Like they say, pain is private. Unlike blood pressure or temperature or other symptoms easily measured and defined, the physical reaction to unpleasant stimuli is hard to quantify or predict. It varies from person to person, with each individual describing pain — and its intensity — differently. The same goes for differences in response to infection, it lies in something a bit more scientific- genetics.
We have all, at a point wondered- why me? (not in the old-fashioned, melodramatic, whiny, god-cursing way though) why is it that your friend, co-worker, or partner doesn’t get as sick as you, even though they caught the same “bug” you did?
Genes determine much of how we perceive pain because all of the bits and pieces of the nervous system are built from instructions in the genetic code, which varies slightly from person to person. Now, a team of researchers from the University of Bonn, Germany, and the New York Genome Center have mapped several genetic variants that affect how much gene expression changes in response to an immune stimulus.
“Our defense mechanisms against microbial pathogens rely on white blood cells that are specialized to detect infection,” explained co-senior study investigator Veit Hornung, Ph.D., chair of immunobiochemistry at the Ludwig-Maxmilians-Universität in Munich. “Upon encounter of microbes, these cells trigger cellular defense programs via activating and repressing the expression of hundreds of genes.”
“We wanted to understand how genetic differences between individuals affect this cellular response to infection,” added co-senior study investigator Johannes Schumacher, Ph.D., a research scientist at the Institute of Human Genetics within the University of Bonn.
Researchers discovered hundreds of genes where the response to immune stimulus depended on the genetic variants carried by the individual. “These genes include many of the well-known genes of the human immune system, demonstrating that genetic variation has an important role in how the human immune system works,” noted Dr. Sarah Kim-Hellmuth, the lead author of the study, from the New York Genome Center, Columbia University, the Max Planck Institute in Munich and formerly from the University of Bonn.
“While earlier studies have mapped some of these effects, this study is particularly comprehensive, with three stimuli and two time points analyzed.”
The study was able to identify a trend of genetic risk for autoimmune diseases and capture the genetic variants whose effects on gene regulation were different depending on the different infectious state of the cells. To do this, they integrated gene expression profiles with genome-wide genetic data of 134 volunteers and treated monocytes.
Co-senior author Tuuli Lappalainen, Ph.D., assistant professor at Columbia University and core member of the New York Genome Center added that this data “supports a paradigm where genetic disease risk is sometimes driven not by genetic variants causing constant cellular dysregulation, but by causing a failure to respond properly to environmental conditions such as infection.”
Using the collected monocyte samples, the researchers treated the cells with three components that mimic infection with bacteria or a virus. They then analyzed how cells from different individuals respond to infection by measuring gene expression both during the early and late immune response. Integrating the gene expression profiles with genome-wide genetic data of each individual, they were able to map how genetic variants affect gene expression, and how this genetic effect changes with the immune stimulus.
The study’s analyses of gene expression patterns in a population scale provide a valuable dataset of innate immune responses and show wide variation among individuals exposed to diverse pathogens over multiple time points. The research identified population differences in immune response and demonstrated that immune response modifies genetic associations to disease. It sheds light on the genomic elements underlying response to environmental stimuli, and the dynamics and evolution of immune response.
“It’s been known for a long time that most diseases have both genetic and environmental risk factors,” concluded Dr. Lappalainen. “But it’s actually more complicated than that because genes and environment interact. As demonstrated in our study, a genetic risk factor may manifest only in certain environments. We are still in early stages of understanding the interplay of genetics and environment, but our results indicate that this is a key component of human biology and disease. The molecular approach that we took in our study can be a particularly powerful way for researchers to delve deeper into this question.”
