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Venous Thromboembolism Risk Rise Reported in Individuals With Extra Sex Chromosomes

NEW YORK – A Geisinger-led team has identified enhanced venous thromboembolism (VTE) risk in individuals with sex chromosome aneuploidies involving one or more extra copies of a given sex chromosome.

"As VTE is a major public health concern, more research into benefits and harms of genetic thrombophilia testing for management and prevention of VTE is needed," senior and corresponding author Matthew Oetjens, an autism and developmental medicine researcher at Geisinger, and his colleagues wrote in JAMA on Tuesday. "Guidelines may evolve in response to new data on VTE risk factors, including inherited forms and sex chromosome aneuploidies, generated from large biobanks."

Following from past research pointing to higher-than-usual VTE risk in men carrying extra sex chromosomes, the researchers tapped into electronic health record (EHR), exome sequence, and/or genotyping data for 108,461 unrelated participants in the US Geisinger MyCode Community Health Initiative to explore relationships between sex chromosome dosage and VTE diagnoses in the white participants between the fall of 1996 and late 2020.

The team performed similar analyses on more than 418,700 unrelated British or Irish individuals enrolled in the UK Biobank study from the spring of 2006 to late 2010.

In both cohorts, the researchers found that VTE risk was significantly bumped up for individuals with documented sex chromosome aneuploidies, particularly supernumerary sex chromosome cases marked by the presence of more than two sex chromosomes.

"The presence of a supernumerary sex chromosome aneuploidy was associated with a small but statistically significant increased risk of VTE, independent of the tested clinical biomarkers," the authors reported. In contrast, that rise in VTE risk was not found in female participants with Turner syndrome, marked by a missing X chromosome.

In MyCode participants, for example, the team identified sex chromosome aneuploidies in one out of every 528 participants, though fewer than 18 percent of the individuals had accompanying clinical diagnoses. Over 10 years of follow-up for MyCode, VTE events occurred at a rate of 1.3 percent per person-year in the individuals with supernumerary sex chromosome aneuploidies, but just 0.25 percent per person-year in those who did not.

The sex chromosome aneuploidies turned up in one in 832 UK Biobank participants over a 10-year follow-up time, the researchers reported, with VTE rates of 0.42 percent per person-year and 0.11 percent per person-year in individuals with or without supernumerary sex chromosome aneuploidies, respectively.

The relationship between VTE risk and the presence of additional sex chromosomes was also observed in a mediation analysis done using trait and biochemical marker data collected for the UK Biobank effort, which was designed to rule out associations linked to traits that can coincide with supernumerary sex chromosome aneuploidy such as taller-than-usual stature.

"The mediation analysis suggested that most of the relationship between supernumerary sex chromosome aneuploidy and VTE was independent of clinical factors, including BMI, height, leg length, cystatin C, C-reactive protein, and albumin," the authors wrote, though they cautioned that the potential clinical utility of identifying supernumerary sex chromosome aneuploidy for VTE risk stratification is unknown.