Browsing by Keyword "VARIANTS"
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Publication A Large Case-Control Study Performed in Spanish Population Suggests That RECQL5 Is the Only RECQ Helicase Involved in Breast Cancer Susceptibility.(Multidisciplinary Digital Publishing Institute (MDPI), 2022-09-28) Marchena-Perea, Erik Michel; Salazar-Hidalgo, Milton Eduardo; Gómez-Sanz, Alicia; Arranz-Ledo, Mónica; Barroso, Alicia; Fernández, Victoria; Tejera-Pérez, Hugo; Pita, Guillermo; Núñez-Torres, Rocío; Pombo, Luz; Morales-Chamorro, Rafael; Cano-Cano, Juana María; Soriano, Maria Del Carmen; Garre, Pilar; Durán, Mercedes; Currás-Freixes, Maria; de la Hoya, Miguel; Osorio, Ana; Unión Europea. Comisión Europea; Centro de Investigación Biomédica en Red - CIBERER (Enfermedades Raras)Around 50% of the familial breast cancer (BC) cases are estimated to be caused by germline variants in known low-, moderate-, and high-risk susceptibility genes, while the other half is of unknown genetic origin. In the present study, we wanted to evaluate the role of the RECQ helicases, some of which have been studied in the past as candidates, with unclear results about their role in the disease. Using next-generation sequencing (NGS) technology, we analyzed the whole coding sequence of BLM, RECQL1, RECQL4, RECQL5, and WRN in almost 2000 index cases from BC Spanish families that had previously tested negative for the known BC susceptibility genes (BRCAX) and compared the results with the controls extracted from gnomAD. Our results suggest that BLM, RECQL1, RECQL4, and WRN do not play a major role in BC susceptibility. However, in the combined analysis, joining the present results with those previously reported in a series of 1334 BC Spanish patients and controls, we found a statistically significant association between Loss of Function (LoF) variants in RECQL5 and BC risk, with an OR of 2.56 (p = 0.009; 95% CI, 1.18-4.98). Our findings support our previous work and places the RECQL5 gene as a new moderate-risk BC gene.Publication A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families(Nature Publishing Group, 2015) Calvete, Oriol; Martinez, Paula; Garcia-Pavia, Pablo; Benitez-Buelga, Carlos; Paumard-Hernandez B; Fernandez, Victoria; Dominguez, Fernando; Salas, Clara; Romero-Laorden, Nuria; Garcia-Donas, Jesus; Carrillo, Jaime; Perona, Rosario; Carlos Trivino, Juan; Andrés, Raquel; Maria Cano, Juana; Rivera, Barbara; Alonso-Pulpon, Luis; Setien, Fernando; Esteller, Manel; Rodriguez Perales, Sandra; Bougeard, Gaelle; Frebourg, Tierry; Urioste, Miguel; Blasco, MA; Benitez, Javier; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomedica en Red - CIBER; Unión Europea. Comisión Europea; Unión Europea. Comisión Europea. European Research Council (ERC); Korber Foundation; Botín Foundation; Fundación Lilly; ICREACardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li-Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility.Publication Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer(Nature Publishing Group, 2019-04-15) Ferreira, Manuel A; Gamazon, Eric R; Al-Ejeh, Fares; Aittomäki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arason, Adalgeir; Arndt, Volker; Aronson, Kristan J; Arun, Banu K; Asseryanis, Ella; Azzollini, Jacopo; Balmaña, Judith; Barnes, Daniel R; Barrowdale, Daniel; Beckmann, Matthias W; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Białkowska, Katarzyna; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Borg, Ake; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Caldés, Trinidad; Caligo, Maria A; Campa, Daniele; Campbell, Ian; Canzian, Federico; Carter, Jonathan; Carter, Brian D; Castelao, Jose E; Chang-Claude, Jenny; Chanock, Stephen J; Christiansen, Hans; Chung, Wendy K; Claes, Kathleen B M; Clarke, Christine L; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Daly, Mary B; de la Hoya, Miguel; Dennis, Joe; Devilee, Peter; Diez, Orland; Dörk, Thilo; Dunning, Alison M; Dwek, Miriam; Eccles, Diana M; Ejlertsen, Bent; Ellberg, Carolina; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A; Fletcher, Olivia; Flyger, Henrik; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gago-Dominguez, Manuela; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; García-Closas, Montserrat; García-Sáenz, José A; Gaudet, Mia M; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Greene, Mark H; Gronwald, Jacek; Guénel, Pascal; Haiman, Christopher A; Hall, Per; Hamann, Ute; He, Wei; Heyworth, Jane; Hogervorst, Frans B L; Hollestelle, Antoinette; Hoover, Robert N; Hopper, John L; Hulick, Peter J; Humphreys, Keith; Imyanitov, Evgeny N; Isaacs, Claudine; Jakimovska, Milena; Jakubowska, Anna; James, Paul A; Janavicius, Ramunas; Jankowitz, Rachel C; John, Esther M; Johnson, Nichola; Joseph, Vijai; Karlan, Beth Y; Khusnutdinova, Elza; Kiiski, Johanna I; Ko, Yon-Dschun; Jones, Michael E; Konstantopoulou, Irene; Kristensen, Vessela N; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Leslie, Goska; Lester, Jenny; Lesueur, Fabienne; Lindström, Sara; Long, Jirong; Loud, Jennifer