Association of Supernumerary Sex Chromosome Aneuploidies With Venous Thromboembolism.

Importance: An increased risk of venous thromboembolism (VTE) has been reported in men with an additional sex chromosome. The association between other sex chromosome aneuploidies and VTE is not well characterized. Objective: To determine if sex chromosome aneuploidy is associated with VTE. Design, Setting, and Participants: Retrospective cohort study of sex chromosome aneuploidy and VTE, performed by analyzing X- and Y-chromosome dosage and VTE incidence in 642 544 individuals from 2 population-scale biobanks: the US Geisinger MyCode Community Health Initiative (N = 154 519) and the UK Biobank (N = 488 025); analysis was limited to participants self-identified as White because of inadequate sample sizes for other race and ethnicity groups. A total of 108 461 unrelated MyCode participants with electronic health record follow-up ranging from September 1996 to December 2020 and 418 725 unrelated British and Irish UK Biobank participants who attended the baseline assessment between March 2006 and October 2010, with follow-up extending to November 2020, were included in analyses of VTE. Exposures: Sex chromosome aneuploidies. Main Outcomes and Measures: Individuals with 1 primary inpatient VTE diagnosis, 2 primary outpatient VTE diagnoses, or a self-reported VTE diagnosis were defined as VTE cases. P values were adjusted for multiple comparisons. Results: Identification of sex chromosome aneuploidy was undertaken among 642 544 individuals aged 18 to 90 years. Identification of a diagnosis of VTE was undertaken among 108 461 unrelated MyCode participants (65 565 [60.5%] female; mean age at last visit, 58.0 [SD, 17.6] years; median follow-up, 15.3 [IQR, 9.7] years) and among 418 725 unrelated UK Biobank participants (224 695 [53.7%] female; mean age at baseline interview, 56.9 [SD, 8.0] years; median follow-up, 12.0 [IQR, 1.6] years). Among MyCode participants, during 10 years of follow-up, 17 incident VTE events per 1353 person-years were detected among those with supernumerary sex chromosome aneuploidy (1.3% per person-year) compared with 2060 per 816 682 person-years among those with 46,XX or 46,XY (0.25% per person-year) (hazard ratio, 5.4 [95% CI, 3.4-8.7]; 10-year risk difference, 8.8% [95% CI, 4.2%-14.0%]; P < .001). Among UK Biobank participants, during 10 years of follow-up, 16 incident VTE events per 3803 person-years were detected among those with supernumerary sex chromosome aneuploidy (0.42% per person-year) compared with 4491 per 3 970 467 person-years among those with 46,XX or 46,XY (0.11% per person-year) (hazard ratio, 4.1 [95% CI, 2.5-6.7]; 10-year risk difference, 3.7% [95% CI, 1.4%-5.9%]; P < .001). Conclusions and Relevance: Adults with supernumerary sex chromosome aneuploidies compared with 2 sex chromosomes had a small but statistically significant increased risk of VTE. Further research is needed to understand the clinical implications of this association.