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. 2020 Feb 1;49(1):289-300.
doi: 10.1093/ije/dyz211.

Metabolomic profiles associated with all-cause mortality in the Women's Health Initiative

Raji Balasubramanian  1 , Nina P Paynter  2 , Franco Giulianini  2 , JoAnn E Manson  2 , Yibai Zhao  1 , Jiu-Chiuan Chen  3 , Mara Z Vitolins  4 , Christine A Albert  2 , Clary Clish  5 , Kathryn M Rexrode  3   6
Affiliations

Metabolomic profiles associated with all-cause mortality in the Women's Health Initiative

Raji Balasubramanian et al. Int J Epidemiol. .

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.

Keywords: All-cause mortality; longevity; metabolomics; women’s health.

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Figures

Figure 1.
Figure 1.
Discovery and validation of novel metabolite associations with all-cause mortality in the Women’s Health Initiative (n = 2298). FDR denotes ‘false-discovery rate’.
Figure 2.
Figure 2.
Replication of 12 metabolite associations discovered in the Framingham Heart Study (FHS). Model (A): adjusted for age, WHI arm, CHD case/control status. Model (B): model (A) factors + BMI, systolic blood pressure, hypertension treatment, diabetes, smoking status, total cholesterol and HDL cholesterol.
Figure 3.
Figure 3.
Eight novel metabolite associations with all-cause mortality in the Women’s Health Initiative Observational Study (WHI-OS) and the Women’s Health Initiative Hormone Trials (WHI-HT). Model (A): adjusted for age, WHI arm, CHD case/control status. Model (B): model (A) factors + BMI, systolic blood pressure, hypertension treatment, diabetes, smoking status, total cholesterol and HDL cholesterol .
Figure 4.
Figure 4.
M-Metabo-score comprising 17 metabolites associated with all-cause mortality in the Women’s Health Initiative Observational Study (WHI-OS) and the Women’s Health Initiative Hormone Trials (WHI-HT). Models adjusted for age, WHI arm, CHD case/control status, BMI, systolic blood pressure, hypertension treatment, diabetes, smoking status, total cholesterol and HDL cholesterol .
Figure 5.
Figure 5.
Nineteen metabolites associated with longevity in the Women’s Health Initiative Observational Study (WHI-OS) and the Women’s Health Initiative Hormone Trials (WHI-HT). Longevity is defined as living to age 85 years. Model (A): adjusted for age, WHI arm, CHD case/control status. Model (B): model (A) factors + BMI, systolic blood pressure, hypertension treatment, diabetes, smoking status, total cholesterol and HDL cholesterol.
Figure 6.
Figure 6.
L-Metabo-score comprising 17 metabolites associated with longevity in the Women’s Health Initiative Observational Study (WHI-OS) and the Women’s Health Initiative Hormone Trials (WHI-HT). Models adjusted for age, WHI arm, CHD case/control status, BMI, systolic blood pressure, hypertension treatment, diabetes, smoking status, total cholesterol and HDL cholesterol.
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References

    1. Weindruch R, Walford RL.. The Retardation of Aging and Disease by Dietary Restriction. Springfield, IL; C C Thomas, 1988.
    1. Fishbein L. International Life Sciences Institute, National Center for Toxicological Research, National Institute on Aging Biological Effects of Dietary Restriction. Berlin, New York: Springer, 1991.
    1. Ala-Korpela M, Kangas AJ, Soininen P.. Quantitative high-throughput metabolomics: a new era in epidemiology and genetics. Genome Med 2012;4:36.. - PMC - PubMed
    1. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G.. The hallmarks of aging. Cell 2013;153:1194–217. - PMC - PubMed
    1. Sebastiani P, Perls TT.. The genetics of extreme longevity: lessons from the New England centenarian study. Front Genet 2012;3:277. - PMC - PubMed

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