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- A 3.2 Mb deletion on 18q12 in a patient with childhood autism and high-grade myopiaPublication . Gilling, M.; Lauritsen, M.B.; Møller, M.; Henriksen, K.F.; Vicente, A.M.; Oliveira, G.; Cintin, C.; Eiberg, H.; Andersen, P.S.; Mors, O.; Rosenberg, T.; Brøndum-Nielsen, K.; Cotterill, R.M.; Lundsteen, C.; Ropers, H.H.; Ullmann, R.; Bache, I.; Tümer, Z.; Tommerup, N.Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with unknown aetiology. Even though ASDs are suggested to be among the most heritable complex disorders, only a few reproducible mutations leading to susceptibility for ASD have been identified. In an attempt to identify ASD susceptibility genes through chromosome rearrangements, we investigated a female patient with childhood autism and high-grade myopia, and an apparently balanced de novo translocation, t(5;18)(q34;q12.2). Further analyses revealed a 3.2 Mb deletion encompassing 17 genes at the 18q break point and an additional deletion of 1.27 Mb containing two genes on chromosome 4q35. Q-PCR analysis of 14 of the 17 genes deleted on chromosome 18 showed that 11 of these genes were expressed in the brain, suggesting that haploinsufficiency of one or more genes may have contributed to the childhood autism phenotype of the patient. Identification of multiple genetic changes in this patient with childhood autism agrees with the most frequently suggested genetic model of ASDs as complex, polygenic disorders.
- Advancements in risk stratification and management strategies in primary cardiovascular preventionPublication . Barkas, Fotios; Sener, Yusuf Ziya; Golforoush, Pelin Arabacilar; Kheirkhah, Azin; Rodriguez-Sanchez, Elena; Novak, Jan; Apellaniz-Ruiz, Maria; Akyea, Ralph Kwame; Bianconi, Vanessa; Ceasovschih, Alexandr; Chee, Ying Jie; Cherska, Mariia; Chora, Joana Rita; D'Oria, Mario; Demikhova, Nadiia; Kocyigit Burunkaya, Duygu; Rimbert, Antoine; Macchi, Chiara; Rathod, Krishnaraj; Roth, Lynn; Sukhorukov, Vasily; Stoica, Svetlana; Scicali, Roberto; Storozhenko, Tatyana; Uzokov, Jamol; Lupo, Maria Giovanna; van der Vorst, Emiel P.C.; Porsch, FlorentinaAtherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality worldwide, highlighting the urgent need for advancements in risk ssessment and management strategies. Although significant progress has been made ecently, identifying and managing apparently healthy individuals at a higher risk of developing atherosclerosis and those with subclinical atherosclerosis still poses significant challenges. Traditional risk assessment tools have limitations in accurately predicting future events and fail to encompass the complexity of the atherosclerosis trajectory. In this review, we describe novel approaches in biomarkers, genetics, advanced imaging techniques, and artificial intelligence that have emerged to address this gap. Moreover, polygenic risk scores and imaging modalities such as coronary artery calcium scoring, and coronary computed tomography angiography offer promising avenues for enhancing primary cardiovascular risk stratification and personalised intervention strategies. On the other hand, interventions aiming against atherosclerosis development or promoting plaque regression have gained attention in primary ASCVD prevention. Therefore, the potential role of drugs like statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, omega-3 fatty acids, antihypertensive agents, as well as glucose-lowering and anti-inflammatory drugs are also discussed. Since findings regarding the efficacy of these interventions vary, further research is still required to elucidate their mechanisms of action, optimize treatment regimens, and determine their long-term effects on ASCVD outcomes. In conclusion, advancements in strategies addressing atherosclerosis prevention and plaque regression present promising avenues for enhancing primary ASCVD prevention through personalised approaches tailored to individual risk profiles. Nevertheless, ongoing research efforts are imperative to refine these strategies further and maximise their effectiveness in safeguarding cardiovascular health.
