key: cord-0691092-dz78p86r
authors: Xie, J.; Prats-Uribe, A.; Gordillo Maranon, M.; Strauss, V. Y.; Gill, D.; PRIETO-ALHAMBRA, D.
title: Genetic risk and incident venous thromboembolism in middle-aged and older adults following 1 Covid-19 vaccination
date: 2022-04-18
journal: nan
DOI: 10.1101/2022.04.14.22273865
sha: d57541d8b4c582f669b28f5640ee4208f4b8f759
doc_id: 691092
cord_uid: dz78p86r

BACKGROUND Covid-19 vaccination has been associated with an increased risk of venous thromboembolism (VTE). However, it is unknown whether genetic predisposition to VTE is associated with an increased risk of thrombosis following vaccination. METHODS Using data from the UK Biobank, which contains in-depth genotyping data and linked vaccination and health outcomes information, we generated a polygenic risk score (PRS) using 299 genetic variants identified from a previous large genome-wide association study. We prospectively assessed associations between PRS and incident VTE after first and the second-dose vaccination separately. We conducted sensitivity analyses stratified by vaccine type (adenovirus- and mRNA-based) and using two historical unvaccinated cohorts. We estimated hazard ratios (HR) for PRS-VTE associations using Cox models. RESULTS Of 359,310 individuals receiving one dose of a Covid-19 vaccine, 160,327 (44.6%) were males, and the mean age at the vaccination date was 69.05 (standard deviation [SD] 8.04) years. After 28- and 90-days follow-up, 88 and 299 individuals developed VTE respectively, equivalent to an incidence rate of 0.88 (95% confidence interval [CI] 0.70 to 1.08) and 0.92 (95% CI 0.82 to 1.04) per 100,000 person-days. The PRS was significantly associated with a higher risk of VTE (HR per 1 SD increase in PRS, 1.41 (95% CI 1.15 to 1.73) in 28 days and 1.36 (95% CI 1.22 to 1.52) in 90 days). Similar associations were found after stratification by vaccine type, in the two-dose cohort and across the historical unvaccinated cohorts. CONCLUSIONS The genetic determinants of post-Covid-19-vaccination VTE are similar to those seen in historical data. This suggests that, at the population level, post-vaccine VTE has similar aetiology to conventional VTE. Additionally, the observed PRS-VTE associations were equivalent for adenovirus- and mRNA-based vaccines.

Venous thromboembolism (VTE), primarily comprising deep vein thrombosis and pulmonary 43 embolism, is predominantly a disease of older age that affects nearly 10 million people worldwide 44 every year and frequently leads to morbidities and death. 1-3 Severe acute respiratory syndrome 45 coronavirus-2 (SARS-CoV-2) infection and coronavirus disease 2019 (Covid-19) have been recognised 46 as novel environmental triggers for VTE. Also, a number of spontaneous thromboembolic 47 complications were reported after Covid-19 vaccination, prompting the withdrawal of the Oxford-48

AstraZeneca vaccine (ChAdOx1) from several markets or restrictions on its use. Later, emerging 49 evidence has suggested that VTE risks are substantially higher after SARS-CoV-2 infection than after 50 vaccination, regardless of vaccine type or brand. 4 

Twins and family studies have shown that VTE is highly heritable, and a few clinical studies suggest 52 that inherited thrombophilia can interact with various environmental risk factors, such as infectious 53 pneumonia. 5, 6 Additionally, many genetic variants associated with VTE and their effect sizes have 54

been identified in large-scale genome-wide association studies (GWASs), making it possible to 55 construct a polygenic risk score (PRS) to quantify genetic predisposition to the VTE trait. 56

The present study aimed to assess the association between a previously validated PRS for 57

conventional VTE and the post-Covid-19-vaccination VTE, where thrombotic events following post-58

Covid-19-vaccination were hypothesised to be involved in distinctive pathobiological mechanisms. 59 physical metrics, and medical history were collected using a computer-based questionnaire and a 66 standardised portfolio of measurements. 7 Genome-wide genotyping was performed using two 67 closely related purpose-designed arrays (the UK BiLEVE Axiom array and UK Biobank Axiom array). 68

The genetic data have been quality controlled as described in previous studies. 8 Polygenic risk score 90 We derived polygenic risk scores (PRS) for VTE as a weighted sum of risk alleles, using summary 91 statistics of 299 single nucleotide polymorphisms (SNPs) from a genome-wide association study 92

