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1.  Single Nucleotide Variant rs2232710 in the Protein Z-Dependent Protease Inhibitor (ZPI, SERPINA10) Gene Is Not Associated with Deep Vein Thrombosis 
PLoS ONE  2016;11(3):e0151347.
Rare mutations in PROC, PROS1 or SERPINC1 as well as common variants in F5, F2, F11 and SERPINC1 have been identified as risk factors for deep vein thrombosis (DVT). To identify novel genetic risk factors for DVT, we have developed and applied next-generation DNA sequencing (NGS) of the coding area of hemostatic and proinflammatory genes. Using this strategy, we previously identified a single nucleotide variant (SNV) rs6050 in the FGA gene and novel, rare SNVs in the ADAMTS13 gene associated with DVT. To identify novel coding variants in the genetic predisposition to DVT, we applied NGS analysis of the coding area of 186 hemostatic and proinflammatory genes in 94 DVT cases and 98 controls and we identified 18 variants with putative role in DVT. A group of 585 Italian idiopathic DVT patients and 550 healthy controls was used to genotype all the 18 risk-associated variants identified by NGS. Replication study in the Italian population identified the rs2232710 variant in the protein Z-dependent protease inhibitor (ZPI) gene to be associated with an increased risk of DVT (OR 2.74; 95% CI 1.33–5.65; P = 0.0045; Bonferroni P = 0.081). However, the rs2232710 SNV showed no association with DVT in two Dutch replication cohorts the LETS study (454 patients and 451 controls) and the MEGA study (3799 patients and 4399 controls), indicating that the rs2232710 variant is not a risk factor for DVT.
doi:10.1371/journal.pone.0151347
PMCID: PMC4794167  PMID: 26982741
2.  A recurrent F8 mutation (c.6046C>T) causing hemophilia A in 8% of northern Italian patients: evidence for a founder effect 
Abstract
Hemophilia A is a heterogeneous hemorrhagic disorder caused by a large number of mutations. Recurrent mutations are rare, except intron 22 and intron 1 inversions. The substitution of a cytosine to a thymine at nucleotide 6046 in F8 gene was identified in a group of Italian patients affected by hemophilia A from a specific region of Northern Italy with a prevalence of 7.6%. This F8 variant was the second most frequent mutation in our cohort, after the intron 22 inversion. The identification of the same mutation in a restricted population gets to suppose the existence of a founder effect. Intragenic and extragenic polymorphic markers were tested to assess this assumption. A peculiar haplotype in linkage disequilibrium with this recurrent mutation (c.6046C>T) was identified in 71% of patients, supporting a founder effect. This distinctive haplotype was not identified in a control group (Fisher's exact test, P < 0.0001), coming from the same geographic region. These data strongly suggested the presence of a founder effect, supporting the existence of a single mutation event. Using DMLE+2.3 software and the mathematical approach described by Bengtsson and Thomson, the inferred age of this mutation is supposed to be about 2325 years (95% CI: 904–5081) ago.
doi:10.1002/mgg3.189
PMCID: PMC4799873  PMID: 27066508
F8 gene; founder effect; hemophilia A; haplotype analysis; recurrent mutation
3.  RARE BLEEDING DISORDERS 
Rare bleeding disorders (RBDs) are inherited deficiencies of coagulation factors as fibrinogen, Factor (F) FII, FV, FVII, combined FV/FVIII, FX, FXI, and FXIII. These disorders have usually a low prevalence in the general population and constitute approximately 3 to 5% of all coagulation disorders. However, in some countries they could have the same prevalence of hemophilia B due to the practice of consanguineous marriage. The clinical picture of RBDs are highly variable and could markedly vary from mild to severe, making either diagnosis and optimal treatment quiet challenging. This review focuses on 1) efforts to establish a bleeding assessment tool adequate to RBDs, 2) the optimal management of patient affected with FXI deficiency and 3) the correlation between clinical severity and laboratory diagnosis for determining the minimum coagulant activity required to prevent bleeding in each RBD.
doi:10.1111/hae.12402
PMCID: PMC4673660  PMID: 24762279
4.  Hypercoagulability Is a Stronger Risk Factor for Ischaemic Stroke than for Myocardial Infarction: A Systematic Review 
PLoS ONE  2015;10(8):e0133523.
