BRIP1 (BACH1) variants and familial breast cancer risk: a case-control study

<p>Abstract</p> <p>Background</p> <p>Inactivating and truncating mutations of the nuclear BRCA1-interacting protein 1 (BRIP1) have been shown to be the major cause of Fanconi anaemia and, due to subsequent alterations of BRCA1 function, predispose to breast cancer (BC).</p> <p>Methods</p> <p>We investigated the effect of BRIP1 -64G>A and Pro919Ser on familial BC risk by means of TaqMan allelic discrimination, analysing <it>BRCA1/BRCA2 </it>mutation-negative index patients of 571 German BC families and 712 control individuals.</p> <p>Results</p> <p>No significant differences in genotype frequencies between BC cases and controls for BRIP1 -64G>A and Pro919Ser were observed.</p> <p>Conclusion</p> <p>We found no effect of the putatively functional BRIP1 variants -64G>A and Pro919Ser on the risk of familial BC.</p

Phase transitions in biological membranes

Native membranes of biological cells display melting transitions of their lipids at a temperature of 10-20 degrees below body temperature. Such transitions can be observed in various bacterial cells, in nerves, in cancer cells, but also in lung surfactant. It seems as if the presence of transitions slightly below physiological temperature is a generic property of most cells. They are important because they influence many physical properties of the membranes. At the transition temperature, membranes display a larger permeability that is accompanied by ion-channel-like phenomena even in the complete absence of proteins. Membranes are softer, which implies that phenomena such as endocytosis and exocytosis are facilitated. Mechanical signal propagation phenomena related to nerve pulses are strongly enhanced. The position of transitions can be affected by changes in temperature, pressure, pH and salt concentration or by the presence of anesthetics. Thus, even at physiological temperature, these transitions are of relevance. There position and thereby the physical properties of the membrane can be controlled by changes in the intensive thermodynamic variables. Here, we review some of the experimental findings and the thermodynamics that describes the control of the membrane function.Comment: 23 pages, 15 figure

Underestimated Effect Sizes in GWAS: Fundamental Limitations of Single SNP Analysis for Dichotomous Phenotypes

Complex diseases are often highly heritable. However, for many complex traits only a small proportion of the heritability can be explained by observed genetic variants in traditional genome-wide association (GWA) studies. Moreover, for some of those traits few significant SNPs have been identified. Single SNP association methods test for association at a single SNP, ignoring the effect of other SNPs. We show using a simple multi-locus odds model of complex disease that moderate to large effect sizes of causal variants may be estimated as relatively small effect sizes in single SNP association testing. This underestimation effect is most severe for diseases influenced by numerous risk variants. We relate the underestimation effect to the concept of non-collapsibility found in the statistics literature. As described, continuous phenotypes generated with linear genetic models are not affected by this underestimation effect. Since many GWA studies apply single SNP analysis to dichotomous phenotypes, previously reported results potentially underestimate true effect sizes, thereby impeding identification of true effect SNPs. Therefore, when a multi-locus model of disease risk is assumed, a multi SNP analysis may be more appropriate

Progression and regression of incident cervical HPV 6, 11, 16 and 18 infections in young women

<p>Abstract</p> <p>Background</p> <p>We describe type-specific progression, regression and persistence of incident human papillomavirus (HPV)-6-11-16 and -18 infections, along with type distribution in cervical intra-epithelial neoplasia (CIN) lesions.</p> <p>Methods</p> <p>The study population consisted of 16–23 year-old women undergoing Pap testing and cervical swab polymerase chain reaction testing for HPV DNA at approximate 6 month intervals for up to 4 years in the placebo arm of a clinical trial of an HPV 16-vaccine. HPV types in incident infections were correlated with types in lesion biopsy specimens.</p> <p>Results</p> <p>56.7% of CIN-1 and nearly one-third of CIN-2/3 lesions following incident HPV-6-11-16 or -18 infections did not correlate with the incident infection HPV type. Cumulative 36-month progression rates to CIN-2/3 testing positive for the relevant HPV type were highest for HPV-16 infections (16.5%), followed by HPV-18 (8.2%). Overall, 26.0% of CIN-1, 50.0% of CIN-2 and 70.6% of CIN-3 biopsies tested positive for HPV-6-11-16-18 infections.</p> <p>Conclusion</p> <p>Women with a given HPV type may often be co-infected or subsequently infected with other types which may lead to subsequent cervical lesions. This issue has been addressed in this study reporting data for the natural history of HPV-6-11-16 and -18 infections and is a relevant consideration in designing future studies to evaluate the incidence/risk of CIN following other type-specific HPV infections.</p

Lipids modulate the conformational dynamics of a secondary multidrug transporter

Direct interactions with lipids have emerged as key determinants of the folding, structure and function of membrane proteins, but an understanding of how lipids modulate protein dynamics is still lacking. Here, we systematically explored the effects of lipids on the conformational dynamics of the proton-powered multidrug transporter LmrP from Lactococcus lactis, using the pattern of distances between spin-label pairs previously shown to report on alternating access of the protein. We uncovered, at the molecular level, how the lipid headgroups shape the conformational-energy landscape of the transporter. The model emerging from our data suggests a direct interaction between lipid headgroups and a conserved motif of charged residues that control the conformational equilibrium through an interplay of electrostatic interactions within the protein. Together, our data lay the foundation for a comprehensive model of secondary multidrug transport in lipid bilayers

