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Article ; Online: Genome-wide analysis of health-related biomarkers in the UK Household Longitudinal Study reveals novel associations.

Prins, Bram P / Kuchenbaecker, Karoline B / Bao, Yanchun / Smart, Melissa / Zabaneh, Delilah / Fatemifar, Ghazaleh / Luan, Jian'an / Wareham, Nick J / Scott, Robert A / Perry, John R B / Langenberg, Claudia / Benzeval, Michaela / Kumari, Meena / Zeggini, Eleftheria

Scientific reports

2017 Volume 7, Issue 1, Page(s) 11008

Abstract: Serum biomarker levels are associated with the risk of complex diseases. Here, we aimed to gain insights into the genetic architecture of biomarker traits which can reflect health status. We performed genome-wide association analyses for twenty serum ... ...

Abstract	Serum biomarker levels are associated with the risk of complex diseases. Here, we aimed to gain insights into the genetic architecture of biomarker traits which can reflect health status. We performed genome-wide association analyses for twenty serum biomarkers involved in organ function and reproductive health. 9,961 individuals from the UK Household Longitudinal Study were genotyped using the Illumina HumanCoreExome array and variants imputed to the 1000 Genomes Project and UK10K haplotypes. We establish a polygenic heritability for all biomarkers, confirm associations of fifty-four established loci, and identify five novel, replicating associations at genome-wide significance. A low-frequency variant, rs28929474, (beta = 0.04, P = 2 × 10
MeSH term(s)	Biomarkers/blood ; Family Characteristics ; Family Health ; Genetic Markers ; Genome-Wide Association Study ; Health Status ; Longitudinal Studies ; Reproductive Health ; United Kingdom
Chemical Substances	Biomarkers ; Genetic Markers
Language	English
Publishing date	2017-09-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-10812-1
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Article ; Online: Selecting instruments for Mendelian randomization in the wake of genome-wide association studies.

Swerdlow, Daniel I / Kuchenbaecker, Karoline B / Shah, Sonia / Sofat, Reecha / Holmes, Michael V / White, Jon / Mindell, Jennifer S / Kivimaki, Mika / Brunner, Eric J / Whittaker, John C / Casas, Juan P / Hingorani, Aroon D

International journal of epidemiology

2016 Volume 45, Issue 5, Page(s) 1600–1616

Abstract: Mendelian randomization (MR) studies typically assess the pathogenic relevance of environmental exposures or disease biomarkers, using genetic variants that instrument these exposures. The approach is gaining popularity-our systematic review reveals a ... ...

Abstract	Mendelian randomization (MR) studies typically assess the pathogenic relevance of environmental exposures or disease biomarkers, using genetic variants that instrument these exposures. The approach is gaining popularity-our systematic review reveals a greater than 10-fold increase in MR studies published between 2004 and 2015. When the MR paradigm was first proposed, few biomarker- or exposure-related genetic variants were known, most having been identified by candidate gene studies. However, genome-wide association studies (GWAS) are now providing a rich source of potential instruments for MR analysis. Many early reviews covering the concept, applications and analytical aspects of the MR technique preceded the surge in GWAS, and thus the question of how best to select instruments for MR studies from the now extensive pool of available variants has received insufficient attention. Here we focus on the most common category of MR studies-those concerning disease biomarkers. We consider how the selection of instruments for MR analysis from GWAS requires consideration of: the assumptions underlying the MR approach; the biology of the biomarker; the genome-wide distribution, frequency and effect size of biomarker-associated variants (the genetic architecture); and the specificity of the genetic associations. Based on this, we develop guidance that may help investigators to plan and readers interpret MR studies.
MeSH term(s)	Biomarkers ; Causality ; Genetic Variation ; Genome-Wide Association Study ; Humans ; Mendelian Randomization Analysis/methods ; Polymorphism, Single Nucleotide
Chemical Substances	Biomarkers
Language	English
Publishing date	2016-06-24
Publishing country	England
Document type	Journal Article ; Review ; Systematic Review
ZDB-ID	187909-1
ISSN	1464-3685 ; 0300-5771
ISSN (online)	1464-3685
ISSN	0300-5771
DOI	10.1093/ije/dyw088
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Article ; Online: Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers.

Journal of the National Cancer Institute

2017 Volume 109, Issue 7

Abstract: Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk ... ...