- Advantages and Versatility of Fluorescence-Based Methodology to Characterize the Functionality of LDLR and Class Mutation AssignmentPublication . Etxebarria, A.; Benito-Vicente, A.; Alves, A.C.; Ostolaza, H.; Bourbon, M.; Martin, C.Familial hypercholesterolemia (FH) is a common autosomal codominant disease with a frequency of 1∶500 individuals in its heterozygous form. The genetic basis of FH is most commonly mutations within the LDLR gene. Assessing the pathogenicity of LDLR variants is particularly important to give a patient a definitive diagnosis of FH. Current studies of LDLR activity ex vivo are based on the analysis of 125I-labeled lipoproteins (reference method) or fluorescent-labelled LDL. The main purpose of this study was to compare the effectiveness of these two methods to assess LDLR functionality in order to validate a functional assay to analyse LDLR mutations. LDLR activity of different variants has been studied by flow cytometry using FITC-labelled LDL and compared with studies performed previously with 125I-labeled lipoproteins. Flow cytometry results are in full agreement with the data obtained by the 125I methodology. Additionally confocal microscopy allowed the assignment of different class mutation to the variants assayed. Use of fluorescence yielded similar results than 125I-labeled lipoproteins concerning LDLR activity determination, and also allows class mutation classification. The use of FITC-labelled LDL is easier in handling and disposal, cheaper than radioactivity and can be routinely performed by any group doing LDLR functional validations.
- Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosisPublication . Chora, J.R.; Medeiros, A.M.; Alves, A.C.; Bourbon, M.PurposeFamilial hypercholesterolemia (FH) is an autosomal disorder of lipid metabolism presenting with increased cardiovascular risk. Although more than 1,700 variants have been associated with FH, the great majority have not been functionally proved to affect the low-density lipoprotein receptor cycle. We aimed to classify all described variants associated with FH and to establish the proportion of variants that lack evidence to support their pathogenicity.MethodsWe followed American College of Medical Genetics and Genomics (ACMG) guidelines for the classification, and collected information from a variety of databases and individual reports. A worldwide overview of publicly available FH variants was also performed.ResultsA total of 2,104 unique variants were identified as being associated with FH, but only 166 variants have been proven by complete in vitro functional studies to be causative of disease. Additionally, applying the ACMG guidelines, 1,097 variants were considered pathogenic or likely pathogenic. Only seven variants were found in all five continents.ConclusionThe lack of functional evidence for about 85% of all variants found in FH patients can compromise FH diagnosis and patient prognosis. ACMG classification improves variant interpretation, but functional studies are necessary to understand the effect of about 40% of all variants reported. Nevertheless, ACMG guidelines need to be adapted to FH for a better diagnosis.
