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265 Publications visible to you, out of a total of 265
Genetic association study of eight steroid hormones and implications for sexual dimorphism of coronary artery disease
LIFE Adult, Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

CONTEXT: Steroid hormones are important regulators of physiological processes in humans and are under genetic control. A link to coronary artery disease (CAD) is supposed. OBJECTIVE: Our main objective …e was to identify genetic loci influencing steroid hormone levels. As secondary aim, we searched for causal effects of steroid hormones on CAD. DESIGN: We conducted genome-wide meta-association studies for eight steroid hormones: cortisol, DHEA-S, estradiol and testosterone in two independent cohorts (LIFE-Adult, LIFE-Heart, max. n=7667), and progesterone, 17-hydroxyprogesterone, androstenedione and aldosterone in LIFE-Heart only (max. n=2070). All genome-wide significant loci were tested for sex interactions. Further, we tested if previously reported CAD SNPs were associated with our steroid hormone panel and investigated causal links between hormone levels and CAD status using Mendelian Randomization (MR) approaches. RESULTS: We discovered 15 novel associated loci for 17-hydroxyprogesterone, progesterone, DHEA-S, cortisol, androstenedione, and estradiol. Five of these loci relate to genes directly involved in steroid metabolism: CYP21A1, CYP11B1, CYP17A1, STS, and HSD17B12, almost completing the set of steroidogenic enzymes with genetic associations. Sexual dimorphisms were found for seven of the novel loci. Other loci correspond, e.g., to the WNT4/β-catenin pathway. MR revealed that cortisol, androstenedione, 17-hydroxyprogesterone and DHEA-S had causal effects on CAD. We also observed enrichment of cortisol and testosterone associations among known CAD hits. CONCLUSION: Our study greatly improves insight into genetic regulation of steroid hormones and their dependency on sex. These results could serve as a basis for analyzing sex-dimorphisms in other complex diseases.

Authors: J. Pott, YJ. Bae, K. Horn, A. Teren, Andreas Kühnapfel, H. Kirsten, U. Ceglarek, Markus Löffler, J. Thiery, J. Kratzsch, Markus Scholz

Date Published: 6th Jun 2019

Publication Type: Not specified

Human Diseases: coronary artery disease

The association between mental demands at the workplace and cognitive functioning: the role of the big five personality traits.
LIFE Adult

Abstract (Expand)

<b>Objectives:</b> Mental demands at the workplace can be preventive against cognitive decline. However, personality shapes the way information is processed and we therefore assume that … Neuroticism, Extraversion, Openness, Agreeableness and Conscientiousness, would moderate the beneficial effects of workplace stimulation on cognitive outcomes. <b>Methods:</b> We analyzed data from the population-based LIFE-Adult-Study (n = 6529). Cognitive outcomes were assessed via the Trail-Making Test (TMTA, TMTB) and the Verbal Fluency Test. Personality was assessed via the Personality Adjective List (16 AM). Mental demands were classified with the indices Verbal and Executive based on the O*NET database. <b>Results:</b> Multivariate regression analyses showed only two significant moderation effects of personality, i.e. in individuals with low scores on Conscientiousness/Openness, index Verbal was connected to better TMTB performance, while this effect disappeared for individuals with high values on the personality trait. However, the additional explained variance remained marginal. <b>Conclusion:</b> The findings suggest that personality does not modify associations between high mental demands at work and better cognitive functioning in old age; however, there is a tendency that high levels of Openness and Conscientiousness may offset effects of mental demands.