Background and Purpose
Hypercoagulability increases the risk of arterial thrombosis; however, this effect may differ between various manifestations of arterial disease.
Methods
In this study, we compared the effect of coagulation factors as measures of hypercoagulability on the risk of ischaemic stroke (IS) and myocardial infarction (MI) by performing a systematic review of the literature. The effect of a risk factor on IS (relative risk for IS, RRIS) was compared with the effect on MI (RRMI) by calculating their ratio (RRR = RRIS/RRMI). A relevant differential effect was considered when RRR was >1+ its own standard error (SE) or <1−SE.
Results
We identified 70 publications, describing results from 31 study populations, accounting for 351 markers of hypercoagulability. The majority (203/351, 58%) had an RRR greater than 1. A larger effect on IS risk than MI risk (RRE>1+1SE) was found in 49/343 (14%) markers. Of these, 18/49 (37%) had an RRR greater than 1+2SE. On the opposite side, a larger effect on MI risk (RRR<1-1SE) was found in only 17/343 (5%) markers.
Conclusions
These results suggest that hypercoagulability has a more pronounced effect on the risk of IS than that of MI.
doi:10.1371/journal.pone.0133523
PMCID: PMC4529149  PMID: 26252207
5.  Procoagulatory State in Inflammatory Bowel Diseases Is Promoted by Impaired Intestinal Barrier Function 
Inflammatory and immune mediated disorders are risk factors for arterial and venous thromboembolism. Inflammatory bowel diseases (IBD) confer an even greater risk of thromboembolic events than other inflammatory conditions. It has been shown that IBD patients display defective intestinal barrier functions. Thus, pathogen-associated molecular patterns (PAMPs) coming from the intestinal bacterial burden might reach systemic circulation and activate innate immunity receptors on endothelial cells and platelets, promoting a procoagulative state. Aim of the study was to test this hypothesis, correlating the presence of circulating PAMPs with the activation of innate immune system and the activation of the coagulatory cascade in IBD patients. Specifically, we studied lipopolysaccharide (LPS), Toll-like receptor (TLR) 2, TLR4, and markers of activated coagulation (i.e., D-Dimer and prothrombin fragment F1+2) in the serum and plasma of IBD patients. We found that LPS levels are increased in IBD and correlate with TLR4 concentrations; although a mild correlation between LPS and CRP levels was detected, clinical disease activity does not appear to influence circulating LPS. Instead, serum LPS correlates with both D-Dimer and F1+2 measurements. Taken together, our data support the role of an impairment of intestinal barrier in triggering the activation of the coagulatory cascade in IBD.
doi:10.1155/2015/189341
PMCID: PMC4342066  PMID: 25767508
6.  Introducing the Tehran Heart Center's Premature Coronary Atherosclerosis Cohort: THC-PAC Study 
Abstract
Background:
Data on premature coronary artery disease (CAD) are scarce. The Tehran Heart Center's Premature Coronary Atherosclerosis Cohort Study (THC-PAC) is the first study of its kind in the Middle East to assess major adverse cardiac events (MACE) in young CAD patients.
Methods:
The cohort consists of CAD patients, males ≤ 45 years old and females ≤ 55 years old. The participants are residents of Tehran or its suburbs and underwent coronary angiography between June 2004 and July 2011. A 10-year follow-up, via either clinical visits or telephone calls at least once a year, was commenced in August 2012. The end point is considered MACE, encompassing death, myocardial infarction, stroke, new coronary involvement, percutaneous coronary intervention, and coronary artery bypass grafting.
Results:
The cohort comprises 1232 eligible patients (613 [49.8%] males) at a mean age of 45.1 years (SD = 5.8). High frequencies of conventional risk factors, including hyperlipidemia (884 [71.8%]), hypertension (575 [46.7%]), positive family history (539 [43.8%]), cigarette smoking (479 [38.8%]), and diabetes mellitus (390 [31.7%]), were seen in the participants. The mean body mass index (BMI) of the enrolled patients was high (29.2 ± 4.8 kg/m2), and 532 (43.3%) and 440 (35.8%) of them were overweight and obese, respectively. The females’ BMI was higher (30.4 ± 5.3 vs. 28.0 ± 3.9 kg/m2; P < 0.001) and they had a greater mean abdominal circumference (99.9 ± 13.5 vs. 98.1 ± 9.3 cm; P = 0.035). Between August 2012 and August 2013, follow-up was successful in 1173 (95.2%) patients (median follow-up duration = 55.3 months, 95%CI: 53.5–57.0 months).
