In a recent study published in PLoS One, researchers assess the predictability of venous thromboembolism (VTE) amongst adults using genetic risk scores (GRSs).

Study:  Prediction of venous thromboembolism incidence in the overall adult population using two published genetic risk scores. Image Credit: Joyseulay / Shutterstock.com

Who’s prone to VTE?

VTE, which comprises venous thrombosis with pulmonary embolism, is a serious reason for mortality and morbidity, with a lifetime risk of just about one in 12 individuals over the age of 45 years in the USA. Between 50% and two-thirds of VTEs are provoked by malignancy, surgery, trauma, or immobilization, while the remaining VTEs are considered unprovoked.

Currently, available VTE prevention techniques don’t goal the prevention of VTE throughout the general population. Moreover, identifying individuals who’re at a greater risk for experiencing VTE is difficult, as only a number of practical risk scores that may facilitate the diagnosis of high-risk individuals have been published.

In regards to the study

In the current study, researchers determine the extent to which published VTE GRS can predict VTE occurrence.

The Atherosclerosis Risk in Communities (ARIC) study enrolled 15,792 primarily Black or White women and men between 45 and 64 years of age from 4 American communities. ARIC conducted a baseline or Visit 1 assessment, which involved genetic testing on preserved deoxyribonucleic acid (DNA) samples after subjects provided informed consent.

Between 1990 and 2019, ARIC maintained longitudinal contact with participants through either semi-annual or annual phone calls and 6 reexamination visits. GRS incorporated signals from several loci by adding the product of the effect sizes and the proportion of effect alleles present at each locus for all participants.

Age, race, gender, hormone alternative therapy, body weight, height, and estimated glomerular filtration rate were measured as VTE risk aspects in the course of the ARIC baseline evaluation. Other significant non-lipid cardiovascular risk variables reported at baseline akin to diabetes, sports physical activity level, smoking status, antihypertensive medication usage, and systolic blood pressure were also included in the ultimate evaluation.

Starting in 2012, ARIC staff contacted participants by telephone, initially annually and later semi-annually, to inquire about all hospital admissions that occurred within the previous 12 months. Then, the team gathered and reported in-hospital International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes related to all discharge diagnoses and noted chosen hospital record materials for VTE validation until 2019. VTEs were ultimately classified as either provoked or unprovoked.

Study findings

Between 1987 and 1989, 11,292 ARIC participants were included within the study, 54% of whom were female, 78% White, and 22% Black. The individuals reported a median rating of 21.4 on the 273-variant GRS and 1.0 on the weighted, imputed five-variant GRS.

F5 Leiden rs6025 and F2 rs1799963, that are two common VTE risk variants within the five-variant GRS, weren’t a part of the 273-variant GRS. Despite this, ARIC enrollees in the highest 5% of the 273-variant GRS exhibited a much greater F5 Leiden rs6025 frequency as in comparison with those in the underside 95% of the distribution, while 75% of those in the highest 1% scores included F5 Leiden.

Altogether, the proportion of F5 Leiden alleles accounted for 9.8% of the variance observed for the 273-variant GRS. Similar frequencies of F2 rs1799963 were also noted in the highest 5% and bottom 95%.

Moreover, ARIC identified 788 participants with VTE across a mean of 28 years of follow-up. This included 467 provoked and 321 unprovoked cases.

Participants who had higher scores related to the 273-variant GRS were at a greater risk of total VTE, with incidence rates of 1.7, 2.7, 3.4, and 4.0 for each 1,000 person-years across all GRS quartiles. The incidence rate of VTE was greater amongst Black individuals than White individuals, although the gradient of risk between quartiles was steeper amongst White individuals. Moreover, unprovoked VTEs were more strongly correlated than provoked VTEs.

The five-variant GRS was positively correlated with VTE incidence, albeit with considerably lesser hazard ratios (HRs) amongst White individuals as in comparison with the 273-variant GRS. When the GRS were adjusted in response to one another throughout the same model encompassing White and Black individuals, HRs adjusted to race, age, and gender for every GRS were reduced; nevertheless, the correlations were still greater for the 273-single nucleotide polymorphisms (SNP) rating. Moreover, jointly adjusted HRs reported for all 273-variant GRS quartiles were 1, 1.24, 1.64, and 1.94, while that for the five-variant GRS were 1, 1.12, 1.15, and 1.39.

Conclusions

Middle-aged individuals in the highest quartile of either genetic risk rating were related to a risk of VTE that was almost two times of people from the bottom quartile. Nevertheless, the genetic risk scores for Black individuals was weakly related to VTE.

Further studies are needed to find out whether VTE prevention throughout the general population is achievable using either a population or a high-risk patient strategy.

Journal reference:

• Folsom, A. R., Tang, W., Hong, C. P., et al. (2023). Prediction of venous thromboembolism incidence in the overall adult population using two published genetic risk scores. PLOS ONE 18(1): e0280657. doi:10.1371/journal.pone.0280657