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Confounding effects of microbiome on the susceptibility of TNFSF15 to Crohn's disease in the Ryukyu Islands
Shigeki Nakagome1,2,3,4, Hiroshi Chinen5, Atsushi Iraha5
1Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0674, Japan. nakagoms@tcd.ie.
Abstract:
Crohn's disease (CD) involves chronic inflammation in the gastrointestinal tract due to dysregulation of the host immune response to the gut microbiome. Even though the host-microbiome interactions are likely contributors to the development of CD, a few studies have detected genetic variants that change bacterial compositions and increase CD risk. We focus on one of the well-replicated susceptible genes, tumor necrosis factor superfamily member 15 (TNFSF15), and apply statistical analyses for personal profiles of genotypes and salivary microbiota collected from CD cases and controls in the Ryukyu Islands, southernmost islands of the Japanese archipelago. Our association test confirmed the susceptibility of TNFSF15 in the Ryukyu Islands. We found that the recessive model was supported to fit the observed genotype frequency of risk alleles slightly better than the additive model, defining the genetic effect on CD if a pair of the chromosomes in an individual consists of all risk alleles. The combined analysis of haplotypes and salivary microbiome from a small set of samples showed a significant association of the genetic effect with the increase of Prevotella, which led to a significant increase of CD risk. However, the genetic effect on CD disappeared if the abundance of Prevotella was low, suggesting the genetic contribution to CD is conditionally independent given a fixed amount of Prevotella. Although our statistical power is limited due to the small sample size, these results support an idea that the genetic susceptibility of TNFSF15 to CD may be confounded, in part, by the increase of Prevotella.
Insights
Genetic variants in TNFSF15 increase Crohn's disease (CD) risk, particularly when Prevotella bacteria are abundant. This suggests a conditional genetic contribution to CD development in the Ryukyu Islands population.
Area of Science:
- Genetics
- Microbiology
- Immunology
Background:
- Crohn's disease (CD) is a chronic gastrointestinal inflammatory condition linked to immune dysregulation and gut microbiome alterations.
- Host-microbiome interactions and specific genetic variants are implicated in CD pathogenesis, yet their precise roles remain under investigation.
- The tumor necrosis factor superfamily member 15 (TNFSF15) gene is a known susceptibility locus for CD.
Purpose of the Study:
- To investigate the association between TNFSF15 genetic variants and Crohn's disease susceptibility in the Ryukyu Islands population.
- To explore the potential interaction between TNFSF15 genotypes and salivary microbiota composition, specifically Prevotella, in relation to CD risk.
Main Methods:
- Statistical analysis of genotype data and salivary microbiota profiles from Crohn's disease cases and controls in the Ryukyu Islands.
- Association testing to confirm TNFSF15 susceptibility.
- Haplotype and microbiome combined analysis to assess gene-microbe interactions.
Main Results:
- The association of TNFSF15 with CD susceptibility was confirmed in the Ryukyu Islands cohort, with a recessive genetic model showing a better fit.
- A significant association was observed between TNFSF15 genetic effects and increased abundance of Prevotella, correlating with higher CD risk.
- The genetic contribution of TNFSF15 to CD risk was conditional on Prevotella abundance, diminishing when Prevotella levels were low.
Conclusions:
- TNFSF15 is a confirmed susceptibility gene for Crohn's disease in the Ryukyu Islands.
- The genetic risk conferred by TNFSF15 appears to be partially mediated or confounded by an increased abundance of Prevotella in the salivary microbiome.
- These findings highlight a conditional genetic contribution to CD, dependent on specific microbial profiles.
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