10 research outputs found
Inherited risk factors for venous thromboembolism
Venous thromboembolism (VTE) has important heritable components. In the past 20 years, knowledge in this field has greatly increased with the identification of a number of gene variants causing hypercoagulability. The two main mechanisms are loss-of-function of anticoagulant proteins and gain-of-function of procoagulants, the latter owing to increased synthesis or impaired downregulation of a normal protein or, more rarely, to synthesis of a functionally hyperactive molecule. Diagnosis of thrombophilia is useful to determine the causes of VTE, recognizing that this multifactorial disease can also be influenced by various acquired factors including cancer, surgery, trauma, prolonged immobilization, or reproduction-associated risk factors. Diagnosis of inherited thrombophilia rarely affects the acute or long-term management of VTE. However, the risk of recurrent VTE is increased in anticoagulant-deficient patients and in homozygotes for gain-of-function mutations. Screening for inherited thrombophilia in thrombosis-free individuals is indicated only for relatives of a proband who is anticoagulant-deficient or has a family history of VTE. In families with thrombophilia and VTE, primary antithrombotic prophylaxis during risk situations lowers the rate of incident VTE. In this Review, we discuss the main causes of inherited thrombophilia, the associated clinical manifestations, and the implications for antithrombotic prophylaxis in the affected individuals
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Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study
Background
Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci.
Methods
We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings.
Findings
We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10–8; OR 1·19 [95% CI 1·12–1·26]) and VTN (rs704; p=2·75 × 10–9; OR 0·84 [0·79–0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10–8; OR 1·18 [1·12–1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15–3·82]; p=1·73 × 10–13).
Interpretation
We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis