Time filter

Source Type

Hamburg, Germany

Hein R.,German Cancer Research Center | Hein R.,University of Cologne | Abbas S.,University of Cologne | Seibold P.,German Cancer Research Center | And 3 more authors.
Breast Cancer Research and Treatment | Year: 2012

Menopausal hormone therapy (MHT) is associated with an increased breast cancer risk in postmenopausal women, with combined estrogen-progestagen therapy posing a greater risk than estrogen monotherapy. However, few studies focused on potential effect modification of MHT-associated breast cancer risk by genetic polymorphisms in the progesterone metabolism. We assessed effect modification of MHT use by five coding single nucleotide polymorphisms (SNPs) in the progesterone metabolizing enzymes AKR1C3 (rs7741), AKR1C4 (rs3829125, rs17134592), and SRD5A1 (rs248793, rs3736316) using a two-center population-based case-control study from Germany with 2,502 postmenopausal breast cancer patients and 4,833 matched controls. An empirical-Bayes procedure that tests for interaction using a weighted combination of the prospective and the retrospective case-control estimators as well as standard prospective logistic regression were applied to assess multiplicative statistical interaction between polymorphisms and duration of MHT use with regard to breast cancer risk assuming a log-additive mode of inheritance. No genetic marginal effects were observed. Breast cancer risk associated with duration of combined therapy was significantly modified by SRD5A1-rs3736316, showing a reduced risk elevation in carriers of the minor allele (p interaction,empirical-Bayes = 0.006 using the empirical-Bayes method, p interaction,logistic regression = 0.013 using logistic regression). The risk associated with duration of use of monotherapy was increased by AKR1C3-rs7741 in minor allele carriers (p interaction,empirical-Bayes = 0.083, p interaction,logistic regression = 0.029) and decreased in minor allele carriers of two SNPs in AKR1C4 (rs3829125: p interaction,empirical-Bayes = 0.07, p interaction,logistic regression = 0.021; rs17134592: p interaction,empirical-Bayes = 0.101, p interaction,logistic regression = 0.038). After Bonferroni correction for multiple testing only SRD5A1-rs3736316 assessed using the empirical-Bayes method remained significant. Postmenopausal breast cancer risk associated with combined therapy may be modified by genetic variation in SRD5A1. Further well-powered studies are, however, required to replicate our finding. © 2011 Springer Science+Business Media, LLC.

Schofl C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Honegger J.,University of Tubingen | Droste M.,Endocrine Practice | Finke R.,Endocrine Practice Kaisereiche | And 15 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Familial and sporadic GH-secreting pituitary adenomas are associated with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. Patients with an AIP mutation (AIPmut) tend to have more aggressive tumors occurring at a younger age. Objective: The objective of the study was to investigate the frequency of AIPmut in patients diagnosed at 30 years of age or younger. Design: The German Acromegaly Registry database (1795 patients in 58 centers) was screened for patients diagnosed with acromegaly at 30 years of age or younger (329 patients). Sixteen centers participated and 91 patients consented to AIPmut analysis. Intervention: DNA was analyzed by direct sequencing and multiplex ligation dependent probe amplification Main outcome Measures: The number of patients with AIPmut was measured. Results: Five patients had either a mutation (c.490C>T, c.844C>T, and c.911G>A, three males) or gross deletions of exons 1 and 2 of the AIP gene (n = 2, one female). The overall frequency of an AIPmut was 5.5%, and 2.3% or 2.4% in patients with an apparently sporadic adenoma or macroadenoma, respectively. By contrast, three of four patients (75%) with a positive family history were tested positive for an AIPmut. Except for a positive family history, there were no significant differences between patients with and without an AIPmut. Conclusions: The frequency of AIPmut in this registry-based cohort of young patients with acromegaly is lower than previously reported. Patients with a positive family history should be tested for an AIPmut, whereas young patients without an apparent family history should be screened, depending on the individual cost to benefit ratio. Copyright © 2014 by the Endocrine Society.