(GWAS) on VTE, which included the two clinically validated mutations: factor V Leiden p.R506Q and 93 prothrombin G20210A. 9 Given that the selected GWAS sample included UKBB participants, we 94 conducted a sensitivity analysis using a newly generated alternative PRS based on a meta-analysis of 95 12 GWASs that did not cover UKBB participants. 10 and "1324691000000104" in EMS (SNOMED CT) and "Y29e7" and "Y29e8" in TPP (READ v3), 105

respectively. 106

Venous thromboembolism 107 VTE, including pulmonary embolism and deep vein thrombosis, was captured from linked hospital 108 admission data from Hospital Episode Statistics, which contains all admissions in NHS hospitals in 109

England. Mortality was ascertained from linked national death registry data. We used the earliest 110 date of VTE diagnosis as the event date. ICD-10 codes used to identify VTE and death are given in the 111 sTable 3. 112

We used Cox proportional-hazards models to assess the associations between the PRS and VTE 114 outcome. We computed hazard ratios (HR) and their 95% confidence intervals (CI) with adjustment 115

for age (at the index date), sex, and genetic ancestry (quantified by the first ten principal 116 components). To identify the high genetic risk group, we tested three cut-off quantiles of PRS 117 separately, including upper tertile (top 33%), quintile (top 20%), and the top 5% with the lower 66% 118 as the reference. To ensure sufficient statistical power, this analysis was only performed in the 90-119 days follow-up window. We evaluated the balance of baseline characteristics within each 120 comparison pair according to a list of pre-specified covariates and adjusted for them in the Cox 121 model if their absolute standardised mean difference was greater than 0.1. Considering varying VTE 122 rates across the reference groups, we derived absolute risk increases (ARI) between high-risk and 123

the reference PRS categories using the formula: (adjusted HR -1) * cumulative incidence in the 124 reference group. 125 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101/2022.04.14.22273865 doi: medRxiv preprint

We calculated HRs for diabetes as a negative control outcome to examine the specificity of the PRS 126 and the likelihood of potential residual confounding. Diabetes was chosen with considerations that it 127 is a well-developed disease phenotype and not biologically related to the VTE PRS. In a sub-cohort 128 where the EMIS system provided the primary care data, and vaccine types were recorded, separate 129

HRs were estimated among either ChAdOx1 or BNT162b2 vaccine recipients. Given that the 130 heterologous prime-boost vaccination schedule in the UK is very uncommon 11 ( with <1% in our 131 data), no specific analyses in this regard have been performed. 132

All the analyses were performed using PLINK1.9, QCTOOL v2, and R 4. window, respectively) ( Table 2) . Although there was a seemingly inverted U-shaped relationship 152 between the PRS and estimate of VTE risk following the second dose of vaccine, wide confidence 153 intervals limit the reliability of this finding. 154

The observed rates and effect sizes of the observed associations were similar when comparing the 155 vaccinated and historical (unvaccinated) cohorts. Also, although absolute incidence rates of VTE in 156 the infected cohort were substantially higher than those in other cohorts, the PRS-VTE association 157 persisted. A sensitivity analysis using an alternative PRS found similar although slightly weaker 158 associations ( 13 Despite being aligned with these findings, the PRS-VTE 189 associations estimated in our study were consistently weaker than the previously reported ones 190 even after the incorporation of the two clinically validated variants, possibly due to the discrepancies 191 in defining VTE phenotypes between the original score deviation and this validation study. Also, 192 because our cohort only consisted of VTE naïve and relatively older participants, those with higher 193 genetic risk might have had a VTE in their earlier age and thus been excluded. As expected, our PRS 194

was not associated with the proposed negative control outcome (incident diabetes), to some extent, 195 demonstrating its specificity for VTE prediction. 196

The results of this study support several noteworthy conclusions. First, our data showed that 197 individuals' genetic susceptibility to VTE was a risk factor for VTE among the Covid-19 vaccinated  198 population. Second, this genetic risk was independent of traditional risk factors such as old age, 199 obesity and comorbidity, as indicated by no associations between the PRS and baseline 200 characteristics (Table 1) . Third, by designing a historical comparison arm in the same population, our 201 data suggest that clinically significant interactions between individuals' genetic background and 202

