Background: Sickle cell trait (SCT) is the heterozygous carrier state for sickle cell disease (SCD) and is common among individuals of African ancestry. While SCT is a known risk factor for chronic kidney disease and end-stage kidney disease (ESKD), the mechanisms underlying this phenotypic association have not been fully characterized. We utilized metabolomic profiling to gain insight into the pathobiology of SCT. Methods: We used a nontargeted metabolomics approach (Metabolon Global Discovery Panel) to measure baseline plasma levels of 851 metabolites in 986 older Black or African American women with SCT (mean age 61 ± 7 years) compared to 998 age- and race-matched controls without SCT from the prospective Women’s Health Initiative (WHI) study. Age-adjusted linear regression was used to assess the association between metabolite levels and SCT. Replication was performed in an independent sample of 1,070 African American men and women (including 70 with SCT) from the Atherosclerosis Risk in Communities (ARIC) study. Results: In age-adjusted models, 69 metabolites were significantly associated with SCT in WHI after correction for multiple testing. Many of the SCT-associated metabolites are markers of kidney glomerular filtration (eGFR) and/or related to oxidative stress metabolic pathways known to be altered in SCD homozygotes. Of the 64 SCT-associated metabolites available for replication, 25 or 39% were replicated in the ARIC study. Inclusion of SCT-associated metabolites was associated with significantly better risk prediction of incident ESKD in WHI among SCT individuals compared with a baseline model adjusted for age + estimated glomerular filtration rate (eGFR). Conclusions: We identified and replicated metabolites associated with SCT, many of which are related to eGFR and/or pathways altered in SCD (e.g., oxidative stress, membrane remodeling). These results suggest that plasma metabolomic profiling may be useful in ESKD risk stratification for individuals with SCT, meriting validation in larger cohorts.
Cai et al. (Fri,) studied this question.