Abstract	Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.
MeSH term(s)	Adolescent ; Adult ; Breast Neoplasms/diagnosis ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Predisposition to Disease/genetics ; Heterozygote ; Humans ; Middle Aged ; Multifactorial Inheritance ; Mutation ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Polymorphism, Single Nucleotide ; Prognosis ; Proportional Hazards Models ; Receptors, Estrogen/metabolism ; Risk Assessment/methods ; Risk Assessment/statistics & numerical data ; Risk Factors ; Young Adult
Chemical Substances	Receptors, Estrogen
Language	English
Publishing date	2017-04-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djw302
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Article ; Online: Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry.

Mueller, Stefanie H / Lai, Alvina G / Valkovskaya, Maria / Michailidou, Kyriaki / Bolla, Manjeet K / Wang, Qin / Dennis, Joe / Lush, Michael / Abu-Ful, Zomoruda / Ahearn, Thomas U / Andrulis, Irene L / Anton-Culver, Hoda / Antonenkova, Natalia N / Arndt, Volker / Aronson, Kristan J / Augustinsson, Annelie / Baert, Thais / Freeman, Laura E Beane / Beckmann, Matthias W /

Behrens, Sabine / Benitez, Javier / Bermisheva, Marina / Blomqvist, Carl / Bogdanova, Natalia V / Bojesen, Stig E / Bonanni, Bernardo / Brenner, Hermann / Brucker, Sara Y / Buys, Saundra S / Castelao, Jose E / Chan, Tsun L / Chang-Claude, Jenny / Chanock, Stephen J / Choi, Ji-Yeob / Chung, Wendy K / Colonna, Sarah V / Cornelissen, Sten / Couch, Fergus J / Czene, Kamila / Daly, Mary B / Devilee, Peter / Dörk, Thilo / Dossus, Laure / Dwek, Miriam / Eccles, Diana M / Ekici, Arif B / Eliassen, A Heather / Engel, Christoph / Evans, D Gareth / Fasching, Peter A / Fletcher, Olivia / Flyger, Henrik / Gago-Dominguez, Manuela / Gao, Yu-Tang / García-Closas, Montserrat / García-Sáenz, José A / Genkinger, Jeanine / Gentry-Maharaj, Aleksandra / Grassmann, Felix / Guénel, Pascal / Gündert, Melanie / Haeberle, Lothar / Hahnen, Eric / Haiman, Christopher A / Håkansson, Niclas / Hall, Per / Harkness, Elaine F / Harrington, Patricia A / Hartikainen, Jaana M / Hartman, Mikael / Hein, Alexander / Ho, Weang-Kee / Hooning, Maartje J / Hoppe, Reiner / Hopper, John L / Houlston, Richard S / Howell, Anthony / Hunter, David J / Huo, Dezheng / Ito, Hidemi / Iwasaki, Motoki / Jakubowska, Anna / Janni, Wolfgang / John, Esther M / Jones, Michael E / Jung, Audrey / Kaaks, Rudolf / Kang, Daehee / Khusnutdinova, Elza K / Kim, Sung-Won / Kitahara, Cari M / Koutros, Stella / Kraft, Peter / Kristensen, Vessela N / Kubelka-Sabit, Katerina / Kurian, Allison W / Kwong, Ava / Lacey, James V / Lambrechts, Diether / Le Marchand, Loic / Li, Jingmei / Linet, Martha / Lo, Wing-Yee / Long, Jirong / Lophatananon, Artitaya / Mannermaa, Arto / Manoochehri, Mehdi / Margolin, Sara / Matsuo, Keitaro / Mavroudis, Dimitrios / Menon, Usha / Muir, Kenneth / Murphy, Rachel A / Nevanlinna, Heli / Newman, William G / Niederacher, Dieter / O'Brien, Katie M / Obi, Nadia / Offit, Kenneth / Olopade, Olufunmilayo I / Olshan, Andrew F / Olsson, Håkan / Park, Sue K / Patel, Alpa V / Patel, Achal / Perou, Charles M / Peto, Julian / Pharoah, Paul D P / Plaseska-Karanfilska, Dijana / Presneau, Nadege / Rack, Brigitte / Radice, Paolo / Ramachandran, Dhanya / Rashid, Muhammad U / Rennert, Gad / Romero, Atocha / Ruddy, Kathryn J / Ruebner, Matthias / Saloustros, Emmanouil / Sandler, Dale P / Sawyer, Elinor J / Schmidt, Marjanka K / Schmutzler, Rita K / Schneider, Michael O / Scott, Christopher / Shah, Mitul / Sharma, Priyanka / Shen, Chen-Yang / Shu, Xiao-Ou / Simard, Jacques / Surowy, Harald / Tamimi, Rulla M / Tapper, William J / Taylor, Jack A / Teo, Soo Hwang / Teras, Lauren R / Toland, Amanda E / Tollenaar, Rob A E M / Torres, Diana / Torres-Mejía, Gabriela / Troester, Melissa A / Truong, Thérèse / Vachon, Celine M / Vijai, Joseph / Weinberg, Clarice R / Wendt, Camilla / Winqvist, Robert / Wolk, Alicja / Wu, Anna H / Yamaji, Taiki / Yang, Xiaohong R / Yu, Jyh-Cherng / Zheng, Wei / Ziogas, Argyrios / Ziv, Elad / Dunning, Alison M / Easton, Douglas F / Hemingway, Harry / Hamann, Ute / Kuchenbaecker, Karoline B

