RESUMO
ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.
Assuntos
Moléculas de Adesão Celular , Fator VIII , Cininogênios , Lectinas Tipo C , Receptores de Superfície Celular , Fator de von Willebrand , Humanos , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismo , Fator VIII/genética , Fator VIII/metabolismo , Polimorfismo de Nucleotídeo Único , Células Endoteliais da Veia Umbilical Humana/metabolismo , Análise da Randomização Mendeliana , Estudo de Associação Genômica Ampla , Trombose/genética , Trombose/sangue , Estudos de Associação Genética , Masculino , Células Endoteliais/metabolismo , FemininoRESUMO
INTRODUCTION: Time spent at home may aid in understanding recovery following traumatic brain injury (TBI) among older adults, including those with Alzheimer's disease and related dementias (ADRD). We examined the impact of ADRD on recovery following TBI and determined whether socioeconomic disadvantages moderated the impact of ADRD. METHODS: We analyzed Medicare beneficiaries aged ≥65 years diagnosed with TBI in 2010-2018. Home time was calculated by subtracting days spent in a care environment or deceased from total follow-up, and dual eligibility for Medicaid was a proxy for socioeconomic disadvantage. RESULTS: A total of 2463 of 20,350 participants (12.1%) had both a diagnosis of ADRD and were Medicaid dual-eligible. Beneficiaries with ADRD and Medicaid spent markedly fewer days at home following TBI compared to beneficiaries without either condition (rate ratio 0.66; 95% confidence interval [CI] 0.64, 0.69). DISCUSSION: TBI resulted in a significant loss of home time over the year following injury among older adults with ADRD, particularly for those who were economically vulnerable. HIGHLIGHTS: Remaining at home after serious injuries such as fall-related traumatic brain injury (TBI) is an important goal for older adults. No prior research has evaluated how ADRD impacts time spent at home after TBI. Older TBI survivors with ADRD may be especially vulnerable to loss of home time if socioeconomically disadvantaged. We assessed the impact of ADRD and poverty on a novel DAH measure after TBI. ADRD-related disparities in DAH were significantly magnified among those living with socioeconomic disadvantage, suggesting a need for more tailored care approaches.