Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes

Abstract The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individ...

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Autores principales:	Eleonora Porcu, Federica Gilardi, Liza Darrous, Loic Yengo, Nasim Bararpour, Marie Gasser, Pedro Marques-Vidal, Philippe Froguel, Gerard Waeber, Aurelien Thomas, Zoltán Kutalik
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/75360a3d5dfd44c5b36df0daa6ce6d32
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spelling	oai:doaj.org-article:75360a3d5dfd44c5b36df0daa6ce6d322021-12-02T11:39:38ZTriangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes10.1038/s41598-021-85684-72045-2322https://doaj.org/article/75360a3d5dfd44c5b36df0daa6ce6d322021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85684-7https://doaj.org/toc/2045-2322Abstract The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.Eleonora PorcuFederica GilardiLiza DarrousLoic YengoNasim BararpourMarie GasserPedro Marques-VidalPhilippe FroguelGerard WaeberAurelien ThomasZoltán KutalikNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Eleonora Porcu Federica Gilardi Liza Darrous Loic Yengo Nasim Bararpour Marie Gasser Pedro Marques-Vidal Philippe Froguel Gerard Waeber Aurelien Thomas Zoltán Kutalik Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes
description	Abstract The number of people affected by Type 2 diabetes mellitus (T2DM) is close to half a billion and is on a sharp rise, representing a major and growing public health burden. Given its mild initial symptoms, T2DM is often diagnosed several years after its onset, leaving half of diabetic individuals undiagnosed. While several classical clinical and genetic biomarkers have been identified, improving early diagnosis by exploring other kinds of omics data remains crucial. In this study, we have combined longitudinal data from two population-based cohorts CoLaus and DESIR (comprising in total 493 incident cases vs. 1360 controls) to identify new or confirm previously implicated metabolomic biomarkers predicting T2DM incidence more than 5 years ahead of clinical diagnosis. Our longitudinal data have shown robust evidence for valine, leucine, carnitine and glutamic acid being predictive of future conversion to T2DM. We confirmed the causality of such association for leucine by 2-sample Mendelian randomisation (MR) based on independent data. Our MR approach further identified new metabolites potentially playing a causal role on T2D, including betaine, lysine and mannose. Interestingly, for valine and leucine a strong reverse causal effect was detected, indicating that the genetic predisposition to T2DM may trigger early changes of these metabolites, which appear well-before any clinical symptoms. In addition, our study revealed a reverse causal effect of metabolites such as glutamic acid and alanine. Collectively, these findings indicate that molecular traits linked to the genetic basis of T2DM may be particularly promising early biomarkers.
format	article
author	Eleonora Porcu Federica Gilardi Liza Darrous Loic Yengo Nasim Bararpour Marie Gasser Pedro Marques-Vidal Philippe Froguel Gerard Waeber Aurelien Thomas Zoltán Kutalik
author_facet	Eleonora Porcu Federica Gilardi Liza Darrous Loic Yengo Nasim Bararpour Marie Gasser Pedro Marques-Vidal Philippe Froguel Gerard Waeber Aurelien Thomas Zoltán Kutalik
author_sort	Eleonora Porcu
title	Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes
title_short	Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes
title_full	Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes
title_fullStr	Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes
title_full_unstemmed	Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes
title_sort	triangulating evidence from longitudinal and mendelian randomization studies of metabolomic biomarkers for type 2 diabetes
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/75360a3d5dfd44c5b36df0daa6ce6d32
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Triangulating evidence from longitudinal and Mendelian randomization studies of metabolomic biomarkers for type 2 diabetes

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