Genome medicine

2023 Volume 15, Issue 1, Page(s) 7

Abstract: Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.: Methods: We evaluated the potential ...

Abstract	Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10 Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10
MeSH term(s)	Humans ; Female ; Breast Neoplasms/genetics ; Genetic Predisposition to Disease ; Black People ; Genetic Testing ; Genome-Wide Association Study/methods ; Polymorphism, Single Nucleotide ; Formins/genetics
Chemical Substances	FMNL3 protein, human ; Formins
Language	English
Publishing date	2023-01-26
Publishing country	England
Document type	Meta-Analysis ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S. ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-022-01152-5
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Article ; Online: The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers.

Laitman, Yael / Kuchenbaecker, Karoline B / Rantala, Johanna / Hogervorst, Frans / Peock, Susan / Godwin, Andrew K / Arason, Adalgeir / Kirchhoff, Tomas / Offit, Kenneth / Isaacs, Claudine / Schmutzler, Rita K / Wappenschmidt, Barbara / Nevanlinna, Heli / Chen, Xiaoqing / Chenevix-Trench, Georgia / Healey, Sue / Couch, Fergus / Peterlongo, Paolo / Radice, Paolo /

Nathanson, Katherine L / Caligo, Maria Adelaide / Neuhausen, Susan L / Ganz, Patricia / Sinilnikova, Olga M / McGuffog, Lesley / Easton, Douglas F / Antoniou, Antonis C / Wolf, Ido / Friedman, Eitan

Breast cancer research and treatment

2012 Volume 132, Issue 3, Page(s) 1119–1126

Abstract: Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The ... ...

Abstract	Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The effect of this variant on breast and ovarian cancer risks in non-Jewish BRCA1/BRCA2 mutation carriers has not been reported. The KL-VS variant was genotyped in women of European ancestry carrying a BRCA mutation: 5,741 BRCA1 mutation carriers (2,997 with breast cancer, 705 with ovarian cancer, and 2,039 cancer free women) and 3,339 BRCA2 mutation carriers (1,846 with breast cancer, 207 with ovarian cancer, and 1,286 cancer free women) from 16 centers. Genotyping was accomplished using TaqMan(®) allelic discrimination or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed within a retrospective cohort approach, stratified by country of origin and Ashkenazi Jewish origin. The per-allele hazard ratio (HR) for breast cancer was 1.02 (95% CI 0.93-1.12, P = 0.66) for BRCA1 mutation carriers and 0.92 (95% CI 0.82-1.04, P = 0.17) for BRCA2 mutation carriers. Results remained unaltered when analysis excluded prevalent breast cancer cases. Similarly, the per-allele HR for ovarian cancer was 1.01 (95% CI 0.84-1.20, P = 0.95) for BRCA1 mutation carriers and 0.9 (95% CI 0.66-1.22, P = 0.45) for BRCA2 mutation carriers. The risk did not change when carriers of the 6174delT mutation were excluded. There was a lack of association of the KL-VS Klotho variant with either breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
MeSH term(s)	Adult ; Aged ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Breast Neoplasms/genetics ; Case-Control Studies ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Glucuronidase/genetics ; Heterozygote ; Humans ; Klotho Proteins ; Middle Aged ; Ovarian Neoplasms/genetics ; Polymorphism, Single Nucleotide ; Proportional Hazards Models
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Glucuronidase (EC 3.2.1.31) ; Klotho Proteins (EC 3.2.1.31)
Language	English
Publishing date	2012-01-03
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604563-7
ISSN	1573-7217 ; 0167-6806
ISSN (online)	1573-7217
ISSN	0167-6806
DOI	10.1007/s10549-011-1938-8
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Article ; Online: Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers.

