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Genetics, Gut Microbes Linked to Blood Levels of Cardiovascular Disease-Related Proteins

NEW YORK (GenomeWeb) – An international team led by investigators in the Netherlands and Norway has identified combined genetic and microbial factors influencing inter-individual differences in circulating levels of proteins implicated in cardiovascular disease (CVD).

As they reported online today in Nature Genetics, researchers from the University of Groningen, University of Oslo, and elsewhere searched for genome-wide and metagenome-wide genetic and microbial contributors to the levels of 92 proteins previously implicated in CVD in SNP, gene expression, blood protein levels, and gut metagenomic sequences from nearly 1,300 individuals.

The team began by addressing the roles that the microbiome and host-microbe interactions might play in cardiovascular disease, building on prior studies of heart disease, inflammatory bowel disease, and other conditions.

"Understanding the impact of genetics, the gut microbiome, and their interactions on the inter-individual variation of circulating plasma proteins will provide deeper insights into host-microbe interactions in health and disease," co-corresponding authors Jingyuan Fu and Alexandra Zhernakova, genetics researchers at the University of Groningen, and their colleagues wrote.

They brought together data for 1,178 participants in the Dutch population LifeLines-DEEP study and another 86 individuals from LifeLines-DEEP2 phase of the study, using array- or whole-genome sequence-based genotyping, blood protein testing by multiplex immunoassay, blood RNA sequencing, and metagenomic sequencing on fecal samples to search for cis- and trans-protein quantitative trait loci on one hand and protein variation related to gut microbial diversity, taxa representation, and pathways on the other.

The team's results uncovered genetic ties for 73 of these proteins and 41 proteins with detectable microbial impacts — a set that included 31 proteins affected by host genetic factors and gut microbial composition. In other words, of the 83 proteins influenced by genetic or gut microbe, all but 10 were linked to genetic contributors.

Together, the group estimated, the genetic and microbial factors found accounted for more than 75 percent of individual-to-individual differences in cardiovascular disease protein levels in the blood.

"Genetics contribute most to concentrations of immune-related proteins, while the gut microbiome contributes most to proteins involved in metabolism and intestinal health," the authors wrote, noting that their search also led to "several host-microbe interactions that impact proteins involved in epithelial function, lipid metabolism, and central nervous system function."

Overall, the researchers noted, "our results demonstrate complex genetic-microbiome interplay in the regulation of circulating proteins that modulate various biological processes and demonstrate that these effects can be seen in many different organs and tissues."

As such, they suggested, the current study "provides conceptual advances that lay important groundwork for future applications in personalized medicine, which will have to take into account both the genome and the metagenome."