Abstract
Saliva, as a biofluid, is inexpensive and non-invasive to obtain, and provides a vital tool to investigate oral health and its interaction with systemic health conditions. There is growing interest in salivary biomarkers for systemic diseases, notably cardiovascular disease. Whereas hundreds of genetic loci have been shown to be involved in the regulation of blood metabolites, leading to significant insights into the pathogenesis of complex human diseases, little is known about the impact of host genetics on salivary metabolites. Here we report the first genome-wide association study exploring 476 salivary metabolites in 1419 subjects from the TwinsUK cohort (discovery phase), followed by replication in the Study of Health in Pomerania (SHIP-2) cohort. A total of 14 distinct locus-metabolite associations were identified in the discovery phase, most of which were replicated in SHIP-2. While only a limited number of the loci that are known to regulate blood metabolites were also associated with salivary metabolites in our study, we identified several novel saliva-specific locus-metabolite associations, including associations for the AGMAT (with the metabolites 4-guanidinobutanoate and beta-guanidinopropanoate), ATP13A5 (with the metabolite creatinine) and DPYS (with the metabolites 3-ureidopropionate and 3-ureidoisobutyrate) loci. Our study suggests that there may be regulatory pathways of particular relevance to the salivary metabolome. In addition, some of our findings may have clinical significance, such as the utility of the pyrimidine (uracil) degradation metabolites in predicting 5-fluorouracil toxicity and the role of the agmatine pathway metabolites as biomarkers of oral health.
Highlights
Metabolic reactions pervade every aspect of human physiology, abnormalities in which underlie a plethora of human diseases [1]
Identification of novel genetic loci regulating salivary metabolite levels Primary genome-wide discovery analysis in TwinsUK identified 13 metabolites that were significantly associated with genetic loci after correcting for multiple testing (P < 10−10)
We identified a total of 11 distinct genetic loci that regulate the level of 14 salivary metabolites, of which three loci were associated with more than one metabolite each
Summary
Metabolic reactions pervade every aspect of human physiology, abnormalities in which underlie a plethora of human diseases [1]. Investigating the genetic underpinnings of population-wide variation of metabolites can offer novel insights into human metabolism and diseases, in addition to providing potential therapeutic targets to modulate metabolite levels. Saliva is an abundantly produced biofluid, and it can be obtained in an inexpensive and non-invasive manner, without the need for healthcare professionals. It is mainly composed of water (>99%) and several other minor constituents such as mucous, digestive enzymes, cytokines, immunoglobulins, antibacterial peptides, and low molecular weight metabolites [10]
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