Non-coding DNA implicated in type 2 diabetes

Variations in non-coding sections of the genome might be important contributors to type 2 diabetes risk, according to a new study.

DNA sequences that don’t encode proteins were once dismissed as “junk DNA”, but scientists are increasingly discovering that some regions are important for controlling which genes are switched on.

The new study, published in Nature Genetics, is one of the first to show how such regions, called regulatory elements, can influence people’s risk of disease.

Type 2 diabetes affects over 300 million people worldwide. Genetic factors have long been known to have an important role in determining a person’s risk of type 2 diabetes, alongside other factors such as body weight, diet and age.

Many studies have identified regions of the genome where variations are linked to diabetes risk, but the function of many of these regions is unknown, making it difficult for scientists to glean insights into how and why the disease develops. Only around two per cent of the genome is made up of genes: the sequences that contain code for making proteins.

Most of the remainder is shrouded in mystery. “Non-coding DNA, or junk DNA as it is sometimes known, is the dark matter of the genome. We’re only just beginning to unravel what it does,” said leading author Professor Jorge Ferrer, a Wellcome Trust Senior Investigator from the Department of Medicine at Imperial College London.

In the new study scientists mapped the regulatory elements that orchestrate gene activity in the cells of the pancreas that produce insulin, a hormone that regulates blood sugar.

In type 2 diabetes, the tissues become less responsive to insulin, resulting in blood sugar levels being too high. Most people can compensate when this happens by producing more insulin, but in people with type 2 diabetes, the pancreas cannot cope with this increased demand.

“The cells that produce insulin appear to be programmed to behave differently in people with type 2 diabetes,” said coauthor Mark McCarthy, a Wellcome Trust Senior Investigator at the University of Oxford. “This study provides some important clues to the mechanisms which are disturbed in the earliest stages of the development of type 2 diabetes, and may point the way to novel ways of treating and preventing the disease.”

The team identified genome sequences that drive gene activity in insulin-producing cells specifically. They found that these sequences are located in clusters, and that genetic variants known to be linked to diabetes risk are also found in these clusters.

“Many people have small DNA variants in such regulatory elements, and these variants affect gene expression in the cells that produce insulin. This knowledge will allow us to understand the detailed mechanisms whereby specific DNA variants predispose to diabetes,” said Professor Ferrer.

doi: 10.1038/ng.2870

Biomarker Alliance set up to create standards needed for personalized medicine

A new independent, non-profit organization, the National Biomarker Development Alliance (NBDA), has been set up in the United States. The mission of the NBDA is to address the complex and urgent challenge of creating the standards needed to support end-to-end evidencebased biomarker development in order to significantly advance precision (personalized) health care.

Effective high quality biomarkers are critical to ultimately realizing the promise of precision (personalized) medicine. The NBDA, will be disease “agnostic” and is the first independent trans-sector organization that brings together key stakeholders from academia, the private sector, payers and patients/advocates to ultimately change the current dismal success rate of biomarker discovery, development and validation.

“Creating the standards and systems for successful biomarker development is complex but achievable through a new generation of networks of stakeholders that integrate knowledge to solve critical problems of this scale,” stated Dr Anna Barker, President, Director and Co-Founder of the NBDA, Co-Director of Complex Adaptive Systems and Professor at Arizona State University, and former Deputy Director of the National Cancer Institute.

“The NBDA was developed not just to relegate the flawed and fragmented approaches to biomarker development processes to history but also to serve as a working example of what purposeful convergence of scientific knowledge and multi-sector collaboration can accomplish,” said Dr Barker.

The NBDA will achieve its goals through a management construct and systems-based approach that integrates and leverages biomarker knowledge networks from all of these stakeholder communities. “We were pleased to enable the development of the NBDA,” said Dr Rick Shangraw, Chief Executive Officer of the Arizona State University Foundation (ASUF).
“Increasingly transformative ideas will be accomplished through new organizational constructs such as NBDA that facilitate the convergence of knowledge to address major societal problems.”

Biomarkers are signals, or indicators (markers) of normal or disease-related processes or measures of pharmacologic response to therapy. They are the key to realizing a future in which patients are treated based on identifying molecular changes in their disease. These molecular profiles will empower physicians to select targeted therapies using molecular diagnostics versus today’s one ‘size fits all’.

Currently, too many drugs and biomarkers fail in late stages of regulatory review, as most explicitly evidenced by the disturbing historical lack of success of many phase III clinical trials for cancer. Powered by advanced genomic and other technologies, biomarker discovery has become a major focus for investigators working in nearly all areas of biomedical research. “Reflecting on the 150,000 papers that documented thousands of biomarker discoveries,” Dr George Poste, interim Chief Science Officer of the NBDA, Co-Director of Complex Adaptive Systems and Regents Professor at ASU and Former President of Research & Development for SmithKline Beecham (now GlaxoSmithKline), stated that “a discovery” does not mean that the technical process was robust, that the findings could be independently reproduced, or that they measure a meaningful change in biology that addresses clinically meaningful questions.

Unfortunately, in the face of this tsunami of biomarker discovery, the approval of protein biomarkers has changed little since the 1990s, with less than 1.5 approved per year by the US Food and Drug Administration (FDA). Moreover, less than 100 biomarkers are used routinely in the clinic today. Failure to develop and implement standards based end-to-end systems approaches for biomarker development has also essentially stalled the advancement of the diagnostics industry, especially smaller biotechnology companies focused on molecular diagnostics. The explosion of genomics- based assays and other non-regulated laboratory developed tests (LDTs) discourages companies from pursuing more rigorous, uncertain and expensive FDA biomarker/diagnostic approval pathways. The undervaluation of biomarkers and reimbursement ambiguities further discourages investment in the field.

“The NBDA is a potentially transformative approach to not just identifying and advancing successful biomarkers, but it will also serve to energize and support the development of the diagnostics industry,” said Mara Aspinall, CEO, Ventana Medical Systems and Co-Founder, DxInsights.

The NBDA is well underway in setting up demonstration projects to develop standards and/or create ideal pathways for four “classes” of biomarkers: genomics, proteomics, imaging and complex biomarkers (e.g., biosignatures). In addition, the NBDA is assembling a database of all guidelines, standard operation procedures and standards developed to date on the collection, stewardship and management of biospecimens. Once assembled, NBDA will organize a consensus conference to define “standards” for thefield that can be agreed to by the stakeholder communities. Dr Carolyn Compton, NBDA’s Chief Medical Officer, Professor at ASU, and former President and CEO of the Critical Path Institute will lead this effort. “I know from long experience, that this is not an easy task, but I believe that we already have a great deal of the information needed to get this done and identification of critical knowledge gaps will guide needed research,” said Dr Compton.

“Creating and broadly implementing the standards (guidelines, standard-operating procedures, best practices, etc.) needed to successfully discover and develop the effective biomarkers we need is not the job of the FDA, but it is the job of the affected stakeholders. A successful NBDA promises to reduce health care costs by accelerating drug development, empowering the diagnostics industry and improving patient engagement and outcomes,” said Dr Barker. “Continuing to tolerate the failure of biomarkers means that the promise of precision medicine will never materialize for patients and that would be tragic and costly.”



 

                                   
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