Genetics of venous thrombosis: insights from a new genome wide association study

Background: Venous Thrombosis (VT) is a common multifactorial disease associated with a major public health burden. Genetics factors are known to contribute to the susceptibility of the disease but how many genes are involved and their contribution to VT risk still remain obscure. We aimed to identify genetic variants associated with VT risk. Methodology/Principal Findings: We conducted a genome-wide association study (GWAS) based on 551,141 SNPs genotyped in 1,542 cases and 1,110 controls. Twelve SNPs reached the genome-wide significance level of 2.0×10−8 and encompassed four known VT-associated loci, ABO, F5, F11 and FGG. By means of haplotype analyses, we also provided novel arguments in favor of a role of HIVEP1, PROCR and STAB2, three loci recently hypothesized to participate in the susceptibility to VT. However, no novel VT-associated loci came out of our GWAS. Using a recently proposed statistical methodology, we also showed that common variants could explain about 35% of the genetic variance underlying VT susceptibility among which 3% could be attributable to the main identified VT loci. This analysis additionally suggested that the common variants left to be identified are not uniformly distributed across the genome and that chromosome 20, itself, could contribute to ∼7% of the total genetic variance. Conclusions/Significance: This study might also provide a valuable source of information to expand our understanding of biological mechanisms regulating quantitative biomarkers for VT

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe

Successful use of eltrombopag for surgical preparation in a patient with ANKRD26-related thrombocytopenia.

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Southeast asian ovalocytosis: the need for a carefull observation of red cell indices and blood smear

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Common Risk Factors Add to Inherited Thrombophilia to Predict Venous Thromboembolism Risk in Families

International audienceThe clinical venous thromboembolism (VTE) pattern often shows wide heterogeneity within relatives of a VTE-affected family, although they carry the same thrombophilia defect. It is then mandatory to develop additional tools for assessing VTE risk in families with thrombophilia. This study aims to assess whether common environmental and genetic risk factors for VTE contribute to explain this heterogeneity. A total of 2,214 relatives from 651 families with known inherited thrombophilia were recruited at the referral center for thrombophilia in Marseilles, France, from 1986 to 2013. A thrombophilia screening was systematically performed in all included relatives. According to the severity of the thrombophilia defect, individuals were split into three groups: no familial defect, mild thrombophilia, and severe thrombophilia. In addition, common genetic factors (ABO blood group and 11 polymorphisms selected on the basis of their association with VTE in the general population) were genotyped. Furthermore, body mass index and smoking were collected. VTE incidence was 1.74, 3.64, and 6.40 per 1,000 person-years in individuals with no familial defect, mild thrombophilia, and severe thrombophilia, respectively. Five common risk factors were associated with VTE in this population: obesity, smoking, ABO blood group, and F11_rs2036914 and FGG_rs2066865 polymorphisms. These common factors were then included into a three-level risk score. The score was highly efficient for assessing VTE risk in mild thrombophilia patients by identifying two groups with different VTE risk; individuals with low score had the same risk as individuals with no familial defect whereas individuals with high score had the same risk as individuals with severe thrombophilia. An overall score including the five items plus the thrombophilia status was built and displayed an area under the receiver operating characteristic curve of 0.702 for discriminating VTE and non-VTE relatives. In conclusion, integrating common environmental and genetic risk factors improved VTE risk assessment in relatives from families with thrombophilia. Ã Equally contributed to the article

A new heterozygous mutation in GP1BA gene responsible for macrothrombocytopenia

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Bernard-Soulier syndrome: first human case due to a homozygous deletion of GP9 gene

International audienceBernard–Soulier Syndrome (BSS) is a rare (1:1 million) hereditary bleeding disorder caused by defects in the platelet glycoprotein (GP)‐Ib/IX/V complex, a receptor for von Willebrand factor (VWF) and thrombin (Lanza, 2006; Berndt & Andrews, 2011). Patients typically present with epistaxis, petechial or gingival bleeding with onset already in infancy. They present with macrothrombocytopenia and their platelets do not agglutinate in response to ristocetin, while maintaining a normal aggregation in response to a variety of aggregating agents. GPIb/IX/V complex consists of two GPIbα and four GPIbβ subunits stabilized by disulphide bonds (Luo et al., 2007). This heterodimer is non‐covalently associated with two GPIX and one GPV subunits. The N‐terminal residues of GPIbα form seven leucine‐rich repeats (LRRs) and include the binding sites for VWF and thrombin. BSS is due to biallelic loss‐of‐function pathogenic variants (deletions, insertions and nonsense mutations) in GPIBA, GPIBB or GP9 genes encoding GPIb/IX/V complex (Savoia et al., 2014). However, so far, no mutation in GP5 causing BSS has been reported yet. Most of the mutations prevent the formation of the complex or trafficking it through the endoplasmic reticulum and Golgi apparatus and alter receptor expression (Salles et al., 2008; Savoia et al., 2011; Nurden et al., 2012)

Association of soluble endothelial protein C receptor plasma levels and PROCR rs867186 with cardiovascular risk factors and cardiovascular events in coronary artery disease patients: The AtheroGene Study.

International audienceABSTRACT: BACKGROUND: Blood coagulation is an essential determinant of coronary artery disease (CAD). Soluble Endothelial Protein C Receptor (sEPCR) may be a biomarker of a hypercoagulable state. We prospectively investigated the relationship between plasma sEPCR levels and the risk of cardiovascular events (CVE). METHODS: We measured baseline sEPCR levels in 1673 individuals with CAD (521 with acute coronary syndrome [ACS] and 1152 with stable angina pectoris [SAP]) from the AtheroGene cohort. During a median follow up of 3.7 years, 136 individuals had a CVE. In addition, 891 of these CAD patients were genotyped for the PROCR rs867186 (Ser219Gly) variant. RESULTS: At baseline, sEPCR levels were similar in individuals with ACS and SAP (median: 111 vs. 115 ng/mL respectively; p=0.20). Increased sEPCR levels were found to be associated with several cardiovascular risk factors including gender (p=0.006), soluble Tissue Factor levels (p=0.0001), diabetes (p=0.0005), and factors reflecting impaired renal function such as creatinine and cystatin C (p<0.0001). sEPCR levels were not significantly associated with the risk of CVE (median: 110 and 114 ng/mL in individuals with and without future CVE respectively; p=0.68) . The rs867186 variant was found to explain 59% of sEPCR levels variability (p<10 -200) but did not associate with CVE risk. CONCLUSION: Our findings show that in patients with CAD, circulating sEPCR levels are related to classical cardiovascular risk factors and renal impairment but are not related to long-term incidence of CVE