The autoimmune disease systemic lupus erythematosus tends to run in families, suggesting it has a strong genetic component. But it’s typically not a condition in which one bad gene causes disease to develop: Most commonly, many different genetic changes have to come together to give rise to lupus. This is one of the big reasons why lupus is so challenging to study.

Physician-scientist Timothy B. Niewold, MD, FACR, Vice Chair for Research in the HSS Department of Medicine, recently received a nearly $4.2 million grant from the National Institutes of Health to learn more about the complex genetics that contribute to lupus. The ultimate goal of this research is to figure out how changes in certain regions of the genome affect the disease, with the hope of eventually understanding immune-related diseases more broadly.

Recently, Dr. Niewold spoke about his plans for this research project, including why he thinks probing the “dark matter” of the genome will lead to a better understanding of what causes lupus.

 What have you already learned through your research?

 Unfortunately, there are no simple answers to questions about which genes cause lupus and the ways in which they cause the disease to arise. We need to take a very broad look across the genome.

 In recent years, the wider scientific community has developed more advanced and high-throughput ways to study people’s whole genomes. In the lupus research community, we’ve come together to use that genomic data to create large registries that can help to ask broad questions about the causes of the disease.

 Thanks to those registries, we are able to compare the genomes of large numbers of people with lupus to large numbers of healthy controls — people who don’t have lupus. Then we can look at which areas of the genome are different between these two groups.

 What we have been able to learn so far is that there are certain regions of the genome where changes are clearly associated with an increased risk of lupus. Notably, many of these changes are found in a region that is often called the “dark matter” of the genome.

 What is the dark matter of the genome?

 When we talk about “genes,” we mean sections of genetic material that contain instructions for making specific proteins. We have about 20,000 genes, which carry the code for all the proteins that are needed to build a whole human being.

 But only about 1% of our genetic material contains genes that get directly made into proteins. The other 99% of our genetic material — the dark matter — has other functions. We are still learning what these are.

 One of the functions of dark matter we have been studying in the context of lupus is the production of molecules called long noncoding RNAs (lncRNAs). These RNAs do not get translated into proteins, but they perform many other jobs that help regulate how genes get transcribed and how proteins get made. Some lncRNAs can affect the immune system.

 What is the focus of your current project?

 We decided to focus on a region of chromosome 12 where we know people with lupus have a lot of variations. There aren’t a lot of genes in this area. But despite that, we expect to find that the genetic variations in these regions are doing something important. It’s likely they are leading to changes that ultimately affect how the immune system is controlled and regulated, including carrying instructions for lncRNAs.

 Although this project is focused on lupus, the big picture is also exciting. Studying how changes in the dark matter affect the immune system could apply to many other autoimmune diseases as well.

 What kinds of studies do you have planned?

 All of this research will be done in human cells. We will be using a registry created by the Feinstein Institutes for Medical Research, a research center on Long Island, as well as a registry at HSS. These registries contain samples from people with lupus and from healthy control subjects.

 Much of the work of this project will focus on samples from the healthy controls. That’s because we need to look at the basic principles of how lncRNAs are supposed to regulate the immune system before we can understand how this process goes wrong in a disease like lupus.

 We will also do work in cell lines. We plan to use CRISPR gene editing tools to study what happens to healthy cells when we remove sections of the dark matter that make lncRNAs. This work will be done with our collaborators at the University of Pittsburgh.

 In particular, we’ll focus on how changes in the dark matter affect certain types of immune cells, especially those that are important for detecting and eliminating infections. We know that both B cells and monocytes in particular are strongly implicated in lupus.

This is a five-year grant. Where do you hope to be with this work in 2028?

I think we’ll have a much better understanding of how the genetic material contained within the dark matter can touch a number of different parts of the immune system.

I’m also excited that we’ll be able to begin to build a roadmap of how different regions of the genome come together in different ways to result in lupus. This will help to inform our understanding of disease and could suggest possible