A strong constitution is in the genes

We all know them: the people who never seem to be affected while the rest of the country is coughing and sneezing or laid up in bed. Why do they get off so lightly? This is the question that researchers from the UMCG tried to answer in a joint project with researchers from Radboudumc (Nijmegen) and Harvard (Boston, USA). They discovered that people’s resistance to bacteria and fungi can vary greatly, and they identified a few genes that may help to explain why this is. In future, it may be possible to carry out a genetic test to estimate someone’s risk of contracting a specific infection. The results of the research were published on 4 July in the journal Nature Medicine.

‘Infections are a problem, particularly among the elderly’, says Vinod Kumar, assistant professor at the UMCG and one of the researchers. ‘Yet some older adults are hardly ever ill. We wanted to find out why.’ The researchers used data and material from an ongoing research project monitoring 200 healthy volunteers, which is currently running at Radboudumc.

Blood taken from the volunteers was used to obtain white blood cells, the cells of the immune system. These white blood cells were then exposed to various bacteria and fungi, or fragments of these organisms. ‘We examined how the cells reacted to the pathogens’, explains Kumar.

Large-scale research

Part of the reaction involves the production of what are known as cytokinins, proteins used by the cells to pass on the signals that partly determine how the immune system responds to attack. The researchers measured the reactions of eight different cytokinins.

UMCG researcher Yang Li, who was responsible for analysing many of the results, explains why this experiment is so unique. ‘First of all, we were able to analyse existing medical data relating to a large group of healthy volunteers. We then monitored the reactions of various cytokinins after stimulating them with a pathogen. This has never been done on this scale before.’

Four million variants

The results of the research show that different people have very different reactions to the same pathogen. In addition, it would appear that the type of cytokinin that reacts depends on the type of pathogen. ‘These results were interesting in themselves, but we also wanted to know why this was’, says Mihai Netea, Professor of Experimental Internal Medicine at the Radboudumc.

A genetic analysis was carried out on a sub-group of the volunteers to monitor the presence of a staggering four million genetic variants. People’s genes differ slightly from each other, and these differences can affect the way certain genes work.

Sensitivity to fungi

The analysis revealed a handful of variants that could be linked to a strong or less strong reaction to a particular pathogen. The clearest example was a genetic variant that affects the functioning of the GOLM1 gene. Cells taken from volunteers with less effective GOLM1 produced less of the cytokinin interleukin 6 when exposed to the fungus Candida albicans. It was concluded that this genetic variant should make the person concerned more sensitive to infection by this particular fungus.

To confirm this conclusion, the researchers then studied a group of patients admitted to hospital with a Candida albicans infection. Their DNA showed that the risk of this infection was higher among people with this particular variant of the GOLM1 gene.

‘Our research shows that it is possible to determine people’s reaction to a pathogen and then find out which genes play a role’, says Netea. This opens new doors to the medical profession. ‘A genetic test would enable you to estimate someone’s risk of contracting a particular infection.’ Once the precision of the link between genetic variants and a heightened risk of infection has been established, it may even become possible to develop drugs to boost the immune system.

Two Spinoza prize-winners took part in this research: Cisca Wijmenga, Professor of Human Genetics at the UMCG (2015) and Mihai Netea, Professor of Experimental Internal Medicine at Radboudumc (2016).