Assessing the causal association of glycine with risk of cardio-metabolic diseases

Laura B.L. Wittemans; Luca A. Lotta; Clare Oliver-Williams; Isobel D. Stewart; Praveen Surendran; Savita Karthikeyan; Felix R. Day; Albert Koulman; Fumiaki Imamura; Lingyao Zeng; Jeanette Erdmann; Heribert Schunkert; Kay Tee Khaw; Julian L. Griffin; Nita G. Forouhi; Robert A. Scott; Angela M. Wood; Stephen Burgess; Joanna M.M. Howson; John Danesh; Nicholas J. Wareham; Adam S. Butterworth; Claudia Langenberg

doi:10.1038/s41467-019-08936-1

Assessing the causal association of glycine with risk of cardio-metabolic diseases

Laura B.L. Wittemans, Luca A. Lotta, Clare Oliver-Williams, Isobel D. Stewart, Praveen Surendran, Savita Karthikeyan, Felix R. Day, Albert Koulman, Fumiaki Imamura, Lingyao Zeng, Jeanette Erdmann, Heribert Schunkert, Kay Tee Khaw, Julian L. Griffin, Nita G. Forouhi, Robert A. Scott, Angela M. Wood, Stephen Burgess, Joanna M.M. Howson, John DaneshNicholas J. Wareham, Adam S. Butterworth, Claudia Langenberg^*

^*Corresponding author for this work

100 Citations (Scopus)

Abstract

Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.

Original language	English
Article number	1060
Journal	Nature Communications
Volume	10
Issue number	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-019-08936-1
Publication status	Published - 01.12.2019

Funding

We are grateful to participants and staff for their contribution to the studies included in this project. The Fenland Study is supported by the UK Medical Research Council (MC_UU_12015/1 and MC_PC_13046). We thank Dr Larissa Richardson and Dr Luke Marney for the acquisition of the metabolomics data. EPIC-Norfolk has received funding from the Medical Research Council (MR/N003284/1, MC_PC_13048 and MR/L00002/1), Cancer Research United Kingdom (14136) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement number 115372 (European Union’s Seventh Framework Programme FP7/2007-2013) and EFPIA companies’ in kind contribution. The EPIC-InterAct study was funded by the EU FP6 Programme (LSHM_CT_2006_037197). We particularly thank Nicola Kerrison (EPIC-InterAct Data Manager). EPIC-CVD has been supported by the European Union Framework 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (G0800270 and MR/L003120/1), the British Heart Foundation (SP/09/ 002 and RG/08/014 and RG13/13/30194) and the UK National Institute of Health Research (NIHR). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. We thank Sarah Spackman (EPIC-CVD Data Manager). INTERVAL: Participants were recruited with the active collaboration of NHS Blood and Transplant England, which has supported field work and other elements of the trial. This study was funded by the NIHR, the NIHR BioResource, the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*], the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1) and the British Heart Foundation (RG/13/13/30194). *The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. UK Biobank: This research has been conducted using the UK Biobank resource under Application Numbers 12885 and 20480. Additional acknowledgements are provided in Supplementary Note 1. Competing interests: R.A.S. is an employee and shareholder of GlaxoSmithKline. C.O.-W. received prize money from Novartis (<£1000). J.D. reports grants and personal fees from Merck Sharp & Dohme (MSD), grants and personal fees from Novartis, grants from British Heart Foundation, grants from European Research Council, grants from NIHR, grants from NHS Blood and Transplant, grants from Pfizer, grants from UK MRC, grants from Wellcome Trust, grants from AstraZeneca, outside the submitted work. J.D. also reports non-financial support from Merck Sharp & Dohme (MSD) and non-financial support from Novartis, outside the submitted work. A.B. has received grants outside of this work from AstraZeneca, Biogen, Merck, Novartis and Pfizer and personal fees outside of this work from Novartis. The remaining authors declare no competing interests.

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Research Area: Medical Genetics

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Wittemans, L. B. L., Lotta, L. A., Oliver-Williams, C., Stewart, I. D., Surendran, P., Karthikeyan, S., Day, F. R., Koulman, A., Imamura, F., Zeng, L., Erdmann, J., Schunkert, H., Khaw, K. T., Griffin, J. L., Forouhi, N. G., Scott, R. A., Wood, A. M., Burgess, S., Howson, J. M. M., ... Langenberg, C. (2019). Assessing the causal association of glycine with risk of cardio-metabolic diseases. Nature Communications, 10(1), Article 1060. https://doi.org/10.1038/s41467-019-08936-1

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abstract = "Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.",

author = "Wittemans, \{Laura B.L.\} and Lotta, \{Luca A.\} and Clare Oliver-Williams and Stewart, \{Isobel D.\} and Praveen Surendran and Savita Karthikeyan and Day, \{Felix R.\} and Albert Koulman and Fumiaki Imamura and Lingyao Zeng and Jeanette Erdmann and Heribert Schunkert and Khaw, \{Kay Tee\} and Griffin, \{Julian L.\} and Forouhi, \{Nita G.\} and Scott, \{Robert A.\} and Wood, \{Angela M.\} and Stephen Burgess and Howson, \{Joanna M.M.\} and John Danesh and Wareham, \{Nicholas J.\} and Butterworth, \{Adam S.\} and Claudia Langenberg",

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doi = "10.1038/s41467-019-08936-1",

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Wittemans, LBL, Lotta, LA, Oliver-Williams, C, Stewart, ID, Surendran, P, Karthikeyan, S, Day, FR, Koulman, A, Imamura, F, Zeng, L, Erdmann, J, Schunkert, H, Khaw, KT, Griffin, JL, Forouhi, NG, Scott, RA, Wood, AM, Burgess, S, Howson, JMM, Danesh, J, Wareham, NJ, Butterworth, AS & Langenberg, C 2019, 'Assessing the causal association of glycine with risk of cardio-metabolic diseases', Nature Communications, vol. 10, no. 1, 1060. https://doi.org/10.1038/s41467-019-08936-1

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T1 - Assessing the causal association of glycine with risk of cardio-metabolic diseases

AU - Wittemans, Laura B.L.

AU - Lotta, Luca A.

AU - Oliver-Williams, Clare

AU - Stewart, Isobel D.

AU - Surendran, Praveen

AU - Karthikeyan, Savita

AU - Day, Felix R.

AU - Koulman, Albert

AU - Imamura, Fumiaki

AU - Zeng, Lingyao

AU - Erdmann, Jeanette

AU - Schunkert, Heribert

AU - Khaw, Kay Tee

AU - Griffin, Julian L.

AU - Forouhi, Nita G.

AU - Scott, Robert A.

AU - Wood, Angela M.

AU - Burgess, Stephen

AU - Howson, Joanna M.M.

AU - Danesh, John

AU - Wareham, Nicholas J.

AU - Butterworth, Adam S.

AU - Langenberg, Claudia

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.

AB - Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.

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AN - SCOPUS:85062584534

SN - 1751-8628

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1060

ER -

Assessing the causal association of glycine with risk of cardio-metabolic diseases

Abstract

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