Sex-stratified association of variants in the serotonin 1A receptor gene with acute crisis pain among African American patients with sickle cell disease

Patients with sickle cell disease (SCD) experience pain in their daily lives. Both the acute and chronic pain phenotypes of this disease exhibit high variability, making pain management a challenge. The underlying reasons for the phenotypic variability are poorly understood. Given the importance of serotonergic neurotransmission in pain signaling, we aimed to explore the role of variants in the 5-HT1A receptor gene (HTR1A) on pain variability in SCD. Four variants (rs6449693, rs878567, rs6294, and rs10042486) in HTR1A were genotyped in a cohort of 131 African Americans with SCD. Acute and chronic pain were measured by the acute care utilization and the McGill Pain Questionnaire, respectively. Association analyses were performed for three genetic models (additive, dominant, and recessive). Three variants (rs6449693, rs6294, and rs10042486) in HTR1A showed significant association with crisis pain in both the additive and dominant models. Although the G allele of rs6449693 and the C allele of rs10042486 associated with lower acute crisis pain, the T allele of rs6294 associated with increased acute crisis pain. Sex-stratified analyses revealed that the associations of these three variants with acute pain were significant only in men, but not in women. Furthermore, the A allele rs878567 that did not reach statistical significance in the overall cohort showed a significant association with lower crisis pain in men. To our knowledge, as the first study to explore the role of HTR1A variants in sickle cell pain, we identified that four variants across the gene are associated with acute crisis pain in SCD in a sex-stratified manner.