Less Than a state, more than an international organization: The Sui generis nature of the European Union

In this paper, I show that the European Union (EU) is less than a state, but more than an international organization. Although it possesses some characteristics of both, the European Union is, I argue, a sui generis project: Although the EU wields extensive influence in some policy areas (such as competition policy or international trade regulation), its institutions’ powers are quite limited in many areas that remain firmly within the grasp of its Member States’ governments (such as security, justice, tax or redistribution policies). The European Union’s supranational elements – especially the EU laws’ supremacy over the laws of individual Member States – distinguish it, furthermore, from international organizations, such as the United Nations or the World Trade Organization. I conclude that the European Union is really a sui generis project that has not been attempted anywhere else: As such, it could be regarded as a useful case study, or perhaps even a “pilot project,” for regional integration projects elsewhere

Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection

Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73\u2009 7\u200910-9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism

Genome-wide association study identifies an early onset pancreatic cancer risk locus

Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore we performed a genome-wide association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset 6460\u2009years, of whom 198 with age of onset 6450, and 3227 controls from PanScan I-II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P <\u20091x10-4 ). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset 6460\u2009years, of whom 265 with age of onset 6450, and 4142 controls from the PANDoRA consortium while in the in silico data we observed no statistically significant association. However, the resulting meta-analysis supported the association (P =\u20091.15x10-4 ). In conclusion we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature. This article is protected by copyright. All rights reserved

Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma

none57siPancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P=7.14×10 -10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumor cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P=3.56×10 -6). This SNP is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.restrictedPistoni, Laura; Gentiluomo, Manuel; Lu, Ye; López de Maturana, Evangelina; Hlavac, Viktor; Vanella, Giuseppe; Darvasi, Erika; Milanetto, Anna Caterina; Oliverius, Martin; Vashist, Yogesh; Di Leo, Milena; Mohelnikova-Duchonova, Beatrice; Talar-Wojnarowska, Renata; Gheorghe, Cristian; Petrone, Maria Chiara; Strobel, Oliver; Arcidiacono, Paolo Giorgio; Vodickova, Ludmila; Szentesi, Andrea; Capurso, Gabriele; Gajdán, László; Malleo, Giuseppe; Theodoropoulos, George E; Basso, Daniela; Soucek, Pavel; Brenner, Hermann; Lawlor, Rita T; Morelli, Luca; Ivanauskas, Audrius; Kauffmann, Emanuele Federico; Macauda, Angelica; Gazouli, Maria; Archibugi, Livia; Nentwich, Michael; Loveček, Martin; Cavestro, Giulia Martina; Vodicka, Pavel; Landi, Stefano; Tavano, Francesca; Sperti, Cosimo; Hackert, Thilo; Kupcinskas, Juozas; Pezzilli, Raffaele; Andriulli, Angelo; Pollina, Luca; Kreivenaite, Edita; Gioffreda, Domenica; Jamroziak, Krzysztof; Hegyi, Péter; Izbicki, Jakob R; Testoni, Sabrina Gloria Giulia; Zuppardo, Raffaella Alessia; Bozzato, Dania; Neoptolemos, John P; Malats, Núria; Canzian, Federico; Campa, DanielePistoni, Laura; Gentiluomo, Manuel; Lu, Ye; López de Maturana, Evangelina; Hlavac, Viktor; Vanella, Giuseppe; Darvasi, Erika; Milanetto, Anna Caterina; Oliverius, Martin; Vashist, Yogesh; Di Leo, Milena; Mohelnikova-Duchonova, Beatrice; Talar-Wojnarowska, Renata; Gheorghe, Cristian; Petrone, Maria Chiara; Strobel, Oliver; Arcidiacono, Paolo Giorgio; Vodickova, Ludmila; Szentesi, Andrea; Capurso, Gabriele; Gajdán, László; Malleo, Giuseppe; Theodoropoulos, George E; Basso, Daniela; Soucek, Pavel; Brenner, Hermann; Lawlor, Rita T; Morelli, Luca; Ivanauskas, Audrius; Kauffmann, Emanuele Federico; Macauda, Angelica; Gazouli, Maria; Archibugi, Livia; Nentwich, Michael; Loveček, Martin; Cavestro, Giulia Martina; Vodicka, Pavel; Landi, Stefano; Tavano, Francesca; Sperti, Cosimo; Hackert, Thilo; Kupcinskas, Juozas; Pezzilli, Raffaele; Andriulli, Angelo; Pollina, Luca; Kreivenaite, Edita; Gioffreda, Domenica; Jamroziak, Krzysztof; Hegyi, Péter; Izbicki, Jakob R; Testoni, Sabrina Gloria Giulia; Zuppardo, Raffaella Alessia; Bozzato, Dania; Neoptolemos, John P; Malats, Núria; Canzian, Federico; Campa, Daniel

Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

Background Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection. Objective We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score. Methods We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes. Results The scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54x10(-10) highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64x10(-8), highest vs lowest quintile of the weighted multifactorial score). Conclusion We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population