Wagner S.,University Medical Center Mainz | Baskaya O.,University Medical Center Mainz | Anicker N.J.,University Medical Center Mainz | Dahmen N.,University Medical Center Mainz | And 3 more authors.
Acta Psychiatrica Scandinavica | Year: 2010

Objective: We analyzed i) the effects of serious life events (SLE) on impulsive aggression, and ii) modulating effects of the COMT Val 158Met polymorphism on the association between SLEs and impulsive aggression in borderline personality disorder (BPD). Method: One hundred and twelve female BPD patients from Germany were included in this study. Impulsive aggression was assessed by the Buss-Durkee-Hostility Inventory (BDHI). Results: Childhood sexual abuse was associated with lower BDHI sum score (P = 0.003). In COMT Val158Val carriers, but not in Val/Met and Met/Met carriers, childhood sexual abuse and the cumulative number of SLEs were associated with lower BDHI sum scores (P < 0.05). Conclusion: This study analyzing a specific gene × environment interaction in female BPD patients suggests an association between SLEs and impulsive aggression, as well as a modulating effect of the COMT Val158Val genotype on the relation between SLEs and impulsive aggression. © 2009 John Wiley & Sons A/S.

Wagner S.,University Medical Center Mainz | Baskaya O.,University Medical Center Mainz | Dahmen N.,University Medical Center Mainz | Dahmen N.,BioGlobe GmbH | And 2 more authors.
Genes, Brain and Behavior | Year: 2010

Impulsive aggression belongs to the key features of borderline personality disorder (BPD). In the development of BPD, serious life events are known to play a major role. Acute and chronic stress has been suggested to inhibit hippocampal brain-derived neurotrophic factor (BDNF) synthesis and to mediate neural plasticity in response to adverse social experiences. Recently it has been reported that the frequency of violent suicide attempts is higher in adult suicide attempters reporting severe childhood sexual abuse and carrying the Val66Val genotype of the BDNF Val66Met polymorphism. In this study we analysed modulating effects of BDNF Val66Met polymorphism on the effects of physical maltreatment, rape and childhood sexual abuse on impulsive aggression. One hundred and fifty-nine BPD patients from Germany and of Caucasian descent were included. Impulsive aggression was assessed by the Buss-Durkee-Hostility Inventory (BDHI). Childhood sexual abuse accounted for 23.6% of the variance of BDHI sum score. Childhood sexual abuse decreased BDHI sum score in BDNF Val/Val carriers but not in Met carriers. In contrast to previous findings this study analysing a specific gene × environment interaction in BPD patients suggests a decreasing effect of childhood sexual abuse on impulsive aggression in BPD patients, particularly in BDNF Val/Val carriers. The interrelations between serious life events, impulsive aggression and the BDNF Val66Met polymorphism as well as their implication for BPD are far from understood and require further investigations. © 2009 Blackwell Publishing Ltd/International Behavioural and Neural Genetics Society.

Machens A.,Martin Luther University of Halle Wittenberg | Lorenz K.,Martin Luther University of Halle Wittenberg | Sekulla C.,Martin Luther University of Halle Wittenberg | Hoppner W.,BioGlobe GmbH | And 3 more authors.
European Journal of Endocrinology | Year: 2013

Objective: Twenty years ago, the groundbreaking discovery that rearranged during transfection (RET) mutations underlie multiple endocrine neoplasia 2 (MEN2) and familial medullary thyroid cancer (FMTC) ushered in the era of personalized medicine. MEN2-associated signs, taking time to manifest, can be subtle. This study sought to clarify to what extent conventional estimates of 1:200 000-500 000 underestimate the incidence of RET mutations in the population. Design: Included in this retrospective investigation were 333 RET carriers born between 1951 and 2000 and operated on at the largest German surgical referral center (286 carriers) or elsewhere (47 carriers). Methods: To estimate the incidence of RET mutations, the number of RET carriers born in Germany in five decades (1951-1960, 1961-1970, 1971-1980, 1981-1990, and 1991-2000) was divided by the corresponding number of German live births. Results: Owing to improved diagnosis and capture of FMTC and MEN2 patients, minimum incidence estimates increased over time: overall from 5.0 (1951-1960) to 9.9 (1991-2000) per million live births and year (P=0.008), and by American Thyroid Association/ATA class from 1.7 to 3.7 for ATA class C (P=0.008); from 1.8 to 2.7 for ATA class A (P=0.017); from 1.5 to 2.2 for ATA class B (P=0.20); and from 0 to 1.4 for ATA class D mutations per million live births and year (P=0.008). Based on 1991-2000 incidence estimates the prevalence in Germany is ∼1:80 000 inhabitants. Conclusions: The molecular minimum incidence estimate of ≈1:100 000 was two-to fivefold greater than conventional estimates of 1:200 000-500 000. © 2013 European Society of Endocrinology.

Discover hidden collaborations