Association of Sickle Cell Trait and Venous Thromboembolism in the 23andMe Cohort

Background: Prior small epidemiologic studies have documented that sickle cell trait (SCT) is a risk factor for venous thromboembolism (VTE); however, these studies have been performed exclusively in Black populations with SCT. Leveraging the large number of research participants in 23andMe, we sought to validate the association of SCT and VTE among 23andMe customers inferred to be African American based on a genetic ancestry classification algorithm and among the entire 23andMe cohort.

Methods: All 23andMe participants age >18 years who had consented to genetic research were included in this study. For this current analysis, existing genetic and phenotypic information in 23andMe that was relevant to our study question and outcome were included. For hemoglobin variants, available genotyping in 23andMe included hemoglobin S (HbS), HbC, and 9 β-thalassemia mutations; α-thalassemia sequencing was not available. Participants with sickle cell disease phenotypes, including HbSS, HbSC, and Hβ-thalassemia as well as those with factor V Leiden or prothrombin gene mutation were excluded from analysis. The outcome of VTE, as well as the subsets of any deep venous thrombosis (DVT) and pulmonary embolism (PE), were assessed by self-report on a baseline health questionnaire. Logistic regression was used to calculate ORs and 95% CIs of prevalent VTE associated with hemoglobin S carrier status. All analyses were adjusted for age, sex, principal components of ancestry, and genotyping platform.

Results: A total of 222,358 individuals inferred to be African American based on a genetic ancestry classification algorithm were included for analysis. The mean age was 43.23 years (range 19-114), and 133,429 (60.01%) were female. The prevalence of SCT was 7.08% (n=15,741), which is similar to the prevalence in the general African American population. 4,369 participants (1.96%) reported a past history of a VTE event, of which 70.00% (n=3,058) reported any DVT event and 49.40% (n=2,155) reported PE events. SCT was associated with an 1.39-fold (95% CI 1.26-1.54) higher risk of VTE. This risk was predominantly explained by increased risk of PE (OR=1.73, 95% CI=1.52-1.97) compared to any DVT (OR=1.17, 95% CI=1.03-1.34).

Conclusions: In this largest study to-date, SCT was found to be a moderate risk factor for VTE, and predominantly PE. Although this current analysis was performed only on the subset of participants of African ancestry, further planned analyses will include all ancestral populations within the 23andMe research program, which will provide much needed data in SCT.

Lin:23andMe: Current Employment, Current equity holder in publicly-traded company, Other: Current holder of stock options in a publicly-held company. Granka:23andMe: Current Employment, Current equity holder in publicly-traded company, Other: Current holder of stock options in a publicly-held company. Shastri:23andMe: Current Employment, Current equity holder in publicly-traded company, Other: Current holder of stock options in a publicly-held company. Research Team:23andMe: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Naik:Elsevier: Consultancy.