Authors: Felix S Hussenoeder, Ines Conrad, Susanne Roehr, Heide Glaesmer, Andreas Hinz, Cornelia Enzenbach, Christoph Engel, Veronika Witte, Matthias L Schroeter, Markus Loeffler, Joachim Thiery, Arno Villringer, Steffi G Riedel-Heller, Francisca S Rodriguez

Date Published: 25th May 2019

Publication Type: Not specified

Human Diseases: mental depression

Breast cancer risk in BRCA1/2 mutation carriers and noncarriers under prospective intensified surveillance.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Comparably little is known about breast cancer (BC) risks in women from families tested negative for BRCA1/2 mutations despite an indicative family history, as opposed to BRCA1/2 mutation carriers. We … determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers of BRCA1/2 mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n = 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n = 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) for BRCA1 mutation carriers, 43.2% (95% CI 32.1-56.3%) for BRCA2 mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) for BRCA1 mutation carriers, 13.5 (95% CI 9.2-19.1) for BRCA2 mutation carriers and 4.9 (95% CI 3.8-6.3) for BRCA1/2 noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) for BRCA1 mutation carriers, 6.6% (95% CI 3.4-12.5%) for BRCA2 mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women from BRCA1/2 negative families with elevated risk.

Authors: C. Engel, C. Fischer, S. Zachariae, K. Bucksch, K. Rhiem, J. Giesecke, N. Herold, B. Wappenschmidt, V. Hubbel, M. Maringa, S. Reichstein-Gnielinski, E. Hahnen, C. R. Bartram, N. Dikow, S. Schott, D. Speiser, D. Horn, E. M. Fallenberg, M. Kiechle, A. S. Quante, A. S. Vesper, T. Fehm, C. Mundhenke, N. Arnold, E. Leinert, W. Just, U. Siebers-Renelt, S. Weigel, A. Gehrig, A. Wockel, B. Schlegelberger, S. Pertschy, K. Kast, P. Wimberger, S. Briest, M. Loeffler, U. Bick, R. K. Schmutzler

Date Published: 13th May 2019

Publication Type: Not specified

Human Diseases: hereditary breast ovarian cancer syndrome

Olfactory function is associated with cognitive performance: results from the population-based LIFE-Adult-Study.
LIFE Adult

Abstract (Expand)

BACKGROUND: Studies in older adults or those with cognitive impairment have shown associations between cognitive and olfactory performance, but there are few population-based studies especially in … younger adults. We therefore cross-sectionally analyzed this association using data from the population-based LIFE-Adult-Study. METHODS: Cognitive assessments comprised tests from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD): verbal fluency (VF), word list learning and recall (WLL, WLR), and the Trail Making Tests (TMT) A and B. The "Sniffin' Sticks Screening 12" test was used to measure olfactory performance. Linear regression analyses were performed to determine associations between the number of correctly identified odors (0 to 12) and the five cognitive test scores, adjusted for sex, age, education, and the presence of depressive symptoms. Receiver operating characteristic (ROC) analysis was carried out to determine the discriminative performance of the number of correctly identified odors regarding identification of cognition impairment. RESULTS: A total of 6783 participants (51.3% female) completed the olfaction test and the VF test and TMT. A subgroup of 2227 participants (46.9% female) also completed the WLL and WLR tests. Based on age-, sex-, and education-specific norms from CERAD, the following numbers of participants were considered cognitively impaired: VF 759 (11.2%), WLL 242 (10.9%), WLR: 132 (5.9%), TMT-A 415 (6.1%), and TMT-B/A ratio 677 (10.0%). On average, score values for VF were higher by 0.42 points (p < 0.001), for WLL higher by 0.32 points (p = 0.001), for WLR higher by 0.31 points (p = 0.002), for TMT-A lower by 0.25 points (p < 0.001), and for TMT-B/A ratio lower by 0.01 points (p < 0.001) per number of correctly identified odors. ROC analysis revealed area under the curve values from 0.55 to 0.62 for the five cognitive tests. CONCLUSIONS: Better olfactory performance was associated with better cognitive performance in all five tests in adults - adjusted for age, sex, education, and the presence of depressive symptoms. However, the ability of the smell test to discriminate between individuals with and without cognitive impairment was limited. The value of olfactory testing in early screening for cognitive impairment should be investigated in longitudinal studies.

