Individual variability in cardiovascular complex disease — affected by genetics and the gut microbiome

On these GEITP pages we have had a continuing dialogue on impact of the human genome vs impact of the gut microbiome — on human health, especially considering the latest advances in high-throughput deep-sequencing [also called next-generation sequencing (NGS); and whole-genome sequencing (WGS)] technology. Genome-wide association studies (GWAS) and metagenome-wide association studies have provided evidence that development of many complex diseases can be highly influenced by the human genome, the microbiome, and their interactions. This has now been shown for cardiovascular diseases, type-2 diabetes, inflammatory bowel disease (IBD), and several different types of cancer.

The impact of gut microbiome and genome–microbe interactions on molecular traits is largely unknown, however — which greatly limits our mechanistic understanding of microbial associations with complex diseases. As repeatedly emphasized in GEITP, this impact and interactions is also relevant to other multifactorial traits, including response to environmental toxicants and response to drugs (either efficacy or toxicity).

Circulating plasma proteins are often used as risk factors, or biomarkers, for various diseases. Authors [see attached article] present a “systems genome and metagenome association analysis” on 92 circulating plasma proteins in two cohorts (one representing 1,178 persons, the other numbering 86 persons). Authors examined genotype (DNA sequence), metagenome (genetic material recovered directly from environmental samples; this field has also been called ‘environmental genomics’, ‘ecogenomics’ or ‘community genomics’), transcriptome [the messenger-RNA (mRNA) transcribed from active genes in the DNA template], and detailed phenotype (trait) data. The 92 proteins were selected a priori, based on their direct or indirect role in development of cardiovascular diseases (CVDs). However, most of these proteins have a broader impact on host health and have also been shown to be relevant to many other diseases.

Authors identified genetic components for 73 proteins and microbial associations for 41 proteins — of which 31 were associated with both. The recognized genetic and microbial factors mostly exerted additive effects and, collectively, were able to explain as much as 76% of inter-individual variation (17.5% on average). Genetic effects contributed mostly to concentrations of immune-related proteins, whereas the gut microbiome contributed mostly to proteins involved in metabolism and intestinal health. Authors found several host–microbe interactions that had an impact on proteins involved in epithelial function, lipid metabolism, and central nervous system (CNS) function. This study therefore provides important evidence for a combined genetic and microbial effect on cardiovascular disease. Authors propose that this approach should provide directions for future applications in personalized medicine.

Nature Genet Nov 2o18; 50: 1524–1532

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