- Analysis of shared heritability in common disorders of the brainPublication . Anttila, Verneri; Bulik-Sullivan, Brendan; Finucane, Hilary K.; Walters, Raymond K.; Bras, Jose; Duncan, Laramie; Escott-Price, Valentina; Falcone, Guido J.; Gormley, Padhraig; Malik, Rainer; Patsopoulos, Nikolaos A.; Schoch, Susanne; Sisodiya, Sanjay M.; Smith, Philip; Sperling, Michael; Striano, Pasquale; Surges, Rainer; Thomas, G. Neil; Visscher, Frank; Whelan, Christopher D.; Berr, Claudine; Kurth, Tobias; Zara, Federico; Heinzen, Erin L.; Marson, Anthony; Becker, Felicitas; Stroink, Hans; Zimprich, Fritz; Gasser, Thomas; Gibbs, Raphael; Heutink, Peter; Martinez, Maria; Ligthart, Lannie; Letenneur, Luc; Morris, Huw R.; Sharma, Manu; Ryten, Mina; Mok, Kin Y.; Pulit, Sara; Bevan, Steve; Holliday, Elizabeth; Attia, John; Battey, Thomas; Terwindt, Gisela M.; Boncoraglio, Giorgio; Hannequin, Didier; Thijs, Vincent; Chen, Wei-Min; Mitchell, Braxton; Rothwell, Peter; Sharma, Pankaj; Sudlow, Cathie; Vicente, Astrid; Markus, Hugh; Freilinger, Tobias; Kourkoulis, Christina; Pera, Joana; Amouyel, Philippe; Raffeld, Miriam; Silliman, Scott; Boraska Perica, Vesna; Thornton, Laura M.; Huckins, Laura M.; William Rayner, N.; Lewis, Cathryn M.; Ran, Caroline; Gratacos, Monica; Rybakowski, Filip; Keski-Rahkonen, Anna; Boland, Anne; Raevuori, Anu; Hudson, James I.; Reichborn-Kjennerud, Ted; Monteleone, Palmiero; Karwautz, Andreas; Mannik, Katrin; Gordon, Scott D.; Baker, Jessica H.; O’Toole, Julie K.; Trace, Sara E.; Davis, Oliver S. P.; Deleuze, Jean-François; Helder, Sietske G.; Ehrlich, Stefan; Herpertz-Dahlmann, Beate; Danner, Unna N.; van Elburg, Annemarie A.; Borck, Guntram; Clementi, Maurizio; Forzan, Monica; Docampo, Elisa; Lissowska, Jolanta; Hauser, Joanna; Duron, Emmanuelle; Tortorella, Alfonso; Maj, Mario; Gonidakis, Fragiskos; Tziouvas, Konstantinos; Adams, Hieab H.H.; Papezova, Hana; Yilmaz, Zeynep; Wagner, Gudrun; Cohen-Woods, Sarah; Herms, Stefan; Julià, Antonio; Vardarajan, Badri N.; Rabionet, Raquel; Dick, Danielle M.; Ripatti, Samuli; Lehtimäki, Terho; Andreassen, Ole A.; Espeseth, Thomas; Lundervold, Astri J.; Steen, Vidar M.; Pinto, Dalila; Scherer, Stephen W.; Aschauer, Harald; Reitz, Christiane; Schosser, Alexandra; Alfredsson, Lars; Wedenoja, Juho; Padyukov, Leonid; Halmi, Katherine A.; Mitchell, James; Strober, Michael; Bergen, Andrew W.; Kaye, Walter; Szatkiewicz, Jin Peng; Cormand, Bru; Goate, Alison M.; Ramos-Quiroga, Josep Antoni; Ripke, Stephan; Sánchez-Mora, Cristina; Ribasés, Marta; Casas, Miguel; Hervas, Amaia; Arranz, Maria Jesús; Haavik, Jan; Zayats, Tetyana; Johansson, Stefan; Williams, Nigel; Huentelman, Matthew J.; Buring, Julie E.; Elia, Josephine; Dempfle, Astrid; Rothenberger, Aribert; Kuntsi, Jonna; Oades, Robert D.; Banaschewski, Tobias; Franke, Barbara; Buitelaar, Jan K.; Arias Vasquez, Alejandro; Doyle, Alysa E.; Schürks, Markus; Kamboh, M. Ilyas; Reif, Andreas; Lesch, Klaus-Peter; Freitag, Christine; Rivero, Olga; Palmason, Haukur; Romanos, Marcel; Langley, Kate; Rietschel, Marcella; Witt, Stephanie H.; Hrafnsdottir, Maria; Dalsgaard, Soeren; Larson, Eric B.; Børglum, Anders D.; Waldman, Irwin; Wilmot, Beth; Molly, Nikolas; Bau, Claiton