A genetic ensemble approach for gene-gene interaction identification

<p>Abstract</p> <p>Background</p> <p>It has now become clear that gene-gene interactions and gene-environment interactions are ubiquitous and fundamental mechanisms for the development of complex diseases. Though a considerable effort has been put into developing statistical models and algorithmic strategies for identifying such interactions, the accurate identification of those genetic interactions has been proven to be very challenging.</p> <p>Methods</p> <p>In this paper, we propose a new approach for identifying such gene-gene and gene-environment interactions underlying complex diseases. This is a hybrid algorithm and it combines genetic algorithm (GA) and an ensemble of classifiers (called genetic ensemble). Using this approach, the original problem of SNP interaction identification is converted into a data mining problem of combinatorial feature selection. By collecting various single nucleotide polymorphisms (SNP) subsets as well as environmental factors generated in multiple GA runs, patterns of gene-gene and gene-environment interactions can be extracted using a simple combinatorial ranking method. Also considered in this study is the idea of combining identification results obtained from multiple algorithms. A novel formula based on pairwise <it>double fault </it>is designed to quantify the degree of complementarity.</p> <p>Conclusions</p> <p>Our simulation study demonstrates that the proposed genetic ensemble algorithm has comparable identification power to Multifactor Dimensionality Reduction (MDR) and is slightly better than Polymorphism Interaction Analysis (PIA), which are the two most popular methods for gene-gene interaction identification. More importantly, the identification results generated by using our genetic ensemble algorithm are highly complementary to those obtained by PIA and MDR. Experimental results from our simulation studies and real world data application also confirm the effectiveness of the proposed genetic ensemble algorithm, as well as the potential benefits of combining identification results from different algorithms.</p

Effects of residence and race on burden of travel for care: cross sectional analysis of the 2001 US National Household Travel Survey

BACKGROUND: Travel burden is a key element in conceptualizing geographic access to health care. Prior research has shown that both rural and minority populations bear disproportionate travel burdens. However, many studies are limited to specific types of patient or specific locales. The purpose of our study was to quantify geographic and race-based differences in distance traveled and time spent in travel for medical/dental care using representative national data. METHODS: Data were drawn from 2001 National Household Travel Survey (NHTS), a nationally representative, cross-sectional household survey conducted by the US Department of Transportation. Participants recorded all travel on a designated day; the overall response rate was 41%. Analyses were restricted to households reporting at least one trip for medical and/or dental care; 3,914 trips made by 2,432 households. Dependent variables in the analysis were road miles traveled, minutes spent traveling, and high travel burden, defined as more than 30 miles or 30 minutes per trip. Independent variables of interest were rural residence and race. Characteristics of the individual, the trip, and the community were controlled in multivariate analyses. RESULTS: The average trip for care in the US in 2001 entailed 10.2 road miles (16.4 kilometers) and 22.0 minutes of travel. Rural residents traveled further than urban residents in unadjusted analysis (17.5 versus 8.3 miles; 28.2 versus 13.4 km). Rural trips took 31.4% longer than urban trips (27.2 versus 20.7 minutes). Distance traveled did not vary by race. African Americans spent more time in travel than whites (29.1 versus 20.6 minutes); other minorities did not differ. In adjusted analyses, rural residence (odds ratio, OR, 2.67, 95% confidence interval, CI 1.39 5.1.5) was associated with a trip of 30 road miles or more; rural residence (OR, 1.80, CI 1.09 2.99) and African American race/ethnicity (OR 3.04. 95% CI 2.0 4.62) were associated with a trip lasting 30 minutes or longer. CONCLUSION: Rural residents and African Americans experience higher travel burdens than urban residents or whites when seeking medical/dental care

Multistable Decision Switches for Flexible Control of Epigenetic Differentiation

It is now recognized that molecular circuits with positive feedback can induce two different gene expression states (bistability) under the very same cellular conditions. Whether, and how, cells make use of the coexistence of a larger number of stable states (multistability) is however largely unknown. Here, we first examine how autoregulation, a common attribute of genetic master regulators, facilitates multistability in two-component circuits. A systematic exploration of these modules' parameter space reveals two classes of molecular switches, involving transitions in bistable (progression switches) or multistable (decision switches) regimes. We demonstrate the potential of decision switches for multifaceted stimulus processing, including strength, duration, and flexible discrimination. These tasks enhance response specificity, help to store short-term memories of recent signaling events, stabilize transient gene expression, and enable stochastic fate commitment. The relevance of these circuits is further supported by biological data, because we find them in numerous developmental scenarios. Indeed, many of the presented information-processing features of decision switches could ultimately demonstrate a more flexible control of epigenetic differentiation

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesOver the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15).We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls).We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23.This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.National Institutes of Mental Health (NIMH, USA) ACE Network Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA) The Autism Genome Project (AGP) from Autism Speaks (USA) Canadian Institutes of Health Research (CIHR), Genome Canada Health Research Board (Ireland) Hilibrand Foundation (USA) Medical Research Council (UK) National Institutes of Health (USA) Ontario Genomics Institute University of Toronto McLaughlin Centre Simons Foundation Johns Hopkins Autism Consortium of Boston NLM Family foundation National Institute of Health grants National Health Medical Research Council Scottish Rite Spunk Fund, Inc. Rebecca and Solomon Baker Fund APEX Foundation National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD) endowment fund of the Nancy Pritzker Laboratory (Stanford) Autism Society of America Janet M. Grace Pervasive Developmental Disorders Fund The Lundbeck Foundation universities and university hospitals of Aarhus and Copenhagen Stanley Foundation Centers for Disease Control and Prevention (CDC) Netherlands Scientific Organization Dutch Brain Foundation VU University Amsterdam Trinity Centre for High Performance Computing through Science Foundation Ireland Autism Genome Project (AGP) from Autism Speak