Kuchenbaecker, Karoline B / Hopper, John L / Barnes, Daniel R / Phillips, Kelly-Anne / Mooij, Thea M / Roos-Blom, Marie-José / Jervis, Sarah / van Leeuwen, Flora E / Milne, Roger L / Andrieu, Nadine / Goldgar, David E / Terry, Mary Beth / Rookus, Matti A / Easton, Douglas F / Antoniou, Antonis C / McGuffog, Lesley / Evans, D Gareth / Barrowdale, Daniel / Frost, Debra /

Adlard, Julian / Ong, Kai-Ren / Izatt, Louise / Tischkowitz, Marc / Eeles, Ros / Davidson, Rosemarie / Hodgson, Shirley / Ellis, Steve / Nogues, Catherine / Lasset, Christine / Stoppa-Lyonnet, Dominique / Fricker, Jean-Pierre / Faivre, Laurence / Berthet, Pascaline / Hooning, Maartje J / van der Kolk, Lizet E / Kets, Carolien M / Adank, Muriel A / John, Esther M / Chung, Wendy K / Andrulis, Irene L / Southey, Melissa / Daly, Mary B / Buys, Saundra S / Osorio, Ana / Engel, Christoph / Kast, Karin / Schmutzler, Rita K / Caldes, Trinidad / Jakubowska, Anna / Simard, Jacques / Friedlander, Michael L / McLachlan, Sue-Anne / Machackova, Eva / Foretova, Lenka / Tan, Yen Y / Singer, Christian F / Olah, Edith / Gerdes, Anne-Marie / Arver, Brita / Olsson, Håkan

JAMA

2017 Volume 317, Issue 23, Page(s) 2402–2416

Abstract: Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates.: Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and ... ...

Abstract	Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, setting, and participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures: BRCA1/2 mutations, family cancer history, and mutation location. Main outcomes and measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). Conclusions and relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.
MeSH term(s)	Adult ; Age Distribution ; Age Factors ; Aged ; Aged, 80 and over ; Breast Neoplasms/epidemiology ; Breast Neoplasms/genetics ; Family ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Humans ; Incidence ; Middle Aged ; Mutation ; Neoplasms, Second Primary/epidemiology ; Neoplasms, Second Primary/genetics ; Ovarian Neoplasms/epidemiology ; Ovarian Neoplasms/genetics ; Prospective Studies ; Risk Assessment ; Time Factors
Language	English
Publishing date	2017-06-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2958-0
ISSN	1538-3598 ; 0254-9077 ; 0002-9955 ; 0098-7484
ISSN (online)	1538-3598
ISSN	0254-9077 ; 0002-9955 ; 0098-7484
DOI	10.1001/jama.2017.7112
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Article ; Online: Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.

Lecarpentier, Julie / Silvestri, Valentina / Kuchenbaecker, Karoline B / Barrowdale, Daniel / Dennis, Joe / McGuffog, Lesley / Soucy, Penny / Leslie, Goska / Rizzolo, Piera / Navazio, Anna Sara / Valentini, Virginia / Zelli, Veronica / Lee, Andrew / Amin Al Olama, Ali / Tyrer, Jonathan P / Southey, Melissa / John, Esther M / Conner, Thomas A / Goldgar, David E /