H.D.; Crosbie, Jennifer; Schachar, Russell; Loo, Sandra K.; Hottenga, Jouke-Jan; McGough, James J.; Grevet, Eugenio H.; Rogaeva, Ekaterina; Medland, Sarah E.; Robinson, Elise; Weiss, Lauren A.; Bacchelli, Elena; Bailey, Anthony; Bal, Vanessa; Battaglia, Agatino; Penninx, Brenda; Betancur, Catalina; Bolton, Patrick; Cantor, Rita; St George-Hyslop, Peter; Celestino-Soper, Patrícia; Dawson, Geraldine; De Rubeis, Silvia; Duque, Frederico; Green, Andrew; Klauck, Sabine M.; Artto, Ville; Leboyer, Marion; Levitt, Pat; Maestrini, Elena; Mane, Shrikant; Hakonarson, Hakon; De-Luca, Daniel Moreno-; Parr, Jeremy; Regan, Regina; Reichenberg, Abraham; Sandin, Sven; Kaunisto, Mari; Vorstman, Jacob; Wassink, Thomas; Wijsman, Ellen; Cook, Edwin; Santangelo, Susan; Kukull, Walter A.; Delorme, Richard; Rogé, Bernadette; Magalhaes, Tiago; Arking, Dan; Vepsäläinen, Salli; Schulze, Thomas G.; Thompson, Robert C.; Strohmaier, Jana; Matthews, Keith; Melle, Ingrid; Morris, Derek; Farrer, Lindsay A.; Blackwood, Douglas; McIntosh, Andrew; Bergen, Sarah E; Martin, Nicholas G.; Schalling, Martin; Jamain, Stéphane; Maaser, Anna; Fischer, Sascha B.; Reinbold, Céline S.; Fullerton, Janice M.; Grigoroiu-Serbanescu, Maria; Barnes, Lisa L.; Guzman-Parra, José; Mayoral, Fermin; Montgomery, Grant W.; Schofield, Peter R.; Cichon, Sven; Mühleisen, Thomas W.; Degenhardt, Franziska; Schumacher, Johannes; Bauer, Michael; Mitchell, Philip B.; Gershon, Elliot S.; Beach, Thomas G.; Rice, John; Wei, Zhi; Potash, James B.; Zandi, Peter P.; Craddock, Nick; Ferrier, I. Nicol; Alda, Martin; Rouleau, Guy A.; Turecki, Gustavo; Ophoff, Roel; Pato, Carlos; Demirci, F. Yesim; Kurki, Mitja I.; Anjorin, Adebayo; Stahl, Eli; Leber, Markus; Czerski, Piotr M.; Edenberg, Howard J.; Cruceanu, Cristiana; Jones, Ian R.; Posthuma, Danielle; Andlauer, Till F.M.; Forstner, Andreas J.; Hämäläinen, Eija; Head, Elizabeth; Streit, Fabian; Baune, Bernhard T.; Air, Tracy; Sinnamon, Grant; Wray, Naomi R.; MacIntyre, Donald J.; Porteous, David; Homuth, Georg; Rivera, Margarita; Huang, Hailiang; Grove, Jakob; Hulette, Christine M.; Middeldorp, Christel M.; Hickie, Ian; Pergadia, Michele; Mehta, Divya; Smit, Johannes H.; Jansen, Rick; de Geus, Eco; Dunn, Erin; Huang, Jie; Li, Qingqin S.; Nauck, Matthias; Jicha, Gregory A.; Schoevers, Robert A.; Beekman, Aartjan TF; Knowles, James A.; Viktorin, Alexander; Arnold, Paul; Barr, Cathy L.; Bedoya-Berrio, Gabriel; Sandor, Cynthia; Bienvenu, O. Joseph; Brentani, Helena; Burton, Christie; Kauwe, John S.K.; Camarena, Beatriz; Cappi, Carolina; Cath, Danielle; Cavallini, Maria; Cusi, Daniele; Darrow, Sabrina; Webber, Caleb; Denys, Damiaan; Derks, Eske M.; Dietrich, Andrea; Fernandez, Thomas; Kaye, Jeffrey A.; Figee, Martijn; Freimer, Nelson; Gerber, Gloria; Grados, Marco; Greenberg, Erica; Muller-Myhsok, Bertram; Hanna, Gregory L.; Hartmann, Andreas; Hirschtritt, Matthew E.; Hoekstra, Pieter J.; Huang, Alden; Leverenz, James B.; Huyser, Chaim; Illmann, Cornelia; Jenike, Michael; Kuperman, Samuel; Schreiber, Stefan; Leventhal, Bennett; Lochner, Christine; Lyon, Gholson J.; Macciardi, Fabio; Madruga-Garrido, Marcos; Malaty, Irene A.; Levey, Allan