Ancestry-Independent Risk of Venous Thromboembolism in Individuals with Sickle Cell Trait vs. Factor V Leiden.

Sickle cell trait (SCT) is a risk factor for venous thromboembolism (VTE). Prior studies investigating the association of SCT and VTE have been performed nearly exclusively in Black populations. However, race-based research can contribute to systemic racism in medicine. We leveraged data from the 23andMe Research cohort (4,184,082 participants) to calculate the ancestry-independent risk of VTE associated with SCT as well as comparative risk estimates for heterozygous factor V Leiden (FVL). Odds ratios (OR) were calculated using a meta-analysis of 3 genetic ancestry groups (European [n=3,183,142], Latine [n=597,539], and African [n=202,281]) and a secondary full-cohort analysis including 2 additional groups (East Asian [n=159,863] and South Asian [n=41,257]). Among the full cohort, 94,323 (2.25%) participants reported a history of VTE. On meta-analysis, individuals with SCT had a 1.45-fold [CI 1.32-1.60) increased risk of VTE compared to non-SCT-carriers, which was similar to the full cohort estimate. The risk of PE in SCT (OR 1.95[CI 1.72-2.20]) was higher than that of isolated DVT (OR 1.04[CI 0.90-1.21]). FVL-carriers had 3.30-fold [CI 3.24-3.37]) increased risk of VTE compared to non-FVL-carriers, with a higher risk of isolated DVT (OR 3.59 [CI 3.51-3.68]) compared to PE (OR 2.72[CI 2.64-2.81]). In this large, diverse cohort, the risk of VTE was increased among individuals with SCT compared to those without, independent of race or genetic ancestry. The risk of VTE with SCT was lower than that observed in FVL; however, the pattern of VTE in SCT was PE-predominant, which is the opposite to that observed in FVL.