## 3 Discussion
Although we do not know whether the amino acid substitution causes a decrease in the PAF-AH enzymatic activity of PLA2G7, it is possible that PAF-AH activity in an aliquot of plasma decreases in the order of TT \(>\) TC \(>\) CC, and the concentration of PAF would be TT \(<\) TC \(<\) CC, which is consistent with the clinical findings in the present study, in which the development of dysesthesia and postoperative pain were TT \(<\) TC \(<\) CC. Microglia and macrophages are involved in neuropathic pain [41; 42] and are potential PAF-producing cells that are involved in the onset of neuropathic pain in mice [43]. In the public GTEx Portal database, eQTL results of the _PLA2G7_ rs1051931 SNP showed that genotypes of _PLA2G7_ rs1051931 affect _PLA2G7_ mRNA expression levels in the basal ganglia [40]. Another public database, the Human Protein Atlas, showed that macrophages highly express _PLA2G7_ in both the central nervous system and blood, and microglia express _PLA2G7_[44]. Although PAF and PLA2G7 do not penetrate the blood-brain barrier (BBB) [45], PAF is produced and PLA2G7 is expressed even inside the BBB [46], probably by microglia and macrophages. The increase in local concentrations of PAF inside the BBB that depends on genotypes of _PLA2G7_ rs1051931 may stimulate microglia and macrophages in an autocrine and paracrine manner, which would lead to an inflammatory response and the exacerbation of pain in humans. Public data extraction using the ZENBU genome browser revealed that the _PLA2G7_ rs1051931 SNP is located around 300-500 bp upstream of the enhancer region in immune cells and the brain, including CD14 primary cells, the anterior caudate, and the dorsolateral prefrontal cortex (Supplementary Table S1) [47]. DNase-Seq results showed that the _PLA2G7_ rs1051931 SNP is located around 300-500 bp upstream of the genome region with high signals on DNase-Seq on the chromosome of immune cells (score \(>\) 15: CD14 and CD15 blood primary cells and CD14 monocytes), and relatively high signals detected in many tissues, including in the brain (Supplementary Table S2) [47]. DNase-Seq signals indicated that the regions contain open chromatin and are thought to contribute to transcription. CD14 is expressed in both microglia and macrophages and plays an essential role in brain injury in these cells [48; 49]. CD14-positive immune cells, including macrophages, highly express _PLA2G7_[50; 51; 52]. The regions on the chromosome downstream of the _PLA2G7_ rs1051931 SNP would contribute to transcriptional activity of _PLA2G7_ as an enhancer, mainly in CD14-positive immune cells including microglia/macrophages. Together with the fact that CD14-positive cells play a crucial role in the expression of pain-related molecules in human degenerated intervertebral discs [53], PLA2G7 expression in CD14-positive cells, including microglia/macrophages, would contribute to pain development, depending on genotypes of the _PLA2G7_ rs1051931 SNP, through PAF-AH activity. In the present study, the allele frequencies of the _PLA2G7_ rs1051931 SNP in different regional populations were the following. In the TD group, the frequency of the T allele was 9% and the frequency of the C allele was 91%. In the JUH group, the T allele frequency was 10%, and the C allele frequency was 90%. According to the 1000 Genomes Project SNP database [35, 47, 54], the T allele frequency in East Asian populations is 9% and the C allele frequency is 91%. In South Asian populations, the T allele frequency is 14% and the C allele frequency is 86%. In American populations, the T allele frequency is 15% and the C allele frequency is 85%. In African populations, the T allele frequency is 28% and the C allele frequency is 72%. In European populations, the T allele frequency is 24% and the C allele frequency is 76%.