Buys, Saundra S / Janavicius, Ramunas / Steele, Linda / Ding, Yuan Chun / Neuhausen, Susan L / Hansen, Thomas V O / Osorio, Ana / Weitzel, Jeffrey N / Toss, Angela / Medici, Veronica / Cortesi, Laura / Zanna, Ines / Palli, Domenico / Radice, Paolo / Manoukian, Siranoush / Peissel, Bernard / Azzollini, Jacopo / Viel, Alessandra / Cini, Giulia / Damante, Giuseppe / Tommasi, Stefania / Peterlongo, Paolo / Fostira, Florentia / Hamann, Ute / Evans, D Gareth / Henderson, Alex / Brewer, Carole / Eccles, Diana / Cook, Jackie / Ong, Kai-Ren / Walker, Lisa / Side, Lucy E / Porteous, Mary E / Davidson, Rosemarie / Hodgson, Shirley / Frost, Debra / Adlard, Julian / Izatt, Louise / Eeles, Ros / Ellis, Steve / Tischkowitz, Marc / Godwin, Andrew K / Meindl, Alfons / Gehrig, Andrea / Dworniczak, Bernd / Sutter, Christian / Engel, Christoph / Niederacher, Dieter / Steinemann, Doris / Hahnen, Eric / Hauke, Jan / Rhiem, Kerstin / Kast, Karin / Arnold, Norbert / Ditsch, Nina / Wang-Gohrke, Shan / Wappenschmidt, Barbara / Wand, Dorothea / Lasset, Christine / Stoppa-Lyonnet, Dominique / Belotti, Muriel / Damiola, Francesca / Barjhoux, Laure / Mazoyer, Sylvie / Van Heetvelde, Mattias / Poppe, Bruce / De Leeneer, Kim / Claes, Kathleen B M / de la Hoya, Miguel / Garcia-Barberan, Vanesa / Caldes, Trinidad / Perez Segura, Pedro / Kiiski, Johanna I / Aittomäki, Kristiina / Khan, Sofia / Nevanlinna, Heli / van Asperen, Christi J / Vaszko, Tibor / Kasler, Miklos / Olah, Edith / Balmaña, Judith / Gutiérrez-Enríquez, Sara / Diez, Orland / Teulé, Alex / Izquierdo, Angel / Darder, Esther / Brunet, Joan / Del Valle, Jesús / Feliubadalo, Lidia / Pujana, Miquel Angel / Lazaro, Conxi / Arason, Adalgeir / Agnarsson, Bjarni A / Johannsson, Oskar Th / Barkardottir, Rosa B / Alducci, Elisa / Tognazzo, Silvia / Montagna, Marco / Teixeira, Manuel R / Pinto, Pedro / Spurdle, Amanda B / Holland, Helene / Lee, Jong Won / Lee, Min Hyuk / Lee, Jihyoun / Kim, Sung-Won / Kang, Eunyoung / Kim, Zisun / Sharma, Priyanka / Rebbeck, Timothy R / Vijai, Joseph / Robson, Mark / Lincoln, Anne / Musinsky, Jacob / Gaddam, Pragna / Tan, Yen Y / Berger, Andreas / Singer, Christian F / Loud, Jennifer T / Greene, Mark H / Mulligan, Anna Marie / Glendon, Gord / Andrulis, Irene L / Toland, Amanda Ewart / Senter, Leigha / Bojesen, Anders / Nielsen, Henriette Roed / Skytte, Anne-Bine / Sunde, Lone / Jensen, Uffe Birk / Pedersen, Inge Sokilde / Krogh, Lotte / Kruse, Torben A / Caligo, Maria A / Yoon, Sook-Yee / Teo, Soo-Hwang / von Wachenfeldt, Anna / Huo, Dezheng / Nielsen, Sarah M / Olopade, Olufunmilayo I / Nathanson, Katherine L / Domchek, Susan M / Lorenchick, Christa / Jankowitz, Rachel C / Campbell, Ian / James, Paul / Mitchell, Gillian / Orr, Nick / Park, Sue Kyung / Thomassen, Mads / Offit, Kenneth / Couch, Fergus J / Simard, Jacques / Easton, Douglas F / Chenevix-Trench, Georgia / Schmutzler, Rita K / Antoniou, Antonis C / Ottini, Laura

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2017 Volume 35, Issue 20, Page(s) 2240–2250

Abstract: Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic ... ...

Abstract	Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10
MeSH term(s)	Adult ; Age Factors ; Aged ; Aged, 80 and over ; Breast Neoplasms, Male/genetics ; Case-Control Studies ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Predisposition to Disease ; Genetic Testing ; Genome-Wide Association Study ; Heterozygote ; Humans ; Male ; Middle Aged ; Multifactorial Inheritance ; Mutation ; Polymorphism, Single Nucleotide ; Prostatic Neoplasms/genetics ; Risk Assessment/methods
Language	English
Publishing date	2017-04-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.2016.69.4935
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Article ; Online: HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.

