of $560 billion to $635 billion to the economy.

Spector and his colleagues performed MeDIP-sequencing on the 50 monozygotic twins — they were the most discordant pairs for heat pain tolerance as indicated by quantitative sensory testing of the TwinsUK cohort — and 50 unrelated individuals. From this they generated an average 50 million paired-end reads for each individual in the twin cohort and an average 25 million reads per person in the unrelated sample.

To search for differentially methylated regions, the researchers conducted two pain-sensitivity EWAS — one on each cohort — that they combined into a meta-analysis.

Through that meta-analysis, the researchers identified nine differentially methylated regions linked to pain sensitivity. Those nine DMRs mapped to eight distinct locations, including locales in the TRPA1 promoter, the OR8B8 transcription start site, and intergenic regions on chromosome 4, among others.

They validated their finding through a combination of bisulfite sequencing and using the Illumina 450k array.

The strongest signal, Spector and his colleagues noted, emanated from the promoter of the ion channel gene TRPA1. That promoter was hypermethylated in people with lower pain thresholds and, the researchers added, promoter methylation can down-regulate gene expression.

Further, in skin biopsies from 341 unselected female twins, they noted a nominal increase of TRPA1 gene expression in people with higher pain thresholds.

TRPA1 is a ligand-gated ion channel that in some species, like Drosophila, acts as a heat sensor, though it has not been reported to have that role in mammals. It is, though, regulated by and interacts with the thermosensor TRPV1. The researchers noted that both TRPA1 and TRPV1 are expressed in peripheral nociceptors as well as in non-neuronal cells like keratinocytes.

"[O]ur findings suggest the presence of a regulatory DNA methylation region in a CpG-island shore of the TRPA1 promoter, which may have an impact on TRPA1 gene expression and thermal sensitivity," Spector and his colleagues said.

Other top signals could be traced to other candidate genes like ST6GALNAC3 and MICAL.

In a separate cohort of 47 individuals, the researchers examined whether these DMRs contributed to pain sensitivity or a consequence of pain. They searched for methylation quantitative trait loci near the nine meta-analysis pain DMRs (MAP-DMRs), and found that six had evidence for cis meQTL effects. In addition, the researchers examined the discordant twin cohort to account for non-genetic risk factors, but found an enrichment of negative correlations between methylation and heat pain tolerance, results that they noted are consistent with hypermethylation.

For a subset of the twin cohort, the researchers also analyzed longitudinal MeDIP-seq and health pain tolerance data, and noted that for the nine MAP-DMRs, the methylation patterns they saw were fairly stable over time. Additionally, most of the MAP-DMRs exhibited similar methylation patterns in both blood and brain tissue samples.

"DNA methylation levels at a subset of MAP-DMRs showed longitudinal correlation with heat pain tolerance stability, genetic associations in cis, similar patterns across blood and brain tissues and correlations with skin gene expression," the researchers said. "Taken together, the results at these DMRs are consistent with an epigenetic influence on sensitivity to pain in normal human volunteers."