Authors: M. Yahiaoui-Doktor, T. Luck, S. G. Riedel-Heller, M. Loeffler, K. Wirkner, C. Engel

Date Published: 10th May 2019

Publication Type: Not specified

Human Diseases: Alzheimer's disease

High-risk breast cancer surveillance with MRI: 10-year experience from the German consortium for hereditary breast and ovarian cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

PURPOSE To report on 10 years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). METHODS A cohort of 4,573 high-risk, previously …sly unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age. RESULTS A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12 months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9-93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6-85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6-91.7), p \textless 0.001. Cancer detection rates (CDRs) and as a result positive predictive values were strongly dependent on type of screening round, risk group and patient age. CDRs ranged from 43.5‰ (95% CI 29.8-62.9) for the first screening round in BRCA2 carriers to 2.9‰ (95% CI 1.3-6.3) for subsequent screening rounds in high-risk non-carriers in the age group 30 to 39 years. CONCLUSIONS High-risk screening with MRI was successfully implemented in the GC-HBOC with high sensitivity and specificity. Risk prediction and inclusion criteria in high-risk non-carriers need to be adjusted to improve CDRs and thus screening efficacy in these patients.

Authors: Ulrich Bick, Christoph Engel, Barbara Krug, Walter Heindel, Eva M. Fallenberg, Kerstin Rhiem, David Maintz, Michael Golatta, Dorothee Speiser, Dorothea Rjosk-Dendorfer, Irina Lämmer-Skarke, Frederic Dietzel, Karl Werner Fritz Schäfer, Elena Leinert, Stefanie Weigel, Stephanie Sauer, Stefanie Pertschy, Thomas Hofmockel, Anne Hagert-Winkler, Karin Kast, Anne Quante, Alfons Meindl, Marion Kiechle, Markus Loeffler, Rita K. Schmutzler

Date Published: 1st May 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Background BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 …2 mutation carriers remains unclear. Methods We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. Results Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. Conclusion Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

Authors: Frank Qian, Shengfeng Wang, Jonathan Mitchell, Lesley McGuffog, Daniel Barrowdale, Goska Leslie, Jan C. Oosterwijk, Wendy K. Chung, D. Gareth Evans, Christoph Engel, Karin Kast, Cora M. Aalfs, Muriel A. Adank, Julian Adlard, Bjarni A. Agnarsson, Kristiina Aittomäki, Elisa Alducci, Irene L. Andrulis, Banu K. Arun, Margreet G. E. M. Ausems, Jacopo Azzollini, Emmanuelle Barouk-Simonet, Julian Barwell, Muriel Belotti, Javier Benitez, Andreas Berger, Ake Borg, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Trinidad Caldes, Maria A. Caligo, Ian Campbell, Sandrine M. Caputo, Jocelyne Chiquette, Kathleen B. M. Claes, J. Margriet Collée, Fergus J. Couch, Isabelle Coupier, Mary B. Daly, Rosemarie Davidson, Orland Diez, Susan M. Domchek, Alan Donaldson, Cecilia M. Dorfling, Ros Eeles, Lidia Feliubadaló, Lenka Foretova, Jeffrey Fowler, Eitan Friedman, Debra Frost, Patricia A. Ganz, Judy Garber, Vanesa Garcia-Barberan, Gord Glendon, Andrew K. Godwin, Encarna B. Gómez Garcia, Jacek Gronwald, Eric Hahnen, Ute Hamann, Alex Henderson, Carolyn B. Hendricks, John L. Hopper, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Louise Izatt, Ángel Izquierdo, Anna Jakubowska, Katarzyna Kaczmarek, Eunyoung Kang, Beth Y. Karlan, Carolien M. Kets, Sung-Won Kim, Zisun Kim, Ava Kwong, Yael Laitman, Christine Lasset, Min Hyuk Lee, Jong Won Lee, Jihyoun Lee, Jenny Lester, Fabienne Lesueur, Jennifer T. Loud, Jan Lubinski, Noura Mebirouk, Hanne E. J. Meijers-Heijboer, Alfons Meindl, Austin Miller, Marco Montagna, Thea M. Mooij, Patrick J. Morrison, Emmanuelle Mouret-Fourme, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Finn C. Nielsen, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Kai-Ren Ong, Laura Ottini, Sue K. Park, Paolo Peterlongo, Georg Pfeiler, Catherine M. Phelan, Bruce Poppe, Nisha Pradhan, Paolo Radice, Susan J. Ramus, Johanna Rantala, Mark Robson, Gustavo C. Rodriguez, Rita K. Schmutzler, Christina G. Hutten Selkirk, Payal D. Shah, Jacques Simard, Christian F. Singer, Johanna Sokolowska, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Yen Tan, R. Manuel Teixeira, Soo H. Teo, Mary Beth Terry, Mads Thomassen, Marc Tischkowitz, Amanda E. Toland, Katherine M. Tucker, Nadine Tung, Christi J. van Asperen, Klaartje van Engelen, Elizabeth J. van Rensburg, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Drakoulis Yannoukakos, Mark H. Greene, Matti A. Rookus, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, David E. Goldgar, Olufunmilayo I. Olopade, Timothy R. Rebbeck, Dezheng Huo

