Cardiovascular disease is a major killer with complex causes. Genetic susceptibility plays a role, but recent studies have highlighted how gut bacteria can also affect disease risk. Now, in a first-of-its-kind study, geneticists at the University Medical Center Groningen (UMCG)/University of Groningen and their colleagues have shown that the interaction of genes and gut bacteria is an important driver for cardiovascular disease. This finding paves the way for future applications in personalized medicine. The results were published in the journal Nature Genetics on 24 September.
Cardiovascular disease doesn’t just affect the heart; it is a systemic and complex disease affected by interactions of genetics, gut microbiome and environmental factors. This makes it challenging to pinpoint the underlying causes in order to improve disease prevention and treatment. ‘That is why we chose to focus our attention on circulating proteins’, explains Jingyuan Fu, Associate Professor of Genetics at the UMCG and co-supervisor of the study. ‘This way, we were able to assess systemic effects on molecular levels.’ The study, funded by Dutch Heart Foundation, aimed to gain more insights into the mechanisms that cause cardiovascular disease.
A panel of 92 circulating proteins defined to be important for cardiovascular disease by the Swedish company Olink Proteomics was used to determine protein abundance in blood samples from over 1,200 individuals from the LifeLines DEEP Dutch population cohort study. Detailed genetic information was available for all participants, as well as medical information and biological samples, including stool samples.
‘We used the genetic information to assess regulation of the 92 circulating proteins, both by genetic variants in adjacent regions (e.g. cis-regulatory DNA elements) and by those far away via trans-regulation of other genes’, explains Fu. DNA analysis of stool samples provided a metagenome with information on gut bacteria. ‘We looked at variations of circulating proteins which were associated with abundance of bacterial species and metabolic pathways in the gut microbiome.’ This enabled the scientists to estimate the effect of both genes and gut microbiome on the circulating protein panel, and thereby on cardiovascular risk. ‘To our knowledge, we are the first to also identify interactions between the host genes and the gut microbiome.’
The study uncovered several such interactions, like in the regulation of Ep-CAM, a protein that has a role in how tightly the cells that line the gut hold together. It can change how permeable the gut is, which plays a role in cardiovascular disease. Another interaction was found in the way gut bacteria can send signals to the central nervous system which has an effect on appetite.
‘The most important result is that we have provided the first evidence for this host-microbiome interaction on protein expression’, says Fu. ‘This was possible because of the unique data gathered in the LifeLines cohort study.’ In particular, host-microbe interactions were detected for several key regulatory proteins that function in small intestine, central nervous systems and lipid metabolism. This has suggested that the gut microbiome can contribute to CVD risk via different biological processes and different mechanisms. Of course, this is only a first step. ‘We need further work to confirm our results and better understand the mechanisms involved. To this end, we will use a new branch of the LifeLines cohort in which information on the microbiome of 10,000 individuals is collected together with samples of the microbiome in the nose, throat and gut.’
Eventually, this may lead to more personalized medicine based on the interaction of host genes and microbiome, as well as to new leads for drug discovery. ‘For example, it might be interesting to look for bacterial compounds that affect Ep-CAM, which is a biomarker for inflammatory bowel disease and cancer.’ Furthermore, it may be possible to manipulate the microbiome to reduce disease risk. ‘After all, you can’t change your genes, but you could alter the microbiome.’
Zhernakova D., et al. (2018) Individual variations in cardiovascular-disease-related protein levels are driven by genetics and gut microbiome. Nat. Gen. 10.1038/s41588-018-0224-7.