Fig. 2: Association of F12 variant carrier status with venous thromboembolism (VTE) in the UK Biobank and NIH All of Us cohorts (N = 703,745).
a Cox proportional hazards regression with Firth’s penalized likelihood modeling was performed in the UK Biobank (UKB) and NIH All of Us (AoU) datasets, followed by random-effects model meta-analysis. All models were adjusted for sex, the first 10 principal components of genetic ancestry, and additional covariates as depicted in Table S3. (**) = value of ≤20 redacted to comply with NIH reporting regulations. b Cox proportional hazards regression for VTE followed by trans-cohort meta-analysis was repeated across a range of FIS thresholds with adjustment performed as in (a). Effect size estimates are nominally significant for the points displayed in red (P ≤ 0.024; significance threshold not adjusted for multiple comparisons). c A leave-one-variant-out (LOVO) analysis was performed using iterative Firth’s logistic regression modeling across all FIS = 1.0 variants in both cohorts. Outliers identified by the two-sided extreme studentized deviate (Grubbs) test are labeled. d Integrated Kaplan–Meier survival analysis across both UKB and AoU (N = 753,617) comparing incident VTE occurring after study enrollment between F12 variant carriers (blue) and non-carriers (black). Historical (prevalent) VTE events occurring prior to study enrollment were excluded. e For all F12 variant carriers (MAF ≤ 1%) in the UKB Pharma Proteomics Project (PPP) dataset with available plasma proteomics data (N = 626), we plotted variant FIS against the plasma FXII concentration in linearized NPX (L-NPX) units as determined by Olink®. The P-value for trend derived from the F-test is shown. f Mean (±SEM) circulating FXII levels as determined by Olink® (L-NPX) were compared between wild-type individuals (N = 41,041) and carriers of nonsense, frameshift, and insertion/deletion variants in F12 (FIS = 1.0) by unpaired two-sided t-test (N = 11). g Scatter plot showing the distribution of plasma FXII levels vs. the concentrations of GAPDH, a standard plasma housekeeping protein (N = 42,100). Vertical dotted lines represent the median plasma FXII value in L-NPX units for F12 variant carriers at FIS = 1.0 (blue) and the median plasma FXII concentration for the entire population (black). h Plasma samples from F12 variant carriers (FIS = 1.0, N = 29) and age- and sex-matched wild-type controls (N = 29) in the MGB Biobank were assayed for FXII concentration by enzyme-linked immunosorbent assay (ELISA) and compared by unpaired two-sided t-test. Carriers of essential splice site (ESS) variants were excluded from the analyses in (e–h).