Date Published: 1st Apr 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

An integrative web platform for user-friendly application of risk prediction models in hereditary cancer predisposition
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Background and Objective: Predicting individual mutation and cancer risks is essential to assist genetic counsellors in clinical decision making for patients with a hereditary cancer predisposition. … Worldwide a variety of statistical models and empirical data for risk prediction have been developed and published for hereditary breast and ovarian cancer (HBOC), and hereditary non-polyposis colorectal cancer (HNPCC / Lynch syndrome, LS). However, only few models have so far been implemented in convenient and easy-to-use computer applications. We therefore aimed to develop user-friendly applications of selected HBOC and LS risk prediction models, and to make them available through the "Leipzig Health Atlas" (LHA), a web-based multifunctional platform to share research data, novel ontologies, models and software tools with the medical and scientific community. LHA is a project funded within the BMBF initiative "i:DSem – Integrative data semantics in system medicine". Methods and Results: We selected a total of six statistical models and empirical datasets relevant for HBOC and LS: 1) the Manchester Scoring System, 2) the "Mutation Frequency Explorer" of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), 3) an extended version of the Claus model, 4) MMRpredict, 5) PREMM1,2,6, and 6) PREMM5. The Manchester Scoring System allows calculation of BRCA1/2 mutation probabilities based on aggregated family history. The "Mutation Frequency Explorer" allows flexible assessment of mutation risks in BRCA1/2 and other genes for different sets of familial cancer histories based on a large dataset from the GC-HBOC. The extended Claus model (as implemented in the commercial predigree drawing software Cyrillic 2.1.3, which is no longer supported and no longer works on newer operating systems) predicts both mutation and breast cancer risks based on structured pedigree data. MMRpredict, PREMM 1,2,6, and PREMM 5 predict mutation risks in mismatch repair genes for patients from families suspected of having LS. All models were implemented using the statistical software "R" and the R-package "Shiny". "Shiny" allows the development of interactive applications by incorporating "R" with HTML and other web technologies. The Shiny apps are accessible on the website of the "Leipzig Health Atlas" (https://www.health-atlas.de) for registered researchers and genetic counselors. Conclusions: The risk prediction apps allow convenient calculation of mutation or cancer risks for an advice-seeking individual based on pedigree data or aggregated information on the familial cancer history. Target users should be specialized health professionals (physicians and genetic counselors) and scientists to ensure correct handling of the tools and careful interpretation of results.

Authors: Silke Zachariae, Sebastian Stäubert, C. Fischer, Markus Löffler, Christoph Engel

Date Published: 8th Mar 2019

Publication Type: InProceedings

Human Diseases: hereditary breast ovarian cancer syndrome, Lynch syndrome, colorectal cancer

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