Scientists who analysed the genes involved in 10 autoimmune diseases that begin in childhood have discovered 22 genome-wide signals shared by two or more diseases. These shared gene sites may reveal potential new targets for treating many of these diseases, in some cases with existing drugs already available for non-autoimmune disorders.

Autoimmune diseases, such as type 1 diabetes, Crohn’s disease and juvenile idiopathic arthritis, collectively affect 7 to 10 percent of the population in the Western Hemisphere.

Dr. Hakonarson“Our approach did more than finding genetic associations among a group of diseases,” said study leader, Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia (CHOP). “We identified genes with a biological relevance to these diseases, acting along gene networks and pathways that may offer very useful targets for therapy.”

The international study team performed a meta-analysis, including a case-control study of 6,035 subjects with automimmune disease and 10,700 controls, all of European ancestry. The study’s lead analyst, Yun (Rose) Li, an MD/PhD graduate student at the University of Pennsylvania and the Center for Applied Genomics, mentored by Hakonarson and his research team, applied highly innovative and integrative approaches in supporting the study of pathogenic roles of the genes uncovered across multiple diseases.

The research encompassed 10 clinically distinct autoimmune diseases with onset during childhood: type 1 diabetes, celiac disease, juvenile idiopathic arthritis, common variable immunodeficiency disease, systemic lupus erythematosus, Crohn’s disease, ulcerative colitis, psoriasis, autoimmune thyroiditis and ankylosing spondylitis.

Because many of these diseases run in families and because individual patients often have more than one autoimmune condition, clinicians have long suspected these conditions have shared genetic predispositions. Previous genome-wide association studies have identified hundreds of susceptibility genes among autoimmune diseases, largely affecting adults.

The current research was a systematic analysis of multiple paediatric-onset diseases simultaneously. The study team found 27 genome-wide loci, including five novel loci, among the diseases examined. Of those 27 signals, 22 were shared by at least two of the autoimmune diseases, and 19 of them were shared by at least three of them.

Many gene signals found on biological pathways linked to cell activation, proliferation and signalling

Many of the gene signals the investigators discovered were on biological pathways functionally linked to cell activation, cell proliferation and signalling systems important in immune processes. One of the five novel signals, near the CD40LG gene, was especially compelling, said Hakonarson, who added, “That gene encodes the ligand for the CD40 receptor, which is associated with Crohn’s disease, ulcerative colitis and celiac disease. This ligand may represent another promising drug target in treating these diseases.”

Gene signals have biological relevance to autoimmune disease processes, opportunities to better target gene networks and pathways

Many of the 27 gene signals the investigators uncovered have a biological relevance to autoimmune disease processes, Hakonarson said. “Rather than looking at overall gene expression in all cells, we focused on how these genes upregulated gene expression in specific cell types and tissues, and found patterns that were directly relevant to specific diseases. For instance, among several of the diseases, we saw genes with stronger expression in B cells. Looking at diseases such as lupus or juvenile idiopathic arthritis, which feature dysfunctions in B cells, we can start to design therapies to dial down over-expression in those cells.”

He added that “the level of granularity the study team uncovered offers opportunities for researchers to better target gene networks and pathways in specific autoimmune diseases, and perhaps to fine tune and expedite drug development by repurposing existing drugs, based on our findings.” The Children’s Hospital of Philadelphia

Research has led to a greater understanding of how certain genetic variants can ‘switch’ on or off the regulatory elements which control the expression of genes and ultimately the manifestation of an individual’s characteristics and disease predispositions.

These variants are found in regions of the genome which are not directly responsible for coding genes, but which instead have a regulatory function. Not much is yet known about these regions, however, research into how the variants work could eventually lead to new clues about how human diseases might be understood at a genetic level and, ultimately, controlled.

“We know many genetic variants are associated with different diseases, but since most of them lie in the non-coding part of the genome, we often don’t know what the precise mechanisms underlying these associations are,” explains Judith Zaugg, who led the study at EMBL. “Our results, and the computational approaches we have developed mean it will now be possible to take these variants and link them back to the regulatory network within the DNA to identify the specific gene that is associated with them. This might enable us to unravel the causal mechanisms behind certain inherited diseases.”

