Background & Aims
Sickle cell disease (SCD) is a hereditary blood disorder characterized by recurring, intense acute pain episodes as well as persistent, ongoing chronic pain. Amidst the high prevalence and severity of sickle cell pain, the substantial variability in pain phenotypes among patients with SCD compounds the intricacy of pain management. This study aims to explore gene-sex interaction contributing to the heterogeneous nature of pain in SCD.
Methods
At the University of Illinois Health Sickle Cell Center, USA, 131 self-reported African American patients with SCD were recruited as study subjects. The chronic pain phenotype was measured using a modified McGill Pain Questionnaire assessment and quantified as the Composite Pain Index (CPI) on a scale of 0-100. Instances of acute care utilization due to painful crises were recorded and categorized into three groups as a measure of acute crisis pain. Genotyping of candidate gene polymorphisms was conducted using the MassARRAY-iPlex platform. The association of genetic variants with chronic pain and acute pain was assessed through multiple linear regression and negative binomial regression analyses, respectively. To explore sex-specific effects, a variant-sex interaction term was incorporated into the regression model. Subsequent analyses were carried out independently for males and females to further evaluate the stratification.
Results
The high inter-individual variability in sickle cell pain is evident in our patient cohort, as reflected by a broad range of chronic pain scores (CPI: 14.8 ~ 86.5) and instances of acute pain (0 ~ 38 crisis-related hospitalizations in one year). Among the 221 single nucleotide polymorphisms (SNPs) across 80 genes investigated in the present study, multiple variants exhibited significant associations (P < 0.05) with acute crisis pain and/or chronic pain in a sex-specific manner. For instance, the association of three SNPs in 5-HT1A receptor gene (HTR1A) with acute crisis pain was significant only in male, and not in female patients with SCD. Additionally, two SNPs in S100B gene and their haplotype variants were associated with chronic pain in female, but not male patients with SCD. We further performed network-assisted clustering of these genes containing sex-dependent pain-associated SNPs. A polygenetic-sex interaction network was revealed contributing to pain heterogeneity in SCD.
Conclusions
This is the first study to explore the interaction between sex and gene polymorphisms in sickle cell pain. We identify multiple variants across the genome associate with acute crisis pain and chronic pain in SCD in a sex-specific manner. Our findings reveal a polygenetic-sex interaction network, which holds great promising implications for precision pain management in SCD.
References
N/A
Presenting Author
Ying He
Poster Authors
Ying He
PhD
University of Illinois Chicago
Lead Author
Topics
- Gender/Sex Differences