Raji Balasubramanian1, Nina P Paynter2, Franco Giulianini2, JoAnn E Manson2, Yibai Zhao1, Jiu-Chiuan Chen3, Mara Z Vitolins4, Christine A Albert2, Clary Clish5, Kathryn M Rexrode3,6. 1. Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, MA, USA. 2. Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, and Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 3. Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. 4. Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, USA. 5. Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. 6. Division of Women's Health, Brigham and Women's Hospital, Boston, MA, USA.
Abstract
BACKGROUND: Metabolomics profiling has shown promise in elucidating the biological pathways underpinning mortality, but there are limited data in female populations. METHODS: We applied a liquid chromatography-tandem mass spectrometry metabolomics platform to EDTA-plasma to measure 470 metabolites at baseline in a discovery set of 943 postmenopausal women (including 417 incident deaths, median time to death of 10.6 years) with validation in an independent set of 1355 postmenopausal women (including 685 deaths, median time to death of 9.1 years) in the Women's Health Initiative. RESULTS: Eight new metabolites were discovered to be associated with all-cause mortality. Findings included protective effects of increased levels of three amino acids (asparagine, homoarginine and tryptophan) and docosatrienoic acid; and detrimental effects of increased levels of C4-OH-carnitine, hexadecanedioate and two purine/pyrimidines (N2, N2-dimethylguanosine and N4-acetylcytidine). In addition, a set of nine previously published metabolite associations were replicated. A metabolite score comprising 17 metabolites was associated with mortality (P < 10-8) after adjustment for risk factors, with a hazard ratio of 1.95 (95% CI: 1.46-2.62) for women in the highest quartile compared with the lowest quartile of metabolite score. The score was robust among younger women and older women, for both cardiovascular and non-cardiovascular mortality, and associated with both early deaths (within the first 10 years of baseline) and later deaths. CONCLUSIONS: Our study fills a gap in the literature by identifying eight novel metabolite associations with all-cause mortality in women, using a robust study design involving independent discovery and validation datasets.
BACKGROUND: Metabolomics profiling has shown promise in elucidating the biological pathways underpinning mortality, but there are limited data in female populations. METHODS: We applied a liquid chromatography-tandem mass spectrometry metabolomics platform to EDTA-plasma to measure 470 metabolites at baseline in a discovery set of 943 postmenopausal women (including 417 incident deaths, median time to death of 10.6 years) with validation in an independent set of 1355 postmenopausal women (including 685 deaths, median time to death of 9.1 years) in the Women's Health Initiative. RESULTS: Eight new metabolites were discovered to be associated with all-cause mortality. Findings included protective effects of increased levels of three amino acids (asparagine, homoarginine and tryptophan) and docosatrienoic acid; and detrimental effects of increased levels of C4-OH-carnitine, hexadecanedioate and two purine/pyrimidines (N2, N2-dimethylguanosine and N4-acetylcytidine). In addition, a set of nine previously published metabolite associations were replicated. A metabolite score comprising 17 metabolites was associated with mortality (P < 10-8) after adjustment for risk factors, with a hazard ratio of 1.95 (95% CI: 1.46-2.62) for women in the highest quartile compared with the lowest quartile of metabolite score. The score was robust among younger women and older women, for both cardiovascular and non-cardiovascular mortality, and associated with both early deaths (within the first 10 years of baseline) and later deaths. CONCLUSIONS: Our study fills a gap in the literature by identifying eight novel metabolite associations with all-cause mortality in women, using a robust study design involving independent discovery and validation datasets.
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