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Genes Affect Human Immune Response to Pathogens

NEW YORK (GenomeWeb) – In a new study published this week, an international research team found that genetic factors play a role in how the immune cells of healthy individuals respond to pathogens, and that immune response varies depending on the type of pathogen the body encounters.

As they reported yesterday in Nature Medicine, researchers from the University Medical Center Groningen, Radboud University Medical Center, and Harvard Medical School focused on the role of cytokines, which are used by immune cells to guide their response to specific pathogens. 

The team obtained blood samples from 200 participants in the Human Functional Genomics Project's 200 Functional Genomics cohort. They isolated immune cells from the blood and stimulated them in the laboratory with 10 different bacterial and fungal pathogens. After 24 hours and/or seven days, the researchers measured levels of eight different cytokines. They then performed further quality filtering and found 62 different cytokine profiles.

"We observed large differences in cytokine production between individuals," Vinod Kumar, co-senior author and professor of functional genomics and infectious disease at University Medical Center Groningen, said in a statement. "Their responses were also specific to the different pathogens." While previous studies on unstimulated immune cells demonstrated little variation between individuals, this study suggests cytokines contribute to the varied responses to pathogens, and that each infection triggers a specific cytokine response pathway.

"The key to our results is that we performed a large-scale study, using many pathogens and measuring different cytokines," first author and Groningen researcher Yang Li added.

The researchers also genotyped DNA samples from 112 individuals from the cohort using the Illumina HumanOmniExpressExome SNP chip, testing about 4 million SNPs. They were then able to pinpoint six genomic regions that influence cytokine responses, which suggests that cytokine production is at least partly genetically determined. "When a particular variant of the SNP was present, the production of the cytokine interleukin-6 was reduced," Kumar said.

They found one of the strongest examples of how genetics play a role in cytokine response in a SNP that affects expression of GOLM1, a gene known to express strongly in response to viral infections. There was a strong correlation between the SNP and the immune response to the fungus Candida albicans, which is responsible for thousands of deaths each year. 

The researchers verified this result in a cohort of patients with candidemia, where the presence of the fungus in the blood correlated strongly with the same SNP and with low levels of interleukin-6, showing that the presence of the genetic variant results in an inability to clear the pathogen.

"This study is a real proof of concept," Li said. "We found a lot of variation in cytokine production upon stimulation, and showed that an important part of this variation is explained by a genetic component."

The researchers believe these findings, after further study, can be applied in the clinic as it might be possible to find genetic markers that will predict infection risk in various individuals. A better understanding of the genetic mechanisms could also lead to new therapeutic approaches. 

"And it's not just for infections," Kumar added. "Immune diseases, for example inflammatory bowel disease, appear to be caused by an over-responsive immune system. So this work means we can learn more about the way infections trigger immune diseases."