Annual Meeting Research Awards

Blood Methylation QTLs Associated with Chronic Post-Surgical Pain – A Novel, Pilot Study

By Vidya Chidambaran, MBBS, MD; Xue Zhang; Valentina Pilipenko; Xiaoting Chen; Lisa J. Martin; Matthew T. Weirauch; Hong Ji
Department of Anesthesiology, and Division of Human Genetics
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio

Chronic post-surgical pain (CPSP) is a significant clinical problem, influenced by genetic and environmental factors. Our previous genetic-epigenetic studies showed considerable overlap between pathways enriched for genetic variants and epigenetic loci (DNA methylation (DNAm)) associated with CPSP. Since most genetic variants associated with CPSP are non-coding with no known function, we sought to identify if they might have regulatory function, influencing CpG-DNAm influencing CPSP development (methylation quantitative trait loci (meQTL)). We prospectively recruited 74 children undergoing spine fusion (age 14.4 (±1.7) years, 79.7% white, 85.1% female). We collected data about psychological variables, perioperative pain and followed them for 6-12 months after surgery for pain outcomes. CPSP was defined as pain score >3/10 6-12 months post-surgery. Blood samples collected pre-operatively were genotyped and DNAm assayed using commercial arrays.

CPSP incidence was 20/58 (34.5%). After QC/adjusting for covariates, 49,058 variants and DNAm at 680 CpG sites were associated with CPSP (p<0.05). There were 2753 meQTL affecting DNAm at 480 CpG sites identified by testing association between these SNPs and CpG sites (p<0.05; ≥5% change in DNAm). Using causal inference tests (CITs), we found that DNAm at 127 CpGs mediated associations between 470 SNPs and CPSP.  The meQTLs within the PARK16 locus, a genomic region with dopamine regulatory effects, were found to influence regions differentially methylated for CPSP.  Bioinformatics analyses showed enrichment for transcription factor binding sites at these loci for members of the AP-1, Ets, and homeobox families at and within 100bp of the CpG sites.

Our pilot findings are suggestive of novel molecular mechanisms underlying genetic associations with CPSP. These findings could spur new research into biomarkers and modifiable strategies in genetically susceptible individuals.