Conclusion:
Our younger patients with CAD had a high frequency of risk factors compared to the same-age general population and all-age CAD patients, which may predispose them to higher incidence of recurrent MACE.
PMCID: PMC4494517  PMID: 26157461
Epidemiologic studies; Cohort studies; Coronary artery disease; Young adult
7.  Pregnancy complications in acquired thrombotic thrombocytopenic purpura: a case–control study 
Background
Pregnant women with a history of acquired thrombotic thrombocytopenic purpura (TTP) are considered at risk for disease recurrence and might be at risk for miscarriage, similar to other autoimmune disorders. However, the exact entity of these risks and their causes are unknown. The aim of this study was to evaluate risk factors associated with adverse pregnancy outcome, in terms of both gravidic TTP and miscarriage, in women affected by previous acquired TTP.
Methods
We conducted a nested case–control study in women with a history of acquired TTP enrolled in the Milan TTP registry from 1994 to October 2012, with strict inclusion criteria to reduce referral and selection bias.
Results
Fifteen out of 254 women with acquired TTP were included, namely four cases with gravidic TTP, five with miscarriage, and six controls with uncomplicated pregnancy. In the cases, ADAMTS13 activity levels in the first trimester were moderately-to-severely reduced (median levels <3% in gravidic TTP and median levels 20% [range 14-40%] in the women with miscarriage) and anti-ADAMTS13 antibodies were invariably present, while in the control group ADAMTS13 activity levels were normal (median 90%, range 40-129%), with absence of detectable anti-ADAMTS13 antibodies. Reduced levels of ADAMTS13 activity (<25%) in the first trimester were associated with an over 2.9-fold increased risk for gravidic TTP and with an over 1.2-fold increased risk for miscarriage (lower boundary of the confidence interval of the odds ratio). In addition, the presence of anti-ADAMTS13 antibodies during pregnancy was associated with an over 6.6-fold increased risk for gravidic TTP and with an over 4.1-fold increased risk for miscarriage.
Conclusions
ADAMTS13 activity evaluation and detection of anti-ADAMTS13 antibody could help to predict the risk of complications in pregnant women with a history of acquired TTP.
doi:10.1186/s13023-014-0193-6
PMCID: PMC4279798  PMID: 25431165
ADAMTS13; Anti-ADAMTS13 antibodies; Miscarriage; Pregnancy; Thrombotic thrombocytopenic purpura
8.  Salvage therapy with high dose Intravenous Immunoglobulins in acquired Von Willebrand Syndrome and unresponsive severe intestinal bleeding 
A 91-year-old woman affected with acquired Von Willebrand (VW) syndrome and intestinal angiodysplasias presented with severe gastrointestinal bleeding (hemoglobin 5 g/dl). Despite replacement therapy with VW factor/factor VIII concentrate qid, bleeding did not stop (eleven packed red blood cell units were transfused over three days). High circulating levels of anti-VW factor immunoglobulin M were documented immunoenzimatically. Heart ultrasound showed abnormalities of the mitral and aortic valves with severe flow alterations. When intravenous immunoglobulins were added to therapy, prompt clinical and laboratory responses occurred: complete cessation of bleeding, raise in hemoglobin, VW factor antigen, VW ristocetin cofactor and factor VIII levels as well as progressive reduction of the anti-VWF autoantibody levels.
doi:10.1186/2162-3619-3-15
PMCID: PMC4055248  PMID: 24926417
Acquired von Willebrand syndrome; Intravenous immunoglobulin; Gastrointestinal bleeding
9.  The European Haemophilia Network (EUHANET) 
Blood Transfusion  2014;12(Suppl 3):s515-s518.
doi:10.2450/2014.0008-14s
PMCID: PMC4044796  PMID: 24922291
haemophilia; EUHANET; reference networks; European; certification
11.  Preoperative Hematocrit Concentration and the Risk of Stroke in Patients Undergoing Isolated Coronary-Artery Bypass Grafting 
Anemia  2013;2013:206829.
