Phenome-wide association study of Sickle Cell Trait in NIH’s All of Us Research Program

Authors

• JA Shadish
• JC Lee

Abstract

The HbS variant is widespread, particularly among individuals of African descent. While most people with Sickle Cell Trait (SCT) carrying one HbS allele remain symptom-free, some rare cases link carrier status to adverse outcomes. All of Us is a diverse biobank with participants' genomic and health data. This study aimed to investigate the association of SCT with clinical outcomes, focusing on vascular occlusive complications.

Among 39,020 individuals of African descent with genomic and health records, 3,363 carried one HbS allele, while 73 carried two and were excluded. We ran a PheWAS comparing single HbS allele carriers to non-carriers and found strong associations with anemia during pregnancy, iron deficiency anemias, aseptic necrosis of bone, and pulmonary embolism/infarction.

To assess the impact of other hemoglobinopathies, ClinVar variants of the HBB gene were examined, excluding non-HbS variants like beta-thalassemia and HbC. This resulted in 3,162 single HbS carriers and 31,798 non-carriers. A second PheWAS identified the most strongly associated phenotypes in this group as anemia during pregnancy, iron deficiency anemias, gout, and abnormal results of kidney function. The association with aseptic necrosis of bone and the association with pulmonary embolism/infarction decreased.

These findings align with previous research, suggesting that the reported associations between SCT and vascular occlusion phenotypes, except for kidney issues, may be influenced by concomitant hemoglobinopathies. The study provides new insights into phenotypic variations among individuals with SCT. Considering the prevalence of HbC and beta-thalassemia alleles, clinicians should investigate other hemoglobinopathies to determine the risks of vascular occlusive complications in SCT.

Scientific Focus Area: Genetics and Genomics

This page was last updated on Monday, September 25, 2023