BackgroundVenous 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 FindingsWe 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/SignificanceThis study might also provide a valuable source of information to expand our understanding of biological mechanisms regulating quantitative biomarkers for VT.

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery metaanalysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 ؋ 10 ؊8 ) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P ‫؍‬ 3.4 ؋ 10 ؊10 ); chromosome 11p15.2 within ARNTL (rs6486122, discovery P ‫؍‬ 3.0 ؋ 10 ؊8 ); and chromosome 3p25.2 within PPARG (rs11128603, discovery P ‫؍‬ 2.9 ؋ 10 ؊8 ). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1. (Blood. 2012;120(24):4873-4881)

Background Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation. Methods and Results We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE. Conclusion We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.

Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulationfactor deficiencies. One genome-wide association study (GWAS) has been reported previously for aPTT, but no GWAS has been reported for PT. We conducted a GWAS and meta-analysis to identify genetic loci for aPTT and PT. The GWAS for aPTT was conducted in 9,240 individuals of European ancestry from the Atherosclerosis Risk in Communities (ARIC) study, and the GWAS for PT was conducted in 2,583 participants from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS) and the Lothian Birth Cohorts (LBC) of 1921 and 1936. Replication was assessed in 1,041 to 3,467 individuals. For aPTT, previously reported associations with KNG1, HRG, F11, F12, and ABO were confirmed. A second independent association in ABO was identified and replicated (rs8176704, p ¼ 4.26 3 10 À24 ). Pooling the ARIC and replication data yielded two additional loci in F5 (rs6028, p ¼ 3.22 3 10 À9 ) and AGBL1 (rs2469184, p ¼ 3.61 3 10 À8 ). For PT, significant associations were identified and confirmed in F7 (rs561241, p ¼ 3.71 3 10 À56 ) and PROCR/EDEM2 (rs2295888, p ¼ 5.25 3 10 À13 ). Assessment of existing gene expression and coronary artery disease (CAD) databases identified associations of five of the GWAS loci with altered gene expression and two with CAD. In summary, eight genetic loci that account for~29% of the variance in aPTT and two loci that account for~14% of the variance in PT were detected and supported by functional data.

SummaryDeficiencies of antithrombin (AT), protein C (PC) and protein S (PS) or an impaired PC anticoagulant pathway increase the risk of venous thrombosis (VT). By conducting a genome-wide association study (GWAS) on two independent samples of VT patients totalling 951 subjects typed for 472 173 single nucleotide polymorphisms (SNPs), we observed that common SNPs explain 21% and 27% of the genetic variance of plasma AT and PS levels, even though no SNP reached genome-wide significance. For PC, we showed that two PROCR SNPs, rs867186 (Ser219Gly) and rs6060278, additionally explained c. 20% (P = 1AE19 · 10) of the variance of plasma PC levels. We also observed that c. 40% of the remaining genetic variance of PC levels could be due to yet unidentified common SNPs. The PROCR locus was also found to explain c. 8% (P < 10 )10 ) of agkistrodon contortrix venom (ACV) (exploring the PC pathway) variability which was under the main control of the F5 and F2 loci that further explained about 40% and 10%, respectively. We presented here the first GWAS for plasma AT and free-PS levels and ACV in Caucasian samples. We identified three independent loci associated with ACV (F2, F5 and PROCR) and replicated two independent effects on plasma PC levels at the PROCR locus.

Three single nucleotide polymorphisms (SNPs) were recently found to be associated with activated partial thromboplastin time (aPTT). Because shortened aPTT levels have been observed in patients experiencing venous thrombosis (VT), we investigated the effects of these 3 aPTT-associated SNPs, rs2731672, rs9898, and rs710446, on the risk of VT in a sample of 1110 healthy patients and 1542 patients with VT. Among the 3 tested SNPs, only rs710446 was associated with VT risk; the rs710446-C allele was associated with an increased risk of VT (odds ratio 1.196, 95% confidence interval 1.071-1.336, P ‫؍‬ .0012). This association also was observed in an independent sample of 590 controls and 596 patients (odds ratio 1.171, 95% confidence interval 0.889-1.541, P ‫؍‬ .059). We also confirmed that the rs710446-C allele was associated with decreased aPTT levels, making this nonsynonymous Ile581Thr variant a new genetic risk factor for VT. (Blood. 2011; 117(13):3692-3694)

Thyroid cancer is the most common endocrine malignancy and nonmedullary thyroid carcinoma (NMTC) represents 90% of all cases. NMTC risk in first-degree relatives of affected cases is elevated fivefold to ninefold. Familial NMTC (FNMTC) accounts for about 3-7% of all thyroid tumors and is a more aggressive clinical entity than its sporadic counterparts. Linkage analysis on high-risk families performed a decade ago mapped several susceptibility loci, but did not lead to the identification of high-penetrance causal germline mutations. More recently, a genome-wide association study (GWAS) identified common single nucleotide polymorphisms (SNPs) affecting the risk of sporadic NMTC. We sought to verify if the newly identified genetic risk factors for NMTC are relevant for FNMTC as well. We genotyped 23 SNPs at 11 candidate loci in 672 subjects belonging to 133 pedigrees with at least two NMTC cases. Statistical analysis was performed using family-based association tests, modified quasi-likelihood score and logistic-normal models. SNPs at 9q22.33 near FOXE1 showed convincing evidence of association with NMTC risk in these high-risk families. The other tested loci resulted negative. These findings confirm the importance of the SNPs identified by recent GWAS on sporadic NMTC on FNMTC as well. However, the proposed FOXE1 causal variants do not show the strongest association signal. Moreover, mutation screening of the FOXE1 coding sequence in the FNMTC cases did not identify rarer causal variants, suggesting that other yet unidentified variants at this locus are involved in FNMTC etiology.Nonmedullary thyroid carcinoma (NMTC) is a welldifferentiated thyroid cancer of follicular cell origin [either papillary thyroid carcinoma (PTC) or follicular thyroid carcinoma (FTC)], which represents the most common endocrine malignancy. The annual incidence rate throughout the world ranges from 0.5 to 10 cases per 100,000 people and there is a twofold to fourfold higher incidence of new thyroid cancer cases in women than in men.1 In Europe, thyroid cancer affects 47,240 individuals annually, with an estimated mortality rate of 6,366 patients each year.2 The incidence of thyroid cancer is increasing, with one of the fastest increasing rates among common cancers. Improvement in cancer diagnosis can partly explain the phenomenon. However, early diagnosis alone is unlikely to account for this increase, and environmental factors must also play a role. The major known environmental risk factor for PTC, which accounts for about 80% of all thyroid cancers, 1 is prior exposure to radiation, with a dose-dependent effect on cancer risk. Other risk factors for PTC include iodine deficiency and excess, previous history of benign thyroid disease, such as nodules and autoimmune thyroid disease, as well as a family history. Indeed, epidemiological studies have shown that the risk of thyroid cancer has a higher familial relative risk than any

Background: Elevated levels of factor VIII (FVIII) and von Willebrand Factor (vWF) are well-established risk factors for cardiovascular diseases, in particular venous thrombosis. Although high, the heritability of these traits is poorly explained by the genetic factors known so far. The aim of this work was to identify novel single nucleotide polymorphisms (SNPs) that could influence the variability of these traits. Methods: Three independent genome-wide association studies for vWF plasma levels and FVIII activity were conducted and their results were combined into a meta-analysis totalling 1,624 subjects.