Proteins in the pathway from high red blood cell width distribution to all-cause mortality
Yusuke Osawa,
Toshiko Tanaka,
Richard D. Semba,
Giovanna Fantoni,
Ruin Moaddel,
Julián Candia,
Eleanor M. Simonsick,
Stefania Bandinelli,
Luigi Ferrucci
Affiliations
Yusuke Osawa
National Institute on Aging, National Institutes of Health, MedStar Harbor Hospital 5th floor, 3001 S. Hanover Street, Baltimore, MD 21225 USA; Graduate School of Health Management, Keio University, Kanagawa, Japan; Sports Medicine Research Center, Keio University, Kanagawa, Japan; Corresponding authors at: National Institute on Aging, National Institutes of Health, MedStar Harbor Hospital 5th floor, 3001 S. Hanover Street, Baltimore, MD 21225 USA.
Toshiko Tanaka
National Institute on Aging, National Institutes of Health, MedStar Harbor Hospital 5th floor, 3001 S. Hanover Street, Baltimore, MD 21225 USA
Richard D. Semba
Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Giovanna Fantoni
National Institute on Aging, National Institutes of Health, MedStar Harbor Hospital 5th floor, 3001 S. Hanover Street, Baltimore, MD 21225 USA
Ruin Moaddel
National Institute on Aging, National Institutes of Health, MedStar Harbor Hospital 5th floor, 3001 S. Hanover Street, Baltimore, MD 21225 USA
Julián Candia
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Eleanor M. Simonsick
National Institute on Aging, National Institutes of Health, MedStar Harbor Hospital 5th floor, 3001 S. Hanover Street, Baltimore, MD 21225 USA
Stefania Bandinelli
Azienda USL Toscana centro, Geriatric Unit, Florence, Italy
Luigi Ferrucci
National Institute on Aging, National Institutes of Health, MedStar Harbor Hospital 5th floor, 3001 S. Hanover Street, Baltimore, MD 21225 USA; Corresponding authors at: National Institute on Aging, National Institutes of Health, MedStar Harbor Hospital 5th floor, 3001 S. Hanover Street, Baltimore, MD 21225 USA.
Summary: Background: The pathophysiological mechanisms underlying the association between red blood cell distribution width (RDW) and all-cause mortality are unknown. We conducted a data-driven discovery investigation to identify plasma proteins that mediate the association between RDW and time to death in community-dwelling adults. Methods: At baseline, 962 adults (women, 54·4%; age range, 21–98 years) participated in the InCHIANTI, “Aging in the Chianti Area” study, and proteomics data were generated from their plasma specimens. Of these, 623 participants had proteomics data available at the 9-year follow-up. For each visit, a total of 1301 plasma proteins were measured using SOMAscan technology. Complete data on vital status were available up to the 15-year follow-up period. Protein-specific exponential distribution accelerated failure time, and linear regression analyses adjusted for possible covariates were used for mortality and mediation analyses, respectively (survival data analysis). Findings: Baseline values of EGFR, GHR, NTRK3, SOD2, KLRF1, THBS2, TIMP1, IGFBP2, C9, APOB, and LRP1B mediated the association between baseline RDW and all-cause mortality. Changes in IGFBP2 and C7 over 9 years mediated the association between changes in RDW and 6-year all-cause mortality. Interpretation: Cellular senescence may contribute to the association between RDW and mortality. Funding: This study was funded by grants from the National Institutes of Health (NIH) and the National Institute on Aging (NIA) contract and was supported by the Intramural Research Program of the NIA, NIH. The InCHIANTI study was supported as a ‘targeted project’ by the Italian Ministry of Health and in part by the U.S. NIA.
