GABRA5 rs35399885 single nucleotide polymorphism is significantly associated with sensory hypoesthesia and pain sensitivity
A. Enomoto1,2, S. Ohka1, D. Nishizawa1,3, Y. Ogai4,1, S. Kasai1, S. Ide1, J. Hasegawa1, K. Nakayama1,3, M. Hayashida5,6, N. Matsuura7, T. Ichinohe7, K. Fukuda2, K. Ikeda1,3
1Tokyo Metropolitan Institute of Medical Science, Addictive Substance Project, Tokyo, Japan, 2Tokyo Dental College, Department of Oral Health and Clinical Science, Tokyo, Japan, 3National Institute of Mental Health, National Center of Neurology and Psychiatry, Department of Neuropsychopharmacology, Tokyo, Japan, 4University of Tsukuba, Social Psychiatry and Mental Health, Faculty of Medicine, Ibaraki, Japan, 5Juntendo University School of Medicine, Department of Anesthesiology and Pain Medicine, Tokyo, Japan, 6Saitama Medical University International Medical Center, Department of Anesthesiology, Saitama, Japan, 7Tokyo Dental College, Department of Dental Anesthesiology, Tokyo, Japan
Background: Neuropathic pain and nociplastic pain are intractable chronic pain with no established treatment. In the central nervous system, inhibitory synaptic transmission is regulated by gamma-aminobutyric acid type A (GABAA) receptor, and impaired function of GABAA receptor can increase pain sensitivity. The GABRA5 gene, encoding the GABAA receptor α5 subunit, is reportedly associated with chronic pain in rats. In humans, the GABRA5 gene is associated with learning, psychiatric, and neurological diseases, whereas no reports exist on its association with pain. Since the GABRA5 rs35399885 single nucleotide polymorphism (SNP) is reportedly associated with panic disorder in humans, we investigated the association between the SNP and pain-related phenotypes in humans.
Aims & Objectives: This study aimed to clarify the association between the GABRA5 rs35399885 SNP and hypesthesia, a prodromal symptom of neuropathic pain, and pain sensitivity in humans.
Method: We evaluated the occurrence of postoperative hypesthesia in 303 patients (TD group: 116 males and 187 females) who underwent sagittal split ramus osteotomy at Tokyo Dental College. Pain sensitivity was evaluated using pressure pain thresholds on 500 healthy individuals from Azabu University and other institutions (NOC group: 253 males, 242 females, and 5 unknown). Using the previously obtained whole-genome genotyping data and additionally obtained TaqMan genotyping data with clinical data, statistical correlation analyses were performed (χ ² test, Kruskal-Wallis test, Jonckheere-Terpstra test, Mann-Whitney U test). This study was approved by each institutional ethics committee of Tokyo Dental College and Tokyo Metropolitan Institute of Medical Science (Approval Numbers: 1132 and 22-33).
Results: In the male TD group, the GABRA5 rs35399885 SNP was significantly associated with the development of hypesthesia (TT+CT vs CC, p = 0.0005), whereas no significant association was observed in the female TD group (TT+CT vs CC, p > 0.05). In the male TD group, patients with hypesthesia showed a higher proportion of CC genotype than in patients without hypesthesia (proportion of CC genotype: 42.1% in the hypesthesia group; 10.3% in the non-hypesthesia group).
Similarly, in the male NOC group, the GABRA5 rs35399885 SNP showed a significant association with pressure pain thresholds (TT+CT vs CC, p = 0.0312). The carriers of the CC genotype had higher pressure pain thresholds, indicating lower pain sensitivity, compared with the carriers of the TT+CT genotypes (median pressure pain threshold: TT+CT, 2.31 kg; CC, 2.71 kg). No significant associations were observed in the female NOC group (TT+CT vs CC, p > 0.05).
Similarly, in the male NOC group, the GABRA5 rs35399885 SNP showed a significant association with pressure pain thresholds (TT+CT vs CC, p = 0.0312). The carriers of the CC genotype had higher pressure pain thresholds, indicating lower pain sensitivity, compared with the carriers of the TT+CT genotypes (median pressure pain threshold: TT+CT, 2.31 kg; CC, 2.71 kg). No significant associations were observed in the female NOC group (TT+CT vs CC, p > 0.05).
Discussion & Conclusions: In this study, the GABRA5 rs35399885 SNP is associated with hypesthesia and pain sensitivity in a sex-dependent manner. Since metabolites of male sex hormone reportedly enhance inhibitory synaptic transmission via GABAA receptor, endogenous regulation through GABAA receptor may contribute to pain-related phenotypes in males. Furthermore, in males, the carriers of the CC genotype of the GABRA5 rs35399885 SNP may exhibit enhanced GABAA receptor function, suppressing sensory input into the central nervous system, leading to hypesthesia and lower pain sensitivity. In human males, the GABRA5 rs35399885 SNP could be a genetic factor underlying individual differences in hypesthesia, a prodromal symptom of neuropathic pain, and pain sensitivity.
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