I.; Maras, Athanasios; McGrath, Lauren; Miguel, Eurípedes C.; Salomaa, Veikko; Mir, Pablo; Nestadt, Gerald; Nicolini, Humberto; Okun, Michael S.; Pakstis, Andrew; Paschou, Peristera; Piacentini, John; Lieberman, Andrew P.; Pittenger, Christopher; Plessen, Kerstin; Loehrer, Elizabeth; Ramensky, Vasily; Ramos, Eliana M.; Reus, Victor; Richter, Margaret A.; Riddle, Mark A.; Robertson, Mary M.; Roessner, Veit; Rosário, Maria; Pankratz, Vernon S.; Samuels, Jack F.; Yu, Dongmei; Sandor, Paul; Stein, Dan J.; Tsetsos, Fotis; Van Nieuwerburgh, Filip; Weatherall, Sarah; Wendland, Jens R.; Wolanczyk, Tomasz; Worbe, Yulia; Zai, Gwyneth; Poon, Wayne W.; Göbel, Hartmut; Goes, Fernando S.; McLaughlin, Nicole; Nestadt, Paul S.; Grabe, Hans-Jorgen; Depienne, Christel; Konkashbaev, Anuar; Lanzagorta, Nuria; Valencia-Duarte, Ana; Bramon, Elvira; Buccola, Nancy; Macaya, Alfons; Quinn, Joseph F.; Cahn, Wiepke; Cairns, Murray; Chong, Siow A.; Cohen, David; Crespo-Facorro, Benedicto; Crowley, James; Davidson, Michael; DeLisi, Lynn; Dinan, Timothy; Pozo-Rosich, Patricia; Donohoe, Gary; Saykin, Andrew J.; Drapeau, Elodie; Duan, Jubao; Haan, Lieuwe; Hougaard, David; Karachanak-Yankova, Sena; Khrunin, Andrey; Klovins, Janis; Kučinskas, Vaidutis; Hansen, Thomas; Lee Chee Keong, Jimmy; Limborska, Svetlana; Schneider, Lon S.; Loughland, Carmel; Lönnqvist, Jouko; Maher, Brion; Mattheisen, Manuel; McDonald, Colm; Murphy, Kieran C.; Murray, Robin; Werge, Thomas; Nenadic, Igor; van Os, Jim; Pantelis, Christos; Smith, Amanda G.; Pato, Michele; Petryshen, Tracey; Quested, Digby; Roussos, Panos; Sanders, Alan R.; Schall, Ulrich; Kaprio, Jaakko; Schwab, Sibylle G.; Sim, Kang; So, Hon-Cheong; Stögmann, Elisabeth; Sonnen, Joshua A.; Subramaniam, Mythily; Toncheva, Draga; Waddington, John; Walters, James; Weiser, Mark; Metspalu, Andres; Cheng, Wei; Cloninger, Robert; Curtis, David; Gejman, Pablo V.; Henskens, Frans; Stern, Robert A.; Mattingsdal, Morten; Oh, Sang-Yun; Scott, Rodney; Webb, Bradley; Kubisch, Christian; Breen, Gerome; Churchhouse, Claire; Bulik, Cynthia M.; Daly, Mark; Dichgans, Martin; Faraone, Stephen V.; Van Deerlin, Vivianna M.; Guerreiro, Rita; Holmans, Peter; Kendler, Kenneth S.; Ferrari, Michel D.; Koeleman, Bobby; Mathews, Carol A.; Price, Alkes; Scharf, Jeremiah; Sklar, Pamela; Williams, Julie; Wood, Nicholas W.; Van Eldik, Linda J.; Cotsapas, Chris; Palotie, Aarno; Belin, Andrea C.; Smoller, Jordan W.; Sullivan, Patrick; Rosand, Jonathan; Corvin, Aiden; Neale, Benjamin M.; The Brainstorm Consortium; Harold, Denise; Russo, Giancarlo; Rubinsztein, David C.; Bayer, Anthony; Lee, Phil H.; Tsolaki, Magda; Proitsi, Petra; Fox, Nick C.; Hampel, Harald; Owen, Michael J.; Mead, Simon; Passmore, Peter; Morgan, Kevin; Nöthen, Markus M.; Schott, Jonathan M.; van den Maagdenberg, Arn M.J.M.; Rossor, Martin; Lupton, Michelle K.; Hoffmann, Per; Kornhuber, Johannes; Lawlor, Brian; McQuillin, Andrew; Al-Chalabi, Ammar; Bis, Joshua C; Ruiz, Agustin; Boada, Mercè; Zwart, John-Anker; Seshadri, Sudha; Beiser, Alexa; Rice, Kenneth; van der Lee, Sven J.; De Jager, Philip L.; Geschwind, Daniel H.; Riemenschneider, Matthias; Riedel-Heller, Steffi; Rotter, Jerome