Covid-19 vaccination are unlikely, which has particular implications for patients with hereditary VTE 203 predisposing traits who are hesitant to be vaccinated because of concerns regarding related recent 204 vaccine safety signals. Fourth, we identified 5% of people with more than 2-fold higher VTE risk by 205 using this genetic score, it should be of public health relevance and can inform potential intervention 206 policies given the absolute size of Covid-19 vaccinated population. Our analyses have some potential 207

limitations. First, VTE often presents variable clinical manifestations with challenging differential 208 diagnoses such as myocardial infarction and congestive heart failure. 2 Consequently, identification of 209 VTE in a real-world setting is likely subject to information bias, which typically drives risk estimates 210 towards the null. Second, we were not able to generate a parallel unvaccinated comparison group 211 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101/2022.04.14.22273865 doi: medRxiv preprint because more than 99% of UKBB participants had been vaccinated. However, we constructed a 212 historical comparison cohort with similar characteristics to those vaccinated. Also, given the 213 relatively short follow-up after vaccination, the long-term impact of the genetic factor remains to be 214 determined. Third, although we also constructed a secondary PRS for VTE, the weights of each 215 included SNP have not been previously validated, and their utility in a PRS remains unknown. 216

Opportunely, it conferred consistent results as the primary PRS did, likely due to the fact that both 217

PRSs included the factor V Leiden p.R506Q and prothrombin G20210A variants which are known 218 causes of inherited thrombophilia predisposing to acute thrombotic syndromes 14, 15 . Fourth, the HR 219

estimates for each vaccine type should be considered exploratory in nature due to evident 220 differences in the baseline risk for VTE seen between people vaccinated with the two vaccines. Last, 221

the generalizability of our findings should be tested in more diverse ethnic populations as more 222

integrated data sources containing in-depth genetic, vaccination, and health information becomes 223 available. 224

This study benefits from the use of a large prospective cohort with comprehensive genetic, Covid-19 225 vaccination, Covid-19 infection status and VTE phenotype data linked at the individual level, the 226 application of the state-of-the-art PRS, and robust analytic methods by designing multiple 227 comparison groups and a negative control outcome. To our knowledge, this is the first study to show 228 that individuals' who developed post-Covid19-vaccination VTE had a genetic predisposition to VTE, 229 and that the association between the genetic risk factors and post-Covid19-vaccination VTE is similar 230

to the association with conventional VTE. 231

A published PRS for VTE, constructed using common genetic variants with small effects on VTE, was 233 associated with increased VTE risk following Covid-19 vaccination. This association was similar to 234 that seen historically, both in pre-pandemic times and during the first year of the Covid-19 235 pandemic, before vaccines were available. Our data do not support a clinically meaningful interplay 236 between genetic predisposition and Covid-19 vaccines on the occurrence of VTE events. These 237 findings suggest that the clinical management of VTE among the vaccinated population should not 238 be disturbed by the concern of gene-vaccine interaction, and that people at high genetic risk of VTE 239 such as those with inherited thrombophilia might have a modest excess risk of VTE occurrence 240 following vaccination. 241 242 243 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 18, 2022. ; https://doi.org/10.1101/2022.04.14.22273865 doi: medRxiv preprint

The views expressed in this article are the personal views of the author(s) and may not be 245 understood or quoted as being made on behalf of or reflecting the position of the regulatory 246 agency/agencies or organisations with which the author(s) is/are employed/affiliated. 247 

Prof Prieto-Alhambra research group has received grants and advisory or speaker fees from Amgen, 257

Astellas, AstraZeneca, Chiesi- Taylor 

The lead author affirms that this manuscript is an honest, accurate, and transparent account of the 272 study being reported; that no important aspects of the study have been omitted. Indices of Multiple Deprivation offer a more complex and detailed view of deprivation, based on more factors than the Townsend index. All scores has been scaled to 0 to 1, 0 to 100, or even distributions standardized around 0, with higher values indicating more deprived. Details of individual score has been described in the GOV.UK (https://www.gov.uk/government/collections/english-indices-of-deprivation). The pre-pandemic was defined as the period between March 23 2019, and March 23 2020. The early-pandemic was defined as the period between March 23 2020, and December 1 2020. The negative control outcome was incident diabetes.

PRS, polygenic risk score, * per 100,000 person-days, $ Per 1-SD increase of PRS.

Reference: participants with lower 66% PRS. Hazard ratios and absolute risk increases were calcualted in comparison with the referencec group. "I26" Pulmonary embolism "I260"

Pulmonary embolism with mention of acute cor pulmonale "I269"

Pulmonary embolism without mention of acute cor pulmonale "I801"

Phlebitis and thrombophlebitis of femoral vein "I802"

Phlebitis and thrombophlebitis of other deep vessels of lower extremities "I803"

Phlebitis and thrombophlebitis of lower extremities, unspecified "I81" Portal vein thrombosis "I82"

Other venous embolism and thrombosis "I820" Budd-Chiari syndrome "I822"

Embolism and thrombosis of vena cava "I823" Embolism and thrombosis of renal vein "I828" Embolism and thrombosis of other specified veins "I829" Embolism and thrombosis of unspecified vein

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