Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.UK funding includes Cancer Research UK and NIH.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-016-0718-

Simulação de uma linha de montagem de motores An engine assembly line simulation

A Simulação tem-se mostrado bastante eficaz na solução de problemas complexos, tais como aqueles envolvidos no projeto de sistemas de produção orientados a produtos - linhas de montagem e fabricação. Neste trabalho, apresenta-se um exemplo de aplicação nesse contexto, no qual a Simulação foi empregada na avaliação do projeto de uma nova linha de montagem de motores na Ford do Brasil.<br>Simulation has been proven to be very useful on the solution of complex problems, like those ones relating product-oriented manufacturing systems (assembly and manufacturing lines). This paper presents an application concerning design evaluation of a new engine assembly line at Ford of Brazil

The asymptotic variance rate of the output process of finite capacity birth-death queues

We analyze the output process of finite capacity birth-death Markovian queues. We develop a formula for the asymptotic variance rate of the form &#0955; *+&#0963;vi where &#0955; * is the rate of outputs and v i are functions of the birth and death rates. We show that if the birth rates are non-increasing and the death rates are non-decreasing (as is common in many queueing systems) then the values of v i are strictly negative and thus the limiting index of dispersion of counts of the output process is less than unity. In the M/M/1/K case, our formula evaluates to a closed form expression that shows the following phenomenon: When the system is balanced, i.e. the arrival and service rates are equal, &#0963;vi\&#0955;* is minimal. The situation is similar for the M/M/c/K queue, the Erlang loss system and some PH/PH/1/K queues: In all these systems there is a pronounced decrease in the asymptotic variance rate when the system parameters are balanced

A comparative study of enterprise system implementations in large North American corporations

This study proposes measurement systems for assessing the success of implementation, challenges of implementation and success of utilization of enterprise systems. The proposed measurement systems are used empirically to assess the level of success and challenges of Canadian and American large corporations in the implementation of enterprise systems. Based on the findings of the study, a comparative analysis of the Canadian and American corporation is presented. The findings show that US firms are more successful in following their ES implementation master plan, in implementation of ES, and face fewer challenges. However, they are relatively less successful in utilizing the ES in comparison to Canadian firms