‘Switches’ controlling gene expression might be far apart on DNA strand, but close in 3D space.

Key to the process are regions in the non-coding part of the DNA that harbour specific sequences, called enhancers and promoters. These are responsible for activating the expression of a particular gene. Promoters are located close to the gene they regulate. Enhancers, in contrast, can be far away from their target gene in terms of genomic location and might require physical interaction with the promoter of a gene to propagate the activity signal. One of the big challenges in understanding how genes are controlled is to link these enhancers to their target genes.

In this study, the team has generated molecular profiles from 75 human individuals that were sequenced as part of the 1000 Genomes Project – an international collaboration to produce an extensive catalogue of human genetic variation.

They used epigenetic marks to identify enhancers and promoters within the subjects’ genome and, using a second technology (Hi-C) were able to map how enhancers and promoters were interacting in three-dimensional space. As well as charting the specific interactions between promoters and enhancers using genotype information, the team were able to find genetic associations between physically interacting regions of the genome, thus providing evidence for functional interactions between enhancers and promoters.

Map of genetic ‘switches’ will pave the way for understanding the molecular basis of complex genetic diseases.

An unexpected finding was that often it was not only genetic variants in enhancers that were associated with gene expression, but also regulatory elements in promoters of a distal genes that were physically and genetically connected to the gene of interest.

Genes are known to physically interact with multiple enhancers. In addition, the team also discovered that some promoters are genetically controlled by two or more enhancers, meaning that the enhancers either work in combination to affect gene expression or compensate each other. For example, if one individual lacks a particular enhancer there might be a backup enhancer that could compensate for the loss. Such a compensation mechanism could explain why it is so difficult to identify the causal variants of complex genetic diseases.

“The approach we used enables us to map links between genes and their regulatory elements,” says Fabian Grubert, who led the work at Stanford University, in Michael Snyder’s lab. “Further studies in different tissues will add even more detail to the map, and hopefully will allow us to identify all the enhancers and promoters that influence a single gene under different conditions.” EMBL

Two proteins that share the ability to help cells deal with their trash appear to need each other to do their jobs and when they don’t connect, it appears to contribute to development of Parkinson’s disease, scientists report.

Much like a community’s network for garbage handling, cells also have garbage sites called lysosomes, where proteins, which are functioning badly because of age or other reasons, go for degradation and potential recycling, said Dr. Wen-Cheng Xiong, developmental neurobiologist and Weiss Research Professor at the Medical College of Georgia at Georgia Regents University.

Inside lysosomes, other proteins, called proteases, help cut up proteins that can no longer do their job and enable salvaging of things like precious amino acids. It’s a normal cell degradation process called autophagy that actually helps cells survive and is particularly important in cells such as neurons, which regenerate extremely slowly, said Xiong, corresponding author of the study.

Key to the process – and as scientists have shown, to each other – are two more proteins, VPS35 and Lamp2a. VPS35 is essential for retrieving membrane proteins vital to cell function. Levels naturally decrease with age, and mutations in the VPS35 gene have been found in patients with a rare form of Parkinson’s. VPS35 also is a critical part of a protein complex called a retromer, which has a major role in recycling inside cells. Lamp2a enables unfit proteins to be chewed up and degraded inside lysosomes.

If the two sound like a natural couple, scientists now have more evidence that they are. They have shown that without VPS35 to retrieve Lamp2a from the trash site for reuse, Lamp2a, or lysosomal-associated membrane protein 2, will be degraded and its vital function lost.

When the scientists generated VPS35-deficient mice, the mice exhibited Parkinson’s-like deficits, including impaired motor control. When they looked further, they found the lysosomes inside dopamine neurons, which are targets in Parkinson’s, didn’t function properly in the mice. In fact, without VPS35, the degradation of Lamp2a itself is accelerated. Consequently, yet another protein, alpha-synuclein, which is normally destroyed by Lamp2a, is increased. Alpha-synuclein is a major component of abnormal protein clumps, called Lewy bodies, found in the brains of patients with Parkinson’s.