Swerdlow, Daniel I / Preiss, David / Kuchenbaecker, Karoline B / Holmes, Michael V / Engmann, Jorgen E L / Shah, Tina / Sofat, Reecha / Stender, Stefan / Johnson, Paul C D / Scott, Robert A / Leusink, Maarten / Verweij, Niek / Sharp, Stephen J / Guo, Yiran / Giambartolomei, Claudia / Chung, Christina / Peasey, Anne / Amuzu, Antoinette / Li, KaWah /

Palmen, Jutta / Howard, Philip / Cooper, Jackie A / Drenos, Fotios / Li, Yun R / Lowe, Gordon / Gallacher, John / Stewart, Marlene C W / Tzoulaki, Ioanna / Buxbaum, Sarah G / van der A, Daphne L / Forouhi, Nita G / Onland-Moret, N Charlotte / van der Schouw, Yvonne T / Schnabel, Renate B / Hubacek, Jaroslav A / Kubinova, Ruzena / Baceviciene, Migle / Tamosiunas, Abdonas / Pajak, Andrzej / Topor-Madry, Roman / Stepaniak, Urszula / Malyutina, Sofia / Baldassarre, Damiano / Sennblad, Bengt / Tremoli, Elena / de Faire, Ulf / Veglia, Fabrizio / Ford, Ian / Jukema, J Wouter / Westendorp, Rudi G J / de Borst, Gert Jan / de Jong, Pim A / Algra, Ale / Spiering, Wilko / Maitland-van der Zee, Anke H / Klungel, Olaf H / de Boer, Anthonius / Doevendans, Pieter A / Eaton, Charles B / Robinson, Jennifer G / Duggan, David / Kjekshus, John / Downs, John R / Gotto, Antonio M / Keech, Anthony C / Marchioli, Roberto / Tognoni, Gianni / Sever, Peter S / Poulter, Neil R / Waters, David D / Pedersen, Terje R / Amarenco, Pierre / Nakamura, Haruo / McMurray, John J V / Lewsey, James D / Chasman, Daniel I / Ridker, Paul M / Maggioni, Aldo P / Tavazzi, Luigi / Ray, Kausik K / Seshasai, Sreenivasa Rao Kondapally / Manson, JoAnn E / Price, Jackie F / Whincup, Peter H / Morris, Richard W / Lawlor, Debbie A / Smith, George Davey / Ben-Shlomo, Yoav / Schreiner, Pamela J / Fornage, Myriam / Siscovick, David S / Cushman, Mary / Kumari, Meena / Wareham, Nick J / Verschuren, W M Monique / Redline, Susan / Patel, Sanjay R / Whittaker, John C / Hamsten, Anders / Delaney, Joseph A / Dale, Caroline / Gaunt, Tom R / Wong, Andrew / Kuh, Diana / Hardy, Rebecca / Kathiresan, Sekar / Castillo, Berta A / van der Harst, Pim / Brunner, Eric J / Tybjaerg-Hansen, Anne / Marmot, Michael G / Krauss, Ronald M / Tsai, Michael / Coresh, Josef / Hoogeveen, Ronald C / Psaty, Bruce M / Lange, Leslie A / Hakonarson, Hakon / Dudbridge, Frank / Humphries, Steve E / Talmud, Philippa J / Kivimäki, Mika / Timpson, Nicholas J / Langenberg, Claudia / Asselbergs, Folkert W / Voevoda, Mikhail / Bobak, Martin / Pikhart, Hynek / Wilson, James G / Reiner, Alex P / Keating, Brendan J / Hingorani, Aroon D / Sattar, Naveed

Lancet (London, England)

2014 Volume 385, Issue 9965, Page(s) 351–361

Abstract: Background: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.: Methods: We ... ...

Abstract	Background: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target. Methods: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis. Findings: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials). Interpretation: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. Funding: The funding sources are cited at the end of the paper.
MeSH term(s)	Aged ; Body Mass Index ; Body Weight/genetics ; Cholesterol, HDL/metabolism ; Cholesterol, LDL/metabolism ; Diabetes Mellitus, Type 2/genetics ; Female ; Genetic Testing ; Humans ; Hydroxymethylglutaryl CoA Reductases/genetics ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Randomized Controlled Trials as Topic ; Risk Factors
Chemical Substances	Cholesterol, HDL ; Cholesterol, LDL ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; HMGCR protein, human (EC 1.1.1.-) ; Hydroxymethylglutaryl CoA Reductases (EC 1.1.1.-)
Language	English
Publishing date	2014-09-24
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3306-6
ISSN	1474-547X ; 0023-7507 ; 0140-6736
ISSN (online)	1474-547X
ISSN	0023-7507 ; 0140-6736
DOI	10.1016/S0140-6736(14)61183-1
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Article ; Online: Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study.

