Gut microbiota composition explains more variance in the host cardiometabolic risk than genetic ancestry.

Cardiometabolic affections greatly contribute to the global burden of disease. The susceptibility to obesity, cardiovascular disease, and type-2 diabetes, conditions that add to the cardiometabolic syndrome (CMS), was associated with the ancestral genetic composition and gut microbiota. Studies explicitly testing associations between genetic ancestry and gut microbes are growing. We here examined whether the host genetic ancestry was associated with gut microbiota composition, and distinguished the effects of genetic ancestry and non-genetic factors on human cardiometabolic health. We performed a cross-sectional study with 441 community-dwelling Colombian mestizos from five cities spanning the Andes, Pacific, and Caribbean coasts. We characterized the host genetic ancestry by genotyping 40 ancestry informative markers; characterized gut microbiota through 16S rRNA gene sequencing; assessed diet intake, physical activity, cigarette, and medicament consumption; and measured cardiometabolic outcomes that allowed calculating a CMS risk scale. On average, each individual of our cohort was 67 ± 6% European, 21 ± 5% Native American and 12 ± 5% African. Multivariable-adjusted generalized linear models showed that individuals with higher Native American and African ancestries had increased fasting insulin, body mass index and CMS risk, as assessed by the CMS risk scale. Furthermore, we identified 21 OTUs associated to the host genetic ancestry and 20 to cardiometabolic health. While we highlight novel associations between genetic ancestry and gut microbiota, we found that the effect of intestinal microbes was more likely to explain the variance in CMS risk scale than the contributions of European, Native American and African genetic backgrounds.

Variants in genes of innate immunity, appetite control and energy metabolism are associated with host cardiometabolic health and gut microbiota composition.

Identifying the genetic and non-genetic determinants of obesity and related cardiometabolic dysfunctions is cornerstone for their prevention, treatment, and control. While genetic variants contribute to the cardiometabolic syndrome (CMS), non-genetic factors, such as the gut microbiota, also play key roles. Gut microbiota is intimately associated with CMS and its composition is heritable. However, associations between this microbial community and host genetics are understudied. We contribute filling this gap by genotyping 60 variants in 39 genes of three modules involved in CMS risk, measuring cardiometabolic risk factors, and characterizing gut microbiota in a cohort of 441 Colombians. We hypothesized that CMS risk variants were correlated with detrimental levels of clinical parameters and with the abundance of disease-associated microbes. We found several polymorphisms in genes of innate immunity, appetite control, and energy metabolism that were associated with metabolic dysregulation and microbiota composition; the associations between host genetics and cardiometabolic health were independent of the participants' gut microbiota, and those between polymorphisms and gut microbes were independent of the CMS risk. Associations were also independent of the host genetic ancestry, diet and lifestyle. Most microbes explaining genetic-microbiota associations belonged to the families Lachnospiraceae and Ruminococcaceae. Multiple CMS risk alleles were correlated with increased abundance of beneficial microbiota, suggesting that the phenotypic outcome of the evaluated variants might depend upon the genetic background of the studied population and its environmental context. Our results provide additional evidence that the gut microbiota is under the host genetic control and present pathways of host-microbe interactions.