“If alpha-synuclein is not degraded, it just accumulates. If VPS35 function is normal, we won’t see its accumulation,” Xiong said.

Conversely, when scientists increased expression of Lamp2a in the dopamine neurons of the VPS35-deficient mice, alpha-synuclein levels were reduced, a finding that further supports the linkage of the three proteins in the essential ability of the neurons to deal with undesirables in their lysosomes.

Without lamp2a, dopamine neurons essentially start producing more garbage rather than eliminating it. Recycling of valuables such as amino acids basically stops, and alpha-synuclein is free to roam to other places in the cell or other brain regions where it can damage still viable proteins.

The bottom line is dopamine neurons are lost instead of preserved. Brain scans document the empty spaces where neurons used to be in patients with neurodegenerative diseases such as Parkinson’s and Alzheimer’s. One of the many problems with treatment of these diseases is that by the time the empty spaces and sometimes the associated symptoms are apparent, much damage has occurred, Xiong said.

Putting these pieces together provides several new, early targets for disease intervention. “Everything is linked,” Xiong said. Medical College of Georgia at Georgia Regents University

Researchers at IRB Barcelona unravel a role for tumour suppressor genes in restricting the growth of neighbouring cell populations.

The study might have implications for understanding the early events of tumorigenesis and the selection of the tumour-initiating cells.
The healthy development of an organism depends on its tissues and organs growing to the right size, stopping when they need to, and maintaining stability in their form and function. Correct development depends on the availability of nutrients to the cells in their environment, a process that is tightly controlled by signalling mechanisms that occur within and between the cells that form these structures. Disruptions in this signalling can lead to unbalanced growth within a tissue or organ, and can give rise to conditions such as cancer.

The TOR and PI3K signalling pathways regulate tissue growth according to nutrient availability, and are frequently over-activated in human cancer. In the study published, Institute for Research in Biomedicine (IRB Barcelona) PhD student Ana Ferreira and Group Leader and ICREA Research Professor Marco Milán report that the over-activation of these two pathways not only causes the excess growth of cells and tissues, but also restrict the growth of neighbouring cell populations.

They present evidence that the proteoglycan Dally, a protein that is known to modulate the spreading, stability and activity of the growth-promoting signalling molecule called Dpp (in flies) or TGF-β (in humans), is regulated by these two pathways and mediates the effects on neighbouring populations. “They do so by competing for Dpp”, says Ana Ferreira, first author of the paper and funded by a PhD fellowship from Portugal’s Fundação para a Ciência e a Tecnologia.

‘PTEN, a gene that negatively regulates the PI3K pathway, is one of the most commonly lost tumour suppressors in human cancer. Understanding whether this pathway also affects TGF-β spreading in mammals may help us to gain insight into the early events of tumorigenesis and the selection of the tumour-initiating cells,’ she confirms.

‘Tumour initiating cells might be selected by their ability to compete for limiting growth factors and their capacity to restrict the growth of neighbouring cell populations,’ says Marco Milán, head of the Development and Growth Control Laboratory at IRB Barcelona. ‘Seventy percent of men with prostate cancer are estimated to have lost a copy of the PTEN gene at the time of diagnosis. It will be interesting to determine whether this mechanism, identified in fruit flies, is also active in humans.’ IRB Barcelona

ESC Guidelines published recommend DNA analysis as a fundamental component of post mortem assessment in young sudden death victims. Identification of a genetic cause helps to quickly diagnose and protect relatives. The Guidelines focus on preventing sudden cardiac death in patients with ventricular arrhythmias.

“For the first time these guidelines have incorporated the concept proposed by several consensus documents that DNA analysis should be a fundamental component of post mortem assessment in young sudden death victims,” said Professor Silvia Priori, Chairperson of the guidelines Task Force. “The molecular analysis helps to identify the presence of genetic diseases that can occur in a structurally normal heart and therefore cannot be identified during autopsy. Identification of a genetic cause as a substrate for a sudden death facilitates the early diagnosis of affected relatives and may help protect them through a personalised approach that spans from lifestyle modifications to the early use of therapies.” European Society of Cardiologists