Holmes, Michael V / Simon, Tabassome / Exeter, Holly J / Folkersen, Lasse / Asselbergs, Folkert W / Guardiola, Montse / Cooper, Jackie A / Palmen, Jutta / Hubacek, Jaroslav A / Carruthers, Kathryn F / Horne, Benjamin D / Brunisholz, Kimberly D / Mega, Jessica L / van Iperen, Erik P A / Li, Mingyao / Leusink, Maarten / Trompet, Stella / Verschuren, Jeffrey J W / Hovingh, G Kees /

Dehghan, Abbas / Nelson, Christopher P / Kotti, Salma / Danchin, Nicolas / Scholz, Markus / Haase, Christiane L / Rothenbacher, Dietrich / Swerdlow, Daniel I / Kuchenbaecker, Karoline B / Staines-Urias, Eleonora / Goel, Anuj / van 't Hooft, Ferdinand / Gertow, Karl / de Faire, Ulf / Panayiotou, Andrie G / Tremoli, Elena / Baldassarre, Damiano / Veglia, Fabrizio / Holdt, Lesca M / Beutner, Frank / Gansevoort, Ron T / Navis, Gerjan J / Mateo Leach, Irene / Breitling, Lutz P / Brenner, Hermann / Thiery, Joachim / Dallmeier, Dhayana / Franco-Cereceda, Anders / Boer, Jolanda M A / Stephens, Jeffrey W / Hofker, Marten H / Tedgui, Alain / Hofman, Albert / Uitterlinden, André G / Adamkova, Vera / Pitha, Jan / Onland-Moret, N Charlotte / Cramer, Maarten J / Nathoe, Hendrik M / Spiering, Wilko / Klungel, Olaf H / Kumari, Meena / Whincup, Peter H / Morrow, David A / Braund, Peter S / Hall, Alistair S / Olsson, Anders G / Doevendans, Pieter A / Trip, Mieke D / Tobin, Martin D / Hamsten, Anders / Watkins, Hugh / Koenig, Wolfgang / Nicolaides, Andrew N / Teupser, Daniel / Day, Ian N M / Carlquist, John F / Gaunt, Tom R / Ford, Ian / Sattar, Naveed / Tsimikas, Sotirios / Schwartz, Gregory G / Lawlor, Debbie A / Morris, Richard W / Sandhu, Manjinder S / Poledne, Rudolf / Maitland-van der Zee, Anke H / Khaw, Kay-Tee / Keating, Brendan J / van der Harst, Pim / Price, Jackie F / Mehta, Shamir R / Yusuf, Salim / Witteman, Jaqueline C M / Franco, Oscar H / Jukema, J Wouter / de Knijff, Peter / Tybjaerg-Hansen, Anne / Rader, Daniel J / Farrall, Martin / Samani, Nilesh J / Kivimaki, Mika / Fox, Keith A A / Humphries, Steve E / Anderson, Jeffrey L / Boekholdt, S Matthijs / Palmer, Tom M / Eriksson, Per / Paré, Guillaume / Hingorani, Aroon D / Sabatine, Marc S / Mallat, Ziad / Casas, Juan P / Talmud, Philippa J

Journal of the American College of Cardiology

2013 Volume 62, Issue 21, Page(s) 1966–1976

Abstract: Objectives: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.: Background: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of ... ...

