Study reveals genetic balancing act between autoimmunity and cancer risk

An autoimmune disorder that affects the thyroid gland, called autoimmune hypothyroidism (AIHT), is the most common autoimmune disease, yet it remains largely understudied. 

New research from scientists at Broad Institute, University of Helsinki, and other institutions has found more than 400 genetic markers linked to the disorder, far more than previous studies. Nearly 50 of these pinpoint protein-coding changes in genes involved in immunity and thyroid function.

The team discovered that many of the genetic variants that appear to heighten the risk of hypothyroidism may also lower the risk of skin cancer. By performing a genome-wide association analysis of over 81,000 people with AIHT, the scientists were also able to distinguish genetic factors related to thyroid disease from those linked to other autoimmune disorders for the first time. The data they analyzed are from FinnGen, the largest medical research project in Finland that utilizes biobank data, and from the UK Biobank. The study is published in Nature Genetics. 

“This paper charts a clear path to understanding how genetics can not only find the genetic variants linked to a disease, but also dissect them into clearly distinct groups that represent independent components of the disease,” said study coauthor Mark Daly, a Broad institute member, co-director of Broad’s Program in Medical and Population Genetics, and the founding chief of the Analytic and Translational Genetics Unit at Massachusetts General Hospital.  

Like all autoimmune diseases, AIHT is caused by the immune system mistakenly attacking healthy tissue in the body — in this case, the thyroid gland, and as a result it lowers the production of thyroid hormones, which help regulate metabolism. But why does an autoimmune disease attack only certain cells and tissues, and what are the underlying mechanisms? These questions prompted the team to look deeper into the genetic basis of AIHT.

"Hypothyroidism affects millions of people, predominantly women, and yet the biology underlying it has remained largely unexplored," said study lead author Mary Pat Reeve, a data scientist at Broad and doctoral researcher at the Institute for Molecular Medicine Finland (FIMM) of the University of Helsinki. "Conditions like this one are scientifically rich precisely because they sit at the intersection of immunity, organ function, and metabolism. By bringing together over 81,000 cases, we had the statistical power to separate the genetics of autoimmunity from thyroid function — and that separation revealed a connection to cancer risk that opens a window onto fundamental mechanisms of immune regulation that matter far beyond thyroid disease."

Cancer - autoimmunity connection 

Reeve and her colleagues found that many of the AIHT genetic factors have distinct biological roles. For example, 38 percent of them are involved in general autoimmunity, while 20 percent are thyroid-organ specific. 

Additionally, 10 percent of the genetic signals show a protective effect against skin cancer. Some of those genes encode checkpoint proteins, which act as brakes on the immune system to prevent it from attacking healthy tissue. This finding suggests a genetic link between increased autoimmunity risk and decreased cancer risk: gene variants associated with reduced checkpoint activity can lead to a stronger immune attack against both cancer cells and healthy tissue alike. 

Checkpoint proteins are targeted by a class of cancer immunotherapy drugs called checkpoint inhibitors, which release the brakes on the immune system so that it can better attack cancer cells. Some cancer patients who respond well to these medicines experience hypothyroidism as a side effect, and Daly says the study offers a possible genetic explanation for why.

“Our work is consistent with the clinical experience of patients who develop autoimmunity as a side effect of checkpoint inhibitors, and it’s often those same patients who have better cancer outcomes,” Daly said.

Reeve added that the study supports the idea that cancer and autoimmunity risk differ from person to person because of genetic differences. As a next step, the team is working to uncover how these genetic variants contribute to distinct components of a disease, to then eventually find ways to intervene. 

“This project is an example of the value of the deep, longitudinal clinical phenotypes available in FinnGen, enabling the discovery of connections and shared biology across a wide range of diseases while using genetic profiles as causal anchors. A long-term partnership between FIMM and the Broad Institute has made these genetic discoveries possible,” said senior author Samuli Ripatti, director of FIMM, professor of biometry at the University of Helsinki, and affiliated faculty at Broad and Massachusetts General Hospital. 

Author Ramnik Xavier, a Broad core institute member, the Kurt J. Isselbacher Professor of Medicine at Harvard Medical School, and director of the Center for Computational and Integrative Biology and core member in the Department of Molecular Biology at Massachusetts General Hospital, added that Broad Institute and FinnGen investigators have initiated studies to determine how these variants contribute to disease using human organoid models. “Population genetics is a uniquely powerful approach to discover fundamental mechanisms of immune regulation that govern organ specific and systemic autoimmunity,” Xavier said.