Susceptibility to sickle cell co‐morbidities is regulated by single nucleotide polymorphisms of the TOLLIP gene

Abstract

Infectious diseases, despite the availability of vaccines, remain a challenge for sickle cell disease (SCD) patients. This is exacerbated in developing countries with high disease rates, poor hospital infrastructures and preponderance of co‐morbidities, complicating SCD case management. Therefore, elucidating the role of pathogen recognition factors or signaling pathways in immune response is critical in clarifying genes regulating infectious co‐morbidities. We have shown that the dysregulated immune response observed in SCD is not attributable to dendritic cells (CD209 gene promoter polymorphism) or Toll‐like receptor (TLR‐4 polymorphisms). Though there is a significant difference in CD209 gene promoter polymorphism between groups, it does not explain infection overload in African but not African American SCD patients. Toll‐interacting protein (TOLLIP) regulates human TLR signaling pathways, and its polymorphisms have been associated with infectious diseases. To decipher whether TOLLIP polymorphisms affect immune response upstream of TLR‐4 signaling, we examined the genetic diversity of TOLLIP polymorphisms (rs5743899 and rs3750920) within and between control (230, 379 and 159 Africans, African Americans and Caucasians respectively) and disease groups (145 and 331 African and African Americans respectively), utilizing a polymerase chain reaction and restriction fragment length polymorphism assay. We found significant interethnic disparity in the genotypic frequency (15.2%, 21.6% and 2.5%) of rs5743899 mutant variant between Africans, African Americans and Caucasians respectively. In addition, we also found a significant difference for rs5743899 mutant variant between disease and control groups in Africa (22.7% versus 15.2%) but not in the United States (23.3% versus 21.6%), with no difference between sickle cell disease groups. This observation shows that Tollip gene rs5743899 mutant variant is a potential contributor to predisposing sickle cell patients but not control groups in Africa to infectious co‐morbidities, and may explain the high levels of circulating immune complexes in disease groups. This report reveals interethnic susceptibility to infectious co‐morbidities and how this contributes to immune response in sickle cell disease.Support or Funding InformationRIT Louis Stokes Alliance for Minority Participation Fellowship (NSF Award #25901‐03200‐S01) (SEA)Laboratory Support Fund, College of Health Sciences and Technology (BNT)