Background. Identification and management of risk factors for stroke following isolated coronary artery bypass grafting (CABG) could potentially lower the risk of such serious morbidity. Methods. We retrieved data for 30-day stroke incidence and perioperative variables for patients undergoing isolated CABG and used multivariate logistic regression to assess the adjusted effect of preoperative hematocrit concentration on stroke incidence. Results. In 2,313 patients (mean age 65.9 years, 73.6% men), 43 (1.9%, 95% CI: 1.4–2.5) developed stroke within 30 days following CABG (74.4% within 6 days). After adjustment for a priori defined potential confounders, each 1% drop in preoperative hematocrit concentration was associated with 1.07 (95% CI: 1.01–1.13) increased odds for stroke (men, OR: 1.08, 95% CI: 1.01–1.16; women, OR: 1.02, 95% CI: 0.91–1.16). The predicted probability of stroke for descending preoperative hematocrit concentration exceeded 2% for values <37% (<37% for men (adjusted OR: 2.39, 95% CI: 1.08–5.26) and <38% for women (adjusted OR: 2.52, 95% CI: 0.53–11.98), with a steeper probability increase noted in men). The association between lower preoperative hematocrit concentration and stroke was evident irrespective of intraoperative transfusion use. Conclusion. Screening and management of patients with low preoperative hematocrit concentration may alter postoperative stroke risk in patients undergoing isolated CABG.
doi:10.1155/2013/206829
PMCID: PMC3657438  PMID: 23738059
12.  Prevalence of Disease and Relationships between Laboratory Phenotype and Bleeding Severity in Platelet Primary Secretion Defects 
PLoS ONE  2013;8(4):e60396.
Background
The prevalence of platelet primary secretion defects (PSD) among patients with bleeding diathesis is unknown. Moreover, there is paucity of data on the determinants of bleeding severity in PSD patients.
Objective
To determine the prevalence of PSD in patients with clinical bleeding and to study the relationships between the type of platelet defect and bleeding severity.
Methods
Data on patients referred for bleeding to the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan (Italy) in the years between 2008 and 2012 were retrieved to study the prevalence of PSD. Demographic, clinical and laboratory information on 32 patients with a diagnosis of PSD was used to compare patients with or without associated medical conditions and to investigate whether or not the type and extension of platelet defects were associated with the bleeding severity score (crude and age-normalized) or with the age at first bleeding requiring medical attention.
Results
The estimated prevalence of PSD among 207 patients with bleeding diathesis and bleeding severity score above 4 was 18.8% (95% confidence interval [CI]: 14.1–24.7%). Patients without associated medical conditions had earlier age of first bleeding (18 vs 45 years; difference: -27 years; 95% CI: -46 to -9 years) and different platelet functional defect patterns (Fisher's exact test of the distribution of patterns, P = 0.007) than patients with accompanying medical conditions. The type and extension of platelet defect was not associated with the severity of bleeding.
Conclusions
PSD is found in approximately one fifth of patients with clinical bleeding. In patients with PSD, the type and extension of laboratory defect was not associated with bleeding severity.
doi:10.1371/journal.pone.0060396
PMCID: PMC3614926  PMID: 23565241
13.  Two novel heterozygote missense mutations of the ADAMTS13 gene in a child with recurrent thrombotic thrombocytopenic purpura 
Blood Transfusion  2013;11(2):241-244.
Background
Thrombotic thrombocytopenic purpura is a rare, life-threatening disease characterised by microangiopathic haemolytic anaemia, thrombocytopenia and symptoms related to organ ischaemia, mainly involving the brain and the kidney. It is associated with a deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor. The congenital form (Upshaw-Schulman syndrome) is rare and is associated with mutations of the ADAMTS13 gene on chromosome 9q34. The clinical symptoms of congenital thrombotic thrombocytopenic purpura are variable, with some patients developing their first episode during the neonatal period or childhood and others becoming symptomatic in adulthood.
Materials and methods
We describe a case of thrombotic thrombocytopenic purpura, who presented to our attention with a relapsing form of the disease: the first episode occurred at the age of 13 months. Phenotype and genotype tests were performed in the patient and his family.
