A new study published in Nature Genetics suggests that looking beyond the nearest gene may be essential for understanding how immune disease risk variants act in rare immune cells.

The paper, “High-resolution promoter interaction analysis implicates genes involved in activation of type 3 innate lymphoid cells in immune disease risk,” was co-led by researchers at Cincinnati Children’s Hospital, the MRC Laboratory of Medical Sciences, Imperial College London, along with collaborators. The team mapped long-distance DNA interactions in type 3 innate lymphoid cells, or ILC3s, a rare population of tissue-resident immune cells enriched in the gut, airways, and mucosal lymphoid tissues.

ILC3s help regulate inflammation and maintain barrier integrity, but their rarity has made them difficult to study with conventional genome-organization methods. Many approaches for mapping chromosomal contacts require millions of cells, limiting their use in cell types that may be particularly relevant to disease.

“This work opens the door to studying long-distance DNA interactions in rare immune cells,” says Stephen Waggoner, PhD, scientist in the Center of Autoimmune Genomics and Etiology at Cincinnati Children’s. “Until now, most methods required millions of cells, which limited what we could learn from the cell types most relevant to disease.”

To address that limitation, the investigators used a low-input, high-resolution Promoter Capture Hi-C (PCHi-C) approach to map promoter-anchored chromosomal contacts in primary human ILC3s, alongside CD4+ T cells. They then combined those maps with genome-wide association study data using a Bayesian framework, multiCOGS, to connect Crohn’s disease risk variants with the genes they are most likely to regulate.

The analysis linked Crohn’s disease risk variants to more than 100 candidate genes in ILC3s, including both known inflammatory bowel disease genes and less expected candidates. Among the latter was CLN3, a gene best known for its role in Batten disease, a rare neurodegenerative disorder.

“While some disease risk variants act on the genes nearest to them, others do not, so if we only look at the nearest gene, we may get the underlying mechanisms wrong,” says Mikhail Spivakov, PhD, head of the Functional Gene Control Research Group at MRC Laboratory of Medical Sciences. “What is more, the patterns of genome folding differ across cell types, so it is important to study the 3D connections between variants and the genes they control in the cells that are relevant for the disease.”

Follow-up experiments in a mouse ILC3-like cell line supported a possible role for CLN3 in regulating inflammatory activity. According to the paper, CLN3 was downregulated after cytokine stimulation, while increasing CLN3 expression altered stimulation-induced transcriptional programs and cytokine secretion. The findings do not establish CLN3 as a causal gene in Crohn’s disease, but they point to a potential immune-related function for a gene more commonly discussed in the context of neurodevelopmental disease.

The researchers also extended the approach to five additional autoimmune conditions, generating a catalog of ILC3-linked risk genes. These genes were enriched for regulators of the ILC3 inflammatory response identified in a CRISPR interference screen.

The next steps appear to include clarifying how CLN3 influences immune-cell function, testing whether the pathways identified in ILC3s can help explain disease mechanisms, and applying the low-input mapping strategy to other rare cell types that have been difficult to study. “Studying genetic regulation in rare cell types allows us to move closer to mechanism, not just association, and that’s essential for making genetic findings meaningful across medicine,” says Waggoner.

The post Genome Mapping Reveals Autoimmune Disease Risk Genes in Innate Lymphoid Cells appeared first on GEN – Genetic Engineering and Biotechnology News.

In the last three decades, as involuntary outpatient treatment for people with serious mental health conditions like schizophrenia have expanded to almost every state, the evidence for these programs’ efficacy has remained murky. 

A new evaluation of New York’s involuntary outpatient treatment program adds another wrinkle to the complex existing scientific literature on this type of care. Assisted outpatient treatment (AOT) reduced hospitalizations, arrests, and more. So did voluntary treatment. The independent authors concluded that the state should funnel more money toward voluntary services, especially after hearing about the coercion and harms that people experienced under AOT orders.

“When people are engaged in services, they have better outcomes,” said Bevin Croft, director of Human Services Research Institute’s Behavioral Health team and one of the study’s authors. “Whether or not that engagement is voluntary doesn’t seem to make a huge difference.”

Continue to STAT+ to read the full story…

​Read More

The California Supreme Court sided with Gilead Sciences in a closely watched case brought by thousands of patients who argued the company was negligent for slow-walking development of an HIV medicine that was safer than another drug it was already selling.

In a 6-1 decision, the court overturned a state appeals court ruling two years ago that Gilead could be held liable, raising alarm in the pharmaceutical industry that drug development decisions could be influenced by the fear of legal liability.

The case began after more than 24,000 people claimed in federal and state court lawsuits that they unnecessarily suffered kidney injury and bone loss from the older drug. They maintained that Gilead cynically managed its product pipeline at the expense of people who should have been treated with a safer medicine.

Continue to STAT+ to read the full story…