Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels

Abhishek Nag; Yuko Kurushima; Ruth C E Bowyer; Philippa M Wells; Stefan Weiss; Maik Pietzner; Thomas Kocher; Johannes Raffler; Uwe Völker; Massimo Mangino; Timothy D Spector; Michael V Milburn; Gabi Kastenmüller; Robert P Mohney; Karsten Suhre; Cristina Menni; Claire J Steves

doi:10.1093/hmg/ddz308

Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels

Abhishek Nag, Yuko Kurushima, Ruth C E Bowyer, Philippa M Wells, Stefan Weiss, Maik Pietzner, Thomas Kocher, Johannes Raffler, Uwe Völker, Massimo Mangino, Timothy D Spector, Michael V Milburn, Gabi Kastenmüller, Robert P Mohney, Karsten Suhre, Cristina Menni, Claire J Steves

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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.

Original language	English
Article number	ddz308
Pages (from-to)	864-875
Number of pages	12
Journal	Human Molecular Genetics
Volume	29
Issue number	5
Early online date	21 Jan 2020
DOIs	https://doi.org/10.1093/hmg/ddz308
Publication status	Published - 27 Mar 2020

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Nag, A., Kurushima, Y., Bowyer, R. C. E., Wells, P. M., Weiss, S., Pietzner, M., Kocher, T., Raffler, J., Völker, U., Mangino, M., Spector, T. D., Milburn, M. V., Kastenmüller, G., Mohney, R. P., Suhre, K., Menni, C., & Steves, C. J. (2020). Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels. Human Molecular Genetics, 29(5), 864-875. Article ddz308. https://doi.org/10.1093/hmg/ddz308

@article{159886b9e0a24576843090da71433074,

title = "Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels",

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.",

author = "Abhishek Nag and Yuko Kurushima and Bowyer, {Ruth C E} and Wells, {Philippa M} and Stefan Weiss and Maik Pietzner and Thomas Kocher and Johannes Raffler and Uwe V{\"o}lker and Massimo Mangino and Spector, {Timothy D} and Milburn, {Michael V} and Gabi Kastenm{\"u}ller and Mohney, {Robert P} and Karsten Suhre and Cristina Menni and Steves, {Claire J}",

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month = mar,

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doi = "10.1093/hmg/ddz308",

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Nag, A, Kurushima, Y, Bowyer, RCE , Wells, PM, Weiss, S, Pietzner, M, Kocher, T, Raffler, J, Völker, U, Mangino, M, Spector, TD, Milburn, MV, Kastenmüller, G, Mohney, RP, Suhre, K, Menni, C & Steves, CJ 2020, 'Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels', Human Molecular Genetics, vol. 29, no. 5, ddz308, pp. 864-875. https://doi.org/10.1093/hmg/ddz308

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T1 - Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels

AU - Nag, Abhishek

AU - Kurushima, Yuko

AU - Bowyer, Ruth C E

AU - Wells, Philippa M

AU - Weiss, Stefan

AU - Pietzner, Maik

AU - Kocher, Thomas

AU - Raffler, Johannes

AU - Völker, Uwe

AU - Mangino, Massimo

AU - Spector, Timothy D

AU - Milburn, Michael V

AU - Kastenmüller, Gabi

AU - Mohney, Robert P

AU - Suhre, Karsten

AU - Menni, Cristina

AU - Steves, Claire J

PY - 2020/3/27

Y1 - 2020/3/27

N2 - 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.

AB - 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.

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DO - 10.1093/hmg/ddz308

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EP - 875

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 5

M1 - ddz308

ER -

Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels

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