Results
The undetectable level of ADAMTS13 in the patient was caused by two novel heterozygote missense mutations on the ADAMTS13 gene: one mutation is c.788C > T (p.Ser263Phe) on exon 7 and the second is c.3251G > A (p.Cys1084Tyr) on exon 25 of the ADAMTS13 gene. All the relatives who have been investigated were found to carry one of these missense mutations in a heterozygous state.
Discussion
Although Upshaw-Schulman syndrome is a rare disease, it should be considered in all children with thrombocytopenia and jaundice in the neonatal period. In fact, once a child is confirmed to carry mutations of the ADAMTS13 gene causing early thrombotic thrombocytopenic purpura, prophylactic treatment should be started to avoid recurrence of symptoms. Genotype tests of relatives would also be important for those women in the family who could be carriers of ADAMTS13 mutations, particularly during pregnancy.
doi:10.2450/2012.0029-12
PMCID: PMC3626475  PMID: 23058857
ADAMTS13; thrombotic thrombocytopenic purpura; mutation; Upshaw-Schulman syndrome; TTP
14.  Identification of genetic risk variants for deep vein thrombosis by multiplexed next-generation sequencing of 186 hemostatic/pro-inflammatory genes 
Background
Next-generation DNA sequencing is opening new avenues for genetic association studies in common diseases that, like deep vein thrombosis (DVT), have a strong genetic predisposition still largely unexplained by currently identified risk variants. In order to develop sequencing and analytical pipelines for the application of next-generation sequencing to complex diseases, we conducted a pilot study sequencing the coding area of 186 hemostatic/proinflammatory genes in 10 Italian cases of idiopathic DVT and 12 healthy controls.
Results
A molecular-barcoding strategy was used to multiplex DNA target capture and sequencing, while retaining individual sequence information. Genomic libraries with barcode sequence-tags were pooled (in pools of 8 or 16 samples) and enriched for target DNA sequences. Sequencing was performed on ABI SOLiD-4 platforms. We produced > 12 gigabases of raw sequence data to sequence at high coverage (average: 42X) the 700-kilobase target area in 22 individuals. A total of 1876 high-quality genetic variants were identified (1778 single nucleotide substitutions and 98 insertions/deletions). Annotation on databases of genetic variation and human disease mutations revealed several novel, potentially deleterious mutations. We tested 576 common variants in a case-control association analysis, carrying the top-5 associations over to replication in up to 719 DVT cases and 719 controls. We also conducted an analysis of the burden of nonsynonymous variants in coagulation factor and anticoagulant genes. We found an excess of rare missense mutations in anticoagulant genes in DVT cases compared to controls and an association for a missense polymorphism of FGA (rs6050; p = 1.9 × 10-5, OR 1.45; 95% CI, 1.22-1.72; after replication in > 1400 individuals).
Conclusions
We implemented a barcode-based strategy to efficiently multiplex sequencing of hundreds of candidate genes in several individuals. In the relatively small dataset of our pilot study we were able to identify bona fide associations with DVT. Our study illustrates the potential of next-generation sequencing for the discovery of genetic variation predisposing to complex diseases.
doi:10.1186/1755-8794-5-7
PMCID: PMC3305575  PMID: 22353194
Deep vein thrombosis; venous thromboembolism; next-generation sequencing; target capture; multiplexing; FGA; rs6025; heamostateome; DVT; VTE
15.  Factor VIII inhibitor and source of replacement therapy 
Blood Transfusion  2012;10(1):112-113.