Abstract	Objectives: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Background: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. Methods: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. Results: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Conclusions: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
MeSH term(s)	Alleles ; Cardiovascular Diseases/enzymology ; Cardiovascular Diseases/epidemiology ; Cardiovascular Diseases/genetics ; DNA/genetics ; Gene Expression Regulation ; Global Health ; Humans ; Incidence ; Mendelian Randomization Analysis/methods ; Phospholipases A2, Secretory/genetics ; Phospholipases A2, Secretory/metabolism
Chemical Substances	DNA (9007-49-2) ; Phospholipases A2, Secretory (EC 3.1.1.4)
Language	English
Publishing date	2013-07-31
Publishing country	United States
Document type	Journal Article ; Meta-Analysis
ZDB-ID	605507-2
ISSN	1558-3597 ; 0735-1097
ISSN (online)	1558-3597
ISSN	0735-1097
DOI	10.1016/j.jacc.2013.06.044
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Article ; Online: Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Gaudet, Mia M / Kuchenbaecker, Karoline B / Vijai, Joseph / Klein, Robert J / Kirchhoff, Tomas / McGuffog, Lesley / Barrowdale, Daniel / Dunning, Alison M / Lee, Andrew / Dennis, Joe / Healey, Sue / Dicks, Ed / Soucy, Penny / Sinilnikova, Olga M / Pankratz, Vernon S / Wang, Xianshu / Eldridge, Ronald C / Tessier, Daniel C / Vincent, Daniel /

Bacot, Francois / Hogervorst, Frans B L / Peock, Susan / Stoppa-Lyonnet, Dominique / Peterlongo, Paolo / Schmutzler, Rita K / Nathanson, Katherine L / Piedmonte, Marion / Singer, Christian F / Thomassen, Mads / Hansen, Thomas v O / Neuhausen, Susan L / Blanco, Ignacio / Greene, Mark H / Garber, Judith / Weitzel, Jeffrey N / Andrulis, Irene L / Goldgar, David E / D'Andrea, Emma / Caldes, Trinidad / Nevanlinna, Heli / Osorio, Ana / van Rensburg, Elizabeth J / Arason, Adalgeir / Rennert, Gad / van den Ouweland, Ans M W / van der Hout, Annemarie H / Kets, Carolien M / Aalfs, Cora M / Wijnen, Juul T / Ausems, Margreet G E M / Frost, Debra / Ellis, Steve / Fineberg, Elena / Platte, Radka / Evans, D Gareth / Jacobs, Chris / Adlard, Julian / Tischkowitz, Marc / Porteous, Mary E / Damiola, Francesca / Golmard, Lisa / Barjhoux, Laure / Longy, Michel / Belotti, Muriel / Ferrer, Sandra Fert / Mazoyer, Sylvie / Spurdle, Amanda B / Manoukian, Siranoush / Barile, Monica / Genuardi, Maurizio / Arnold, Norbert / Meindl, Alfons / Sutter, Christian / Wappenschmidt, Barbara / Domchek, Susan M / Pfeiler, Georg / Friedman, Eitan / Jensen, Uffe Birk / Robson, Mark / Shah, Sohela / Lazaro, Conxi / Mai, Phuong L / Benitez, Javier / Southey, Melissa C / Schmidt, Marjanka K / Fasching, Peter A / Peto, Julian / Humphreys, Manjeet K / Wang, Qin / Michailidou, Kyriaki / Sawyer, Elinor J / Burwinkel, Barbara / Guénel, Pascal / Bojesen, Stig E / Milne, Roger L / Brenner, Hermann / Lochmann, Magdalena / Aittomäki, Kristiina / Dörk, Thilo / Margolin, Sara / Mannermaa, Arto / Lambrechts, Diether / Chang-Claude, Jenny / Radice, Paolo / Giles, Graham G / Haiman, Christopher A / Winqvist, Robert / Devillee, Peter / García-Closas, Montserrat / Schoof, Nils / Hooning, Maartje J / Cox, Angela / Pharoah, Paul D P / Jakubowska, Anna / Orr, Nick / González-Neira, Anna / Pita, Guillermo / Alonso, M Rosario / Hall, Per / Couch, Fergus J / Simard, Jacques / Altshuler, David / Easton, Douglas F / Chenevix-Trench, Georgia / Antoniou, Antonis C / Offit, Kenneth

PLoS genetics

2013 Volume 9, Issue 3, Page(s) e1003173

Abstract: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast ... ...

Abstract	Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
MeSH term(s)	Adult ; Aged ; Alleles ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Chromosomes, Human, Pair 6/genetics ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Heterozygote ; Humans ; Middle Aged ; Mutation ; Polymorphism, Single Nucleotide ; Risk Factors
Chemical Substances	BRCA1 Protein ; BRCA2 Protein ; BRCA2 protein, human
Language	English
Publishing date	2013-03-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1003173
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