Overview of the eQTL study and transcriptional immune response in primary human monocytes. (a) Stepwise experimental design to identify genetic effects on immune response in human monocytes. (b) Mean mRNA profiles of differentially expressed genes [Nature Communications 2017;8:266 doi:10.1038/s41467-017-00366-1]
Overview of the eQTL study and transcriptional immune response in primary human monocytes. (a) Stepwise experimental design to identify genetic effects on immune response in human monocytes. (b) Mean mRNA profiles of differentially expressed genes [Nature Communications 2017;8:266 doi:10.1038/s41467-017-00366-1]

Ever wonder why your friend, co-worker, or partner doesn’t get as sick as you, even though they caught the same “bug” you did? Maybe they made some Faustian bargain that affords them greater protection to infections, or perhaps they are part of some top-secret government experiment that injects them with an array of antigens isolated from an alien race living in Area 51. While both theories are “potential” explanations, it seems likely that differences in response to infection lie in something a bit more scientific—like genetics. Now, a collaborative team of investigators from the University of Bonn, Germany, and the New York Genome Center has just published findings that map several genetic variants that affect how much gene expression changes in response to an immune stimulus.     

Results from the new study—published in Nature Communications in an article entitled “Genetic Regulatory Effects Modified by Immune Activation Contribute to Autoimmune Disease Associations”—offer novel insights into the genetic contribution to varying immune responses among individuals and its consequences on immune-mediated diseases.

“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.

The human immune system plays a central role in autoimmune and inflammatory diseases, cancer, metabolism, and aging. The 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 lead study investigator Sarah Kim-Hellmuth, Ph.D., a postdoctoral researcher at the  New York Genome Center. “While earlier studies have mapped some of these effects, this study is particularly comprehensive, with three stimuli and two-time points analyzed.”

In the current study, the research team captured genetic variants whose effects on gene regulation were different depending on the different infectious state of the cells. These included four associations to diseases such as cholesterol level and celiac disease. Moreover, the researchers discovered a trend of genetic risk for autoimmune diseases such as lupus and celiac disease to be enriched for gene regulatory effects modified by the immune state.

“Here, we isolate monocytes from 134 genotyped individuals, stimulate these cells with three defined microbe-associated molecular patterns (LPS, MDP, and 5′-ppp-dsRNA) [lipopolysaccharide, muramyl dipeptide, and 5' triphosphate double-stranded RNA], and profile the transcriptomes at three-time points,” the authors wrote. “Mapping expression quantitative trait loci (eQTL), we identify 417 response eQTLs (reQTLs) with varying effects between conditions. We characterize the dynamics of genetic regulation on early and late immune response and observe an enrichment of reQTLs in distal cis-regulatory elements. In addition, reQTLs are enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover reQTL effects in multiple GWAS [genome-wide association study] loci and showed a stronger enrichment for response than constant eQTLs in GWAS signals of several autoimmune diseases.”

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.

Findings from this new study provide a highly robust and comprehensive dataset of innate immune responses and show wide variation among individuals exposed to diverse pathogens over multiple time points. The investigators identified population differences in immune response and demonstrated that immune response modifies genetic associations to disease. The research 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.”








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