I; Ransmayr, Gerhard; Boomsma, Dorret; Hyman, Bradley T.; Cruchaga, Carlos; Alegret, Montserrat; Winsvold, Bendik; Palta, Priit; Farh, Kai-How; Cuenca-Leon, Ester; Furlotte, Nicholas; Eriksson, Nicholas; Olesen, Jes; Chasman, Daniel I.; Nyholt, Dale R.; Anney, Richard; Avbersek, Andreja; Baum, Larry; Turley, Patrick; Berkovic, Samuel; Bradfield, Jonathan; Buono, Russell; Catarino, Claudia B.; Cossette, Patrick; De Jonghe, Peter; Depondt, Chantal; Dlugos, Dennis; Ferraro, Thomas N.; French, Jacqueline; Grenier-Boley, Benjamin; Hjalgrim, Helle; Jamnadas-Khoda, Jennifer; Kälviäinen, Reetta; Kunz, Wolfram S.; Lerche, Holger; Leu, Costin; Lindhout, Dick; Lo, Warren; Lowenstein, Daniel; McCormack, Mark; Chouraki, Vincent; Møller, Rikke S.; Molloy, Anne; Ng, Ping-Wing; Oliver, Karen; Privitera, Michael; Radtke, Rodney; Ruppert, Ann-Kathrin; Sander, Thomas; Schachter, Steven; Schankin, Christoph; Kamatani, Yoichiro; Scheffer, IngridDisorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
- Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patientsPublication . Yan, J.; Oliveira, G.; Coutinho, A.; Yang, C.; Feng, J.; Katz, C.; Sram, J.; Bockholt, A.; Jones, I.R.; Craddock, N.; Cook Jr, E.H.; Vicente, A.M.; Sommer, S.S.
- Ancestry of the major long-range regulatory site of the α-globin genes in the Portuguese population with the common 3.7 kb α-thalassemia deletionPublication . Pena, Rita; Lopes, Pedro; Gaspar, Gisela; Miranda, Armandina; Faustino, PaulaBackground: The α-Major Regulatory Element (α-MRE), also known as HS-40, is located upstream of the α-globin gene cluster and has a crucial role in the long-range regulation of the α-globin gene expression. This enhancer is polymorphic and several haplotypes were identified in different populations, with haplotype D almost exclusively found in African populations. The purpose of this research was to identify the HS-40 haplotype associated with the 3.7 kb α-thalassemia deletion (-α3.7del) in the Portuguese population, and determine its ancestry and influence on patients' hematological phenotype. Methods and results: We selected 111 Portuguese individuals previously analyzed by Gap-PCR to detect the presence of the -α3.7del: 50 without the -α3.7del, 34 heterozygous and 27 homozygous for the -α3.7del. The HS-40 region was amplified by PCR followed by Sanger sequencing. Four HS-40 haplotypes were found (A to D). The distribution of HS-40 haplotypes and genotypes are significantly different between individuals with and without the -α3.7del, being haplotype D and genotype AD the most prevalent in patients with this deletion in homozygosity. Furthermore, multiple correspondence analysis revealed that individuals without the -α3.7del are grouped with other European populations, while samples with the -α3.7del are separated from these and found more closely related to the African population. Conclusion: This study revealed for the first time an association of the HS-40 haplotype D with the -α3.7del in the Portuguese population, and its likely African ancestry. These results may have clinical importance as in vitro analysis of haplotype D showed a decrease in its enhancer activity on α-globin gene.
