Pain in SCD: Are Genetic Variations Responsible?

A study published in Gene Reports suggested that small nuclei polymorphisms (SNPs) are associated with non-crisis pain in patients with sickle cell disease (SCD). Furthermore, there may be sex-specific associations affecting this patient population.¹

Genetic variation and sex-specific differences may be related to pain in SCD | image credit: Lila Patel - stock.adobe.com

SCD is a group of inherited hemoglobinopathies that are characterized by mutations in the β-globin chain of hemoglobin.² Patients with SCD suffer from chronic hemolytic anemia, severe acute and chronic pain and end-organ damage. The pain in SCD is highly variable and although hemoglobin genotype can explain the variation, there are differences in pain experience in individuals with the same hemoglobin genotype.¹ Several genes have previously been associated with the clinical characteristics of SCD. A study that examined SNPs in 9 pain-related genes, found that the minor allele in ICAM1 rs1799969 was associated with lower average pain intensity, the present authors wrote.

Polymorphisms in glucocorticoid receptor gene NR3C1, transient receptor potential A gene (TRPA1), and GCH1 gene were shown to be associated with acute care pain visits. Seven SNPs in ADRB2 were also associated with chronic pain and variations in ADRB2 may contribute to chronic pain heterogeneity and severity in SCD. Polymorphisms in Val158Met SNP in the COMT gene and Ser9Gly SNP in the dopamine D3 receptor gene may contribute to acute pain crisis heterogeneity in SCD.

In the present study, saliva samples from 59 adults with SCD were collected to discover new genes associated with central sensitization. A total of 4145 SNPs were included in the analysis and vaso-occlusive pain (crisis pain) and non-vaso-occlusive pain (non-crisis pain) status were determined by an average of daily participant pain reports over 3 months. A total of 28 healthy controls with available SNP genotype data were also used to identify SNPs that deviated from Hardy Weinberg Equilibrium. Thirty-eight participants had homozygous hemoglobin S (Hb SS) genotype, 11 had sickle hemoglobin C (hemoglobin S and hemoglobin C, Hb SC) genotype, 7 had hemoglobin S beta thalassemia genotype, and 3 had hemoglobin S beta 0 thalassemia hemoglobin genotype.

Central sensitization was not significantly associated with hemoglobin genotype in this study. The researchers noted that this could be due to a limited study sample. SNP rs7778077 located in PRKAG2 was significantly associated with average weekly non-crisis pain reported in weekly calls (P = .001). Participants with G/G genotypes at rs7778077 SNP were reported to have more pain than participants with either A/G or A/A genotypes.

The study also looked into sex-specific associations and analyzed 86 X chromosomes in males and females. They found several SNPs associated with general sensitivity, average pain, average combined diary pain and average pain during crisis in both males and females, suggesting that sex chromosome SNPs could play a role in SCD. However, the researchers noted that these findings should be replicated in a large sample size for further validation.

Eight out of the 11 genes (C6orf15, GHR, RELA, HRH1, TRPMS, GRIA1, VARS1, and VARS2 genes) with SNPs that were associated with Quantitative Sensory Testing (QST) central sensitization belonged to cellular processes including biological regulation, stimulus-response, metabolic processes and biological processes. QST refers to a set of standardized procedures that are used to test sensory sensitivity. Out of these 8 SNPs associated with QST central sensitization, three of them (rs11575839, rs2233976, and rs4678) have been previously associated with other chronic conditions. The rs4678 in the VARS2 gene has been associated with an increased risk of lung cancer and has been benignly associated with rheumatoid arthritis. The rs11575839 has been associated with complement C4 levels in Chinese patients. Deficiencies or overexpression of C3 and C4 is associated with the pathogenesis of inflammatory and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and asthma.

Due to the small sample size of this study, only individual SNP analysis could be performed. The researchers note that multiple SNPs may have additive or synergistic effects on QST sensitization scores however, this analysis would need a larger sample size.

References 

1. Hamilton KR, McGill LS, Campbell CM, et al. Genetic contributions to pain modulation in sickle cell: a focus on single nucleotide polymorphisms. Gene Rep. 2024;36:101983. doi:10.1016/j.genrep.2024.101983

2. Brandow AM, Liem RI. Advances in the diagnosis and treatment of sickle cell disease. J Hematol Oncol. 2022;15(1):20. doi:10.1186/s13045-022-01237-z