doi:10.2450/2011.0064-11
PMCID: PMC3259001  PMID: 22044948
16.  Large-scale association analyses identifies 13 new susceptibility loci for coronary artery disease 
Schunkert, Heribert | König, Inke R. | Kathiresan, Sekar | Reilly, Muredach P. | Assimes, Themistocles L. | Holm, Hilma | Preuss, Michael | Stewart, Alexandre F. R. | Barbalic, Maja | Gieger, Christian | Absher, Devin | Aherrahrou, Zouhair | Allayee, Hooman | Altshuler, David | Anand, Sonia S. | Andersen, Karl | Anderson, Jeffrey L. | Ardissino, Diego | Ball, Stephen G. | Balmforth, Anthony J. | Barnes, Timothy A. | Becker, Diane M. | Becker, Lewis C. | Berger, Klaus | Bis, Joshua C. | Boekholdt, S. Matthijs | Boerwinkle, Eric | Braund, Peter S. | Brown, Morris J. | Burnett, Mary Susan | Buysschaert, Ian | Carlquist, Cardiogenics, John F. | Chen, Li | Cichon, Sven | Codd, Veryan | Davies, Robert W. | Dedoussis, George | Dehghan, Abbas | Demissie, Serkalem | Devaney, Joseph M. | Do, Ron | Doering, Angela | Eifert, Sandra | El Mokhtari, Nour Eddine | Ellis, Stephen G. | Elosua, Roberto | Engert, James C. | Epstein, Stephen E. | Faire, Ulf de | Fischer, Marcus | Folsom, Aaron R. | Freyer, Jennifer | Gigante, Bruna | Girelli, Domenico | Gretarsdottir, Solveig | Gudnason, Vilmundur | Gulcher, Jeffrey R. | Halperin, Eran | Hammond, Naomi | Hazen, Stanley L. | Hofman, Albert | Horne, Benjamin D. | Illig, Thomas | Iribarren, Carlos | Jones, Gregory T. | Jukema, J.Wouter | Kaiser, Michael A. | Kaplan, Lee M. | Kastelein, John J.P. | Khaw, Kay-Tee | Knowles, Joshua W. | Kolovou, Genovefa | Kong, Augustine | Laaksonen, Reijo | Lambrechts, Diether | Leander, Karin | Lettre, Guillaume | Li, Mingyao | Lieb, Wolfgang | Linsel-Nitschke, Patrick | Loley, Christina | Lotery, Andrew J. | Mannucci, Pier M. | Maouche, Seraya | Martinelli, Nicola | McKeown, Pascal P. | Meisinger, Christa | Meitinger, Thomas | Melander, Olle | Merlini, Pier Angelica | Mooser, Vincent | Morgan, Thomas | Mühleisen, Thomas W. | Muhlestein, Joseph B. | Münzel, Thomas | Musunuru, Kiran | Nahrstaedt, Janja | Nelson, Christopher P. | Nöthen, Markus M. | Olivieri, Oliviero | Patel, Riyaz S. | Patterson, Chris C. | Peters, Annette | Peyvandi, Flora | Qu, Liming | Quyyumi, Arshed A. | Rader, Daniel J. | Rallidis, Loukianos S. | Rice, Catherine | Rosendaal, Frits R. | Rubin, Diana | Salomaa, Veikko | Sampietro, M. Lourdes | Sandhu, Manj S. | Schadt, Eric | Schäfer, Arne | Schillert, Arne | Schreiber, Stefan | Schrezenmeir, Jürgen | Schwartz, Stephen M. | Siscovick, David S. | Sivananthan, Mohan | Sivapalaratnam, Suthesh | Smith, Albert | Smith, Tamara B. | Snoep, Jaapjan D. | Soranzo, Nicole | Spertus, John A. | Stark, Klaus | Stirrups, Kathy | Stoll, Monika | Tang, W. H. Wilson | Tennstedt, Stephanie | Thorgeirsson, Gudmundur | Thorleifsson, Gudmar | Tomaszewski, Maciej | Uitterlinden, Andre G. | van Rij, Andre M. | Voight, Benjamin F. | Wareham, Nick J. | Wells, George A. | Wichmann, H.-Erich | Wild, Philipp S. | Willenborg, Christina | Witteman, Jaqueline C. M. | Wright, Benjamin J. | Ye, Shu | Zeller, Tanja | Ziegler, Andreas | Cambien, Francois | Goodall, Alison H. | Cupples, L. Adrienne | Quertermous, Thomas | März, Winfried | Hengstenberg, Christian | Blankenberg, Stefan | Ouwehand, Willem H. | Hall, Alistair S. | Deloukas, Panos | Thompson, John R. | Stefansson, Kari | Roberts, Robert | Thorsteinsdottir, Unnur | O’Donnell, Christopher J. | McPherson, Ruth | Erdmann, Jeanette | Samani, Nilesh J.
Nature genetics  2011;43(4):333-338.
