TY  - JOUR
A1  - Ocak, Gurbey
A1  - Drechsler, Christiane
A1  - Vossen, Carla Y.
A1  - Vos, Hans L.
A1  - Rosendaal, Frits R.
A1  - Reitsma, Pieter H.
A1  - Hoffmann, Michael M.
A1  - März, Winfried
A1  - Ouwehand, Willem H.
A1  - Krediet, Raymond T.
A1  - Boeschoten, Elisabeth W.
A1  - Dekker, Frido W.
A1  - Wanner, Christoph
A1  - Verduijn, Marion
T1  - Single Nucleotide Variants in the Protein C Pathway and Mortality in Dialysis Patients
JF  - PLOS ONE
N2  - Background: The protein C pathway plays an important role in the maintenance of endothelial barrier function and in the inflammatory and coagulant processes that are characteristic of patients on dialysis. We investigated whether common single nucleotide variants (SNV) in genes encoding protein C pathway components were associated with all-cause 5 years mortality risk in dialysis patients. 
Methods: Single nucleotides variants in the factor V gene (F5 rs6025; factor V Leiden), the thrombomodulin gene (THBD rs1042580), the protein C gene (PROC rs1799808 and 1799809) and the endothelial protein C receptor gene (PROCR rs867186, rs2069951, and rs2069952) were genotyped in 1070 dialysis patients from the NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort) and in 1243 dialysis patients from the German 4D cohort. 
Results: Factor V Leiden was associated with a 1.5-fold (95% CI 1.1-1.9) increased 5-year all-cause mortality risk and carriers of the AG/GG genotypes of the PROC rs1799809 had a 1.2-fold (95% CI 1.0-1.4) increased 5-year all-cause mortality risk. The other SNVs in THBD, PROC, and PROCR were not associated with 5-years mortality. 
Conclusion: Our study suggests that factor V Leiden and PROC rs1799809 contributes to an increased mortality risk in dialysis patients.
KW  - human brian endothelium
KW  - factor-V-Leiden
KW  - venous thrombosis
KW  - activated receptor-1
KW  - vascular access
KW  - severe sepsis
KW  - gene polymorphism
KW  - organ dysfunktion
KW  - ischemic stroke
KW  - renal disease
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116265
SN  - 1932-6203
VL  - 9
IS  - 5
ER  - 
TY  - JOUR
A1  - Westbury, Sarah K
A1  - Turro, Ernest
A1  - Greene, Daniel
A1  - Lentaigne, Claire
A1  - Kelly, Anne M
A1  - Bariana, Tadbir K
A1  - Simeoni, Ilenia
A1  - Pillois, Xavier
A1  - Attwood, Antony
A1  - Austin, Steve
A1  - Jansen, Sjoert BG
A1  - Bakchoul, Tamam
A1  - Crisp-Hihn, Abi
A1  - Erber, Wendy N
A1  - Favier, Rémi
A1  - Foad, Nicola
A1  - Gattens, Michael
A1  - Jolley, Jennifer D
A1  - Liesner, Ri
A1  - Meacham, Stuart
A1  - Millar, Carolyn M
A1  - Nurden, Alan T
A1  - Peerlinck, Kathelijne
A1  - Perry, David J
A1  - Poudel, Pawan
A1  - Schulman, Sol
A1  - Schulze, Harald
A1  - Stephens, Jonathan C
A1  - Furie, Bruce
A1  - Robinson, Peter N
A1  - van Geet, Chris
A1  - Rendon, Augusto
A1  - Gomez, Keith
A1  - Laffan, Michael A
A1  - Lambert, Michele P
A1  - Nurden, Paquita
A1  - Ouwehand, Willem H
A1  - Richardson, Sylvia
A1  - Mumford, Andrew D
A1  - Freson, Kathleen
T1  - Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders
JF  - Genome Medicine
N2  - Background: 
Heritable bleeding and platelet disorders (BPD) are heterogeneous and frequently have an unknown genetic basis. The BRIDGE-BPD study aims to discover new causal genes for BPD by high throughput sequencing using cluster analyses based on improved and standardised deep, multi-system phenotyping of cases. 
Methods: 
We report a new approach in which the clinical and laboratory characteristics of BPD cases are annotated with adapted Human Phenotype Ontology (HPO) terms. Cluster analyses are then used to characterise groups of cases with similar HPO terms and variants in the same genes. Results: 
We show that 60% of index cases with heritable BPD enrolled at 10 European or US centres were annotated with HPO terms indicating abnormalities in organ systems other than blood or blood-forming tissues, particularly the nervous system. Cases within pedigrees clustered closely together on the bases of their HPO-coded phenotypes, as did cases sharing several clinically suspected syndromic disorders. Cases subsequently found to harbour variants in ACTN1 also clustered closely, even though diagnosis of this recently described disorder was not possible using only the clinical and laboratory data available to the enrolling clinician. 
Conclusions: 
These findings validate our novel HPO-based phenotype clustering methodology for known BPD, thus providing a new discovery tool for BPD of unknown genetic basis. This approach will also be relevant for other rare diseases with significant genetic heterogeneity.
KW  - disease
KW  - thrombocytopenia
KW  - guidelines
KW  - complex
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143329
VL  - 7
IS  - 36
ER  -