- Angiogenesis in Schistosoma haematobium-associated urinary bladder cancerPublication . Dematei, A.; Fernandes, R.; Soares, R.; Alves, H.; Richter, J.; Botelho, M.C.Schistosoma haematobium, a parasitic flatworm that infects more than 100 million people, mostly in the developing world, is the causative agent of urogenital schistosomiasis, and is associated with a high incidence of squamous cell carcinoma (SCC) of the bladder. During infection, eggs are deposited in the bladder causing an intense inflammatory reaction. Angiogenesis is defined as the formation of new blood vessels from preexisting ones and is recognized as a key event in cell proliferation and carcinogenesis and spread of malignant lesions. A growing amount of evidence points to angiogenesis playing a key role in schistosomiasis-associated bladder cancer. Thus, identifying biomarkers of this process plays an important role in the study of cancer. Here, we review recent findings on the role of angiogenesis in bladder cancer and the growth factors that induce and assist in their development, particularly SCC of the bladder associated to urogenital schistosomiasis.
- Annexin A11 gene polymorphism (R230C variant) and sarcoidosis in a Portuguese populationPublication . Morais, A.; Lima, B.; Peixoto, M.; Melo, N.; Alves, H.; Marques, J.A.; Delgado, L.A recent genome-wide association study detected a protective effect for the annexin A11 rs1049550*T allele (R230Cvariant) in susceptibility to sarcoidosis. We evaluated the association between rs1049550 C/T and sarcoidosis susceptibility, distinct disease phenotypes and evolution in a Portuguese population. We performed a case-control study of 208 patients and 197 healthy controls. Samples were genotyped for rs1049550 C/T using real-time polymerase chain reaction. The frequency of the annexin A11 rs1049550*T allele was significantly lower in patients than in controls (33.2 vs 44.9%, P < 0.001). Odds ratio of 0.52 and 0.44 were obtained, respectively for carriers of one (CT) and two (TT) copies normalized to the CC wild-type genotype (P < 0.001). There were no significant differences in patients with and without Löfgren syndrome. A significant increase in the frequency of the T allele was observed in patients with bronchoalveolar lavage (BAL) fluid neutrophilia (P = 0.04). No significant associations were seen for lung function pattern, radiological stages or different forms of disease evolution. Our study confirms that rs1049550*T allele exerts a significant protective effect on sarcoidosis susceptibility. Given the role of annexin A11 in cell division, apoptosis and neutrophil function, this polymorphism may affect key elements of granulomatous and interstitial inflammation in sarcoidosis.
- Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope ProjectPublication . Schiele, F.; De Bacquer, D.; Vincent-Viry, M.; Beisiegel, U.; Ehnholm, C.; Evans, A.; Kafatos, A.; Martins, M.C.; Sans, S.; Sass, C.; Visvikis, S.; De Backer, G.; Siest, G.As part of the ApoEurope Project, the apolipoprotein E (apo E) serum concentration and polymorphism were determined in 6934 healthy subjects aged 25-64 years recruited in six European countries: Finland; France; Greece; Northern Ireland; Portugal and Spain. Age and sex influenced apo E concentration with concentrations being significantly higher in men than in women for those aged between 25 and 44 years. The age effect differed between the sexes after the age of 44 years, displaying a linear increase in women and a plateau in men. As expected, the serum apo E concentration was highest in varepsilon2 carriers and lowest in varepsilon4 carriers in each country with a significantly higher frequency of the varepsilon4 allele in the northern regions. The main finding of this study was a clear increasing North-South gradient in serum apo E concentration independent of age, sex and apo E genotype. In subjects aged <45 years and with the varepsilon3/varepsilon3 genotype, apo E concentration was higher in the South-East (Greece) as compared to the North by 20% for men and 32% for women. In addition to the genetic polymorphism, the geographical area is an important factor to take into account when studying serum apo E concentration in multicentre studies and defining reference values.