We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 cases and 64,762 controls of European descent, followed by genotyping of top association signals in 60,738 additional individuals. This genomic analysis identified 13 novel loci harboring one or more SNPs that were associated with CAD at P<5×10−8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 novel loci displayed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6 to 17 percent increase in the risk of CAD per allele. Notably, only three of the novel loci displayed significant association with traditional CAD risk factors, while the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the novel CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
doi:10.1038/ng.784
PMCID: PMC3119261  PMID: 21378990
17.  Role of von Willebrand factor in the haemostasis 
Blood Transfusion  2011;9(Suppl 2):s3-s8.
doi:10.2450/2011.002S
PMCID: PMC3159913  PMID: 21839029
von Willebrand factor; molecular biology; haemostasis; platelets adhesion; ADAMTS-13
18.  Genome-Wide Association Studies in Myocardial Infarction and Coronary Artery Disease 
Myocardial infarction (MI) and its major determinant, coronary artery disease (CAD), are complex diseases arising from the interaction between several genetic and environmental factors. Until recently, the genetic basis of these diseases was poorly understood. Genome-wide genetic association studies have afforded a comprehensive insight into the association between genetic variants and diseases. To date, seven genome-wide association studies have been conducted in CAD/MI, identifying thirteen genomic regions at which common genetic variants influence the predisposition to these diseases. This review article summarizes the progress achieved in the genetic basis of MI and CAD by means of genome-wide association studies and the potential clinical applications of these findings.
PMCID: PMC3466835  PMID: 23074578
Genome-wide association study; Myocardial infarction; Coronary artery disease
19.  New susceptibility locus for coronary artery disease on chromosome 3q22.3 
Nature genetics  2009;41(3):280-282.
We present a three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls, in silico replication in three additional genome-wide datasets of coronary artery disease (CAD) and subsequent replication in ~25,000 subjects. We identified one new CAD risk locus on 3q22.3 in MRAS (P = 7.44 × 10−13; OR = 1.15, 95% CI = 1.11–1.19), and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 (P = 4.81 × 10−7; OR = 1.08, 95% CI = 1.05–1.11).
doi:10.1038/ng.307
PMCID: PMC2695543  PMID: 19198612
20.  National and international registries of rare bleeding disorders 
Blood Transfusion  2008;6(Suppl 2):s45-s48.
Rare bleeding disorders (RBDs) are autosomal recessive disorders, representing 3–5% of all the inherited deficiencies of coagulation factors. Their frequency in the general population ranges from 1:500.000 to 1:2 millions. In countries with a high rate of consanguineous marriages RBDs occur more frequently, representing a significant clinical and social problem. Patients affected by RBDs have a wide spectrum of clinical symptoms that vary from a mild or moderate bleeding tendency to potentially serious or life-threatening haemorrhages. Current treatment is based on both replacement therapy and non-transfusional treatment. However, despite the existence of several concentrates, there is no Factor V concentrate available for the treatment of Factor V deficiency, yet. In 2004, to improve the understanding of RBDs prevalence, diagnosis and treatments, the Rare Bleeding Disorders database (RBDD, www.rbdd.org) was developed. The RBDD project allowed the collection of epidemiological information on 3,230 patients from 66 Centres scattered all over the world. Epidemiological data can also be derived from the annual survey of the World Federation of Hemophilia (www.wfh.org) and from other existing national registries. However, these data are not homogenous and global surveys provide a non-real picture of the distribution ofRBDs, as about 50% of data refers to European patients. Hence, we focused on Europe and, thanks to a European project (EN-RBD), we set up a network of 10 Treatment Centres to develop a homogeneous communication tool for inserting, managing and viewing information on RBD patients (www.rbdd.eu).
This on-line database resulted to be a powerful tool to improve the quality of data collection. Preliminary results showed that a homogeneous and harmonized data collection using a unique model will help to have more accurate data for statistical analysis.
doi:10.2450/2008.0037-08
PMCID: PMC2652224  PMID: 19115503
Rare Bleeding Disorders; RBDs; registry; database
21.  Rare coagulation disorders: an emerging issue 
Blood Transfusion  2007;5(4):185-186.
doi:10.2450/2007.0044-07
PMCID: PMC2581911  PMID: 19204773

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