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2015 ; 16 Suppl 7
(Suppl 7
): S4
Nephropedia Template TP
gab.com Text
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English Wikipedia
A genome-wide systems analysis reveals strong link between colorectal cancer and
trimethylamine N-oxide (TMAO), a gut microbial metabolite of dietary meat and
fat
#MMPMID26100814
Xu R
; Wang Q
; Li L
BMC Genomics
2015[]; 16 Suppl 7
(Suppl 7
): S4
PMID26100814
show ga
BACKGROUND: Dietary intakes of red meat and fat are established risk factors for
both colorectal cancer (CRC) and cardiovascular disease (CVDs). Recent studies
have shown a mechanistic link between TMAO, an intestinal microbial metabolite of
red meat and fat, and risk of CVDs. Data linking TMAO directly to CRC is,
however, lacking. Here, we present an unbiased data-driven network-based systems
approach to uncover a potential genetic relationship between TMAO and CRC.
MATERIALS AND METHODS: We constructed two different epigenetic interaction
networks (EINs) using chemical-gene, disease-gene and protein-protein interaction
data from multiple large-scale data resources. We developed a network-based
ranking algorithm to ascertain TMAO-related diseases from EINs. We systematically
analyzed disease categories among TMAO-related diseases at different ranking
cutoffs. We then determined which genetic pathways were associated with both TMAO
and CRC. RESULTS: We show that CVDs and their major risk factors were ranked
highly among TMAO-related diseases, confirming the newly discovered mechanistic
link between CVDs and TMAO, and thus validating our algorithms. CRC was ranked
highly among TMAO-related disease retrieved from both EINs (top 0.02%, #1 out of
4,372 diseases retrieved based on Mendelian genetics and top 10.9% among 882
diseases based on genome-wide association genetics), providing strong supporting
evidence for our hypothesis that TMAO is genetically related to CRC. We have also
identified putative genetic pathways that may link TMAO to CRC, which warrants
further investigation. Through systematic disease enrichment analysis, we also
demonstrated that TMAO is related to metabolic syndromes and cancers in general.
CONCLUSIONS: Our genome-wide analysis demonstrates that systems approaches to
studying the epigenetic interactions among diet, microbiome metabolisms, and
disease genetics hold promise for understanding disease pathogenesis. Our results
show that TMAO is genetically associated with CRC. This study suggests that TMAO
may be an important intermediate marker linking dietary meat and fat and gut
microbiota metabolism to risk of CRC, underscoring opportunities for the
development of new gut microbiome-dependent diagnostic tests and therapeutics for
CRC.