T; Lubiński, Jan; Makalic, Enes; Mannermaa, Arto; Manoochehri, Mehdi; Margolin, Sara; Maurer, Tabea; Mavroudis, Dimitrios; McGuffog, Lesley; Meindl, Alfons; Menon, Usha; Michailidou, Kyriaki; Miller, Austin; Montagna, Marco; Moreno, Fernando; Moserle, Lidia; Mulligan, Anna Marie; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nevelsteen, Ines; Nielsen, Finn C; Nikitina-Zake, Liene; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olsson, Håkan; Osorio, Ana; Papp, Janos; Park-Simon, Tjoung-Won; Parsons, Michael T; Pedersen, Inge Sokilde; Peixoto, Ana; Peterlongo, Paolo; Pharoah, Paul D P; Plaseska-Karanfilska, Dijana; Poppe, Bruce; Presneau, Nadege; Radice, Paolo; Rantala, Johanna; Rennert, Gad; Risch, Harvey A; Saloustros, Emmanouil; Sanden, Kristin; Sawyer, Elinor J; Schmidt, Marjanka K; Schmutzler, Rita K; Sharma, Priyanka; Shu, Xiao-Ou; Simard, Jacques; Singer, Christian F; Soucy, Penny; Southey, Melissa C; Spinelli, John J; Spurdle, Amanda B; Stone, Jennifer; Swerdlow, Anthony J; Tapper, William J; Taylor, Jack A; Teixeira, Manuel R; Terry, Mary Beth; Teulé, Alex; Thomassen, Mads; Thöne, Kathrin; Thull, Darcy L; Tischkowitz, Marc; Toland, Amanda E; Torres, Diana; Truong, Thérèse; Tung, Nadine; Vachon, Celine M; van Asperen, Christi J; van den Ouweland, Ans M W; van Rensburg, Elizabeth J; Vega, Ana; Viel, Alessandra; Wang, Qin; Wappenschmidt, Barbara; Weitzel, Jeffrey N; Wendt, Camilla; Winqvist, Robert; Yang, Xiaohong R; Yannoukakos, Drakoulis; Ziogas, Argyrios; Kraft, Peter; Antoniou, Antonis C; Zheng, Wei; Easton, Douglas F; Milne, Roger L; Beesley, Jonathan; Chenevix-Trench, Georgia; National Institutes of Health (Estados Unidos); American Cancer Society; Institut Curie; Ligue Nationale Contre le Cancer (Francia); Agence Nationale de la Recherche (Francia); Societe Francaise de lutte contre les Cancers et les leucemies de l'Enfant et de l'adolescent; Unión Europea. Comisión Europea. European Research Council (ERC); Instituto de Salud Carlos III; Munich Center of Health Sciences; Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der LMU München; Walter Schulz FoundationGenome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.Publication Novel association of the obesity risk-allele near Fas Apoptotic Inhibitory Molecule 2 (FAIM2) gene with heart rate and study of its effects on myocardial infarction in diabetic participants of the PREDIMED trial(BioMed Central (BMC), 2014) Corella, Dolores; Sorli, Jose V.; Gonzlez, Jose I.; Ortega, Carolina; Fit, Montserrat; Bull, Monica; Martinez-Gonzalez, Miguel Angel; Ros, Emilio; Ars, Fernando; Lapetra, Jose; Gmez-Gracia, Enrique; Serra-Majem, Lluis; Ruiz-Gutierrez, Valentina; Fiol, Miquel; Coltell, Oscar; Vinyoles, Ernest; Pinto, Xavier; Marti, Amelia; Saiz, Carmen; Ordovas, Jose M; Estruch, Ramn; Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); United States Department of Agriculture; Generalitat Valenciana (España)Background: The Fas apoptotic pathway has been implicated in type 2 diabetes and cardiovascular disease. Although a polymorphism (rs7138803; G > A) near the Fas apoptotic inhibitory molecule 2 (FAIM2) locus has been related to obesity, its association with other cardiovascular risk factors and disease remains uncertain. Methods: We analyzed the association between the FAIM2-rs7138803 polymorphism and obesity, blood pressure and heart rate in 7,161 participants (48.3\% with type 2 diabetes) in the PREDIMED study at baseline. We also explored gene-diet interactions with adherence to the Mediterranean diet (MedDiet) and examined the effects of the polymorphism on cardiovascular disease incidence per diabetes status after a median 4.8-year dietary intervention (MedDiet versus control group) follow-up. Results: We replicated the association between the FAIM2-rs7138803 polymorphism and greater obesity risk (OR: 1.08; 95\% CI: 1.01-1.16; P = 0.011; per-A allele). Moreover, we detected novel associations of this polymorphism with higher diastolic blood pressure (DBP) and heart rate at baseline (B = 1.07; 95\% CI: 0.97-1.28 bmp in AA vs G-carriers for the whole population), that remained statistically significant even after adjustment for body mass index (P = 0.012) and correction for multiple comparisons. This association was greater and statistically significant in type-2 diabetic subjects (B = 1.44: 95\% CI: 0.23-2.56 bmp; P = 0.010 for AA versus G-carriers). Likewise, these findings were also observed longitudinally over 5-year follow-up. Nevertheless, we found no statistically significant gene-diet interactions with MedDiet for this trait. On analyzing myocardial infarction risk, we detected a nominally significant (P = 0.041) association in type-2 diabetic subjects (HR: 1.86; 95\% CI: 1.03-3.37 for AA versus G-carriers), although this association did not remain statistically significant following correction for multiple comparisons. Conclusions: We confirmed the FAIM2-rs7138803 relationship with obesity and identified novel and consistent associations with heart rate in particular in type 2 diabetic subjects. Furthermore, our results suggest a possible association of this polymorphism with higher myocardial infarction risk in type-2 diabetic subjects, although this result needs to be replicated as it could represent a false positive.