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Genomics discoveries reveal clues to preventing, treating endocrine diseases
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NEW ORLEANS — The science of genomics is a driver for nearly everything researchers are learning about health and disease, and the pace of new discoveries is rapidly changing what is known about metabolic conditions like type 2 diabetes, according to a speaker at The Endocrine Society Annual Meeting.
“This is a time of rapid progress in endocrinology research,” NIH director Francis S. Collins, MD, PhD, told Endocrine Today before his presidential plenary presentation. “Built upon new technologies like high throughput DNA sequencing and epigenomic analyses, the molecular causes of both rare and common diseases are being elucidated, and are suggesting new means of prevention and treatment. Type 2 diabetes is a major example of this.”
Genomic discoveries, Collins said, are proceeding at a pace that has far exceeded expectations. The cost of sequencing a whole human genome — an effort Collins famously spearheaded with the Human Genome Project — has fallen dramatically in the span of two decades, from approximately $100 million in 2001 to roughly $850 today, he said.
“That is a pace that outstrips Moore’s law in terms of the rate of dropping of costs,” Collins said. “All of this is also done today with higher quality and greater speed. It is phenomenal to consider that kind of pace, and that has made it possible to do a lot.”
NIH genome projects
Today, researchers are using DNA sequencing for several key NIH projects with the aim of cataloging genomic data, accessible to the public, to learn about the function of the 98% of the genome that does not code for protein, Collins said.
“You have to have a way of decorating that genome sequence with a lot of functional information,” Collins said. “The NIH has invested heavily in projects following the original sequencing effort to try and provide that functional information.”
The ENCODE Project, launched in 2003, is a community resource project designed to better understand the functional elements of the human genome beyond coding and exons, and develop a comprehensive catalog of those functional elements. The related NIH Epigenomics Project is designed to understand how genes are turned on or off and how that contributes to health or disease.
The most recent addition, the Genotype Tissue Expression Program, or GTEx, is an effort to organize a national whole genome sequencing project looking at multiple tissues derived from rapid autopsies of adult donors.
“All of that has done a lot to provide information about the regulatory components of the human genome,” Collins said. “What this does tell us is we continue to need more data, and it’s a lot of data. We have arrived at the point with genomics where we really are in the big data space. We do have big data problems now. The amount of information being generated by NIH-funded research every day is absolutely breathtaking.”
Applications for diabetes
Using genomic data, Collins and colleagues are working to better understand how genetic variants can predispose individuals to metabolic diseases like type 2 diabetes. The goal of the Finland-United States Investigation of NIDDM Genetics (FUSION) study, led by Collins and other researchers, is to identify and map those genetic variants, he said.
“What we really want to understand in my research lab is how the genetic and the environmental factors work together and what we could do to have a better chance of intervening and preventing the consequences of this incredibly common disorder,” Collins said.
Through genotyping, researchers have now identified more than 100 highly statistically significant variants in the genome that are associated with an elevated risk for type 2 diabetes, Collins said.
“An awful lot of the field of common disease genetics is now focused on this effort of trying to understand how these risk variants — that are not in the coding region — actually have the functional effect they do,” Collins said.
Next steps
Many non-coding risk variants lie in long stretches of open chromatin, designated as so-called “stretch enhancers,” that are typically tissue-specific, Collins said. The risk variants influence the level of expression of nearby genes, but often not the nearest ones, and their effect appears to be mediated by reduction or enhancement of the binding of specific transcription factors, Collins said.
These epigenomic findings, he said, open up a new world of potential therapeutic targets to treat type 2 diabetes.
To learn more, the NIH Foundation launched the Accelerating Medicines Partnership Type 2 Diabetes Project (AMP T2D) in 2014, a multi-sector, pre-competitive partnership among government, industry and nonprofit organizations. This program includes a type 2 diabetes “knowledge portal,” a database of genotypic, phenotypic and epigenomic information linked to clinical data from large cohorts of patients with diabetes.
“This is a way to try and prioritize what is the next generation of potential drug targets,” Collins said. “All of the data [are] here to allow you to sort that out.”
‘All of Us’ project
Beyond diabetes, scientists want to use genomic data to prevent or treat scores of other diseases, including common, chronic illnesses that researchers still do not know enough about. The NIH All of Us research program is a longitudinal effort, launched last May, to gather data from 1 million or more people living in the U.S. The program considers individual differences in lifestyle, socioeconomic background, environment and biology to accelerate health research and medical breakthroughs.
“In many instances, we are still in a one-size-fits-all world, and we would like to change that,” Collins said. “To do that, you need a lot of data.”
As of March 22, more than 200,000 participants are enrolled in All of Us, Collins said — already making it the largest NIH study in history.
The project, originally proposed by Collins in 2004, would have been “expensive beyond words” at that time, he said, and would not have had the opportunities available to researchers now with access to electronic health records and smartphones.
Today, he said, that has all changed.
“We’ve never tried to do anything of this scale,” Collins said. “It is bold, it is ambitious, the Congress loves it, it is well-funded and it is going to happen. Think about it as a research opportunity.”
Looking ahead, “a lot of the future is still pretty unclear,” he said. “We are trying to enable it, and I hope a group like this will make that dream come true that gives more of an opportunity for people to enjoy full and healthy lives.” – by Regina Schaffer
Reference:
Collins F. Presidential Plenary 01. Presented at: The Endocrine Society Annual Meeting; March 23-26, 2019; New Orleans.
For more information:
All of Us Project. Available at www.allofus.org. Accessed on: March 23, 2019.
Disclosure: Collins is director of the NIH.