Age at Menopause, Leukocyte Telomere Length, and Coronary Artery Disease in Postmenopausal Women

Art Schuermans; Tetsushi Nakao; Md Mesbah Uddin; Whitney Hornsby; Shriie Ganesh; Aladdin H Shadyab; Simin Liu; Bernhard Haring; Chrisandra L Shufelt; Margaret A Taub; Rasika A Mathias; Charles Kooperberg; Alexander P Reiner; Alexander G Bick; JoAnn E Manson; Pradeep Natarajan; Michael C Honigberg

doi:10.1161/CIRCRESAHA.123.322984

Age at Menopause, Leukocyte Telomere Length, and Coronary Artery Disease in Postmenopausal Women

Circ Res. 2023 Aug 18;133(5):376-386. doi: 10.1161/CIRCRESAHA.123.322984. Epub 2023 Jul 25.

Authors

Art Schuermans^{1

2

3}, Tetsushi Nakao^{1

2

4}, Md Mesbah Uddin^{1

2}, Whitney Hornsby^{1

2}, Shriie Ganesh^{1

2}, Aladdin H Shadyab⁵, Simin Liu⁶, Bernhard Haring^{7

8}, Chrisandra L Shufelt⁹, Margaret A Taub¹⁰, Rasika A Mathias¹¹, Charles Kooperberg¹², Alexander P Reiner¹², Alexander G Bick¹³, JoAnn E Manson^{14

15}, Pradeep Natarajan^{1

2

16}, Michael C Honigberg^{1

2

16}

Affiliations

¹ Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (A.S., T.N., M.M.U., W.H., S.G., P.N., M.C.H.).
² Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital (A.S., T.N., M.M.U., W.H., S.G., P.N., M.C.H.), Harvard Medical School, Boston.
³ Faculty of Medicine, KU Leuven, Belgium (A.S.).
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (T.N.).
⁵ Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla (A.H.S.).
⁶ Department of Epidemiology and Brown Center for Global Cardiometabolic Health, Brown University, Providence, RI (S.L.).
⁷ Department of Medicine III, Saarland University Medical Center, Homburg, Germany (B.H.).
⁸ Department of Medicine I, University of Wuerzburg, Bavaria, Germany (B.H.).
⁹ Division of Internal Medicine, Women's Health Research Center, Mayo Clinic, Jacksonville, FL (C.L.S.).
¹⁰ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD (M.A.T.).
¹¹ GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (R.A.M.).
¹² Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA (C.K., A.P.R.).
¹³ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (A.G.B.).
¹⁴ Division of Preventive Medicine, Brigham and Women's Hospital (J.E.M.), Harvard Medical School, Boston.
¹⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (J.E.M.).
¹⁶ Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA (P.N., M.C.H.).

Abstract

Background: Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease.

Methods: Participants from the UK Biobank and Women's Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause and LTL with incident coronary artery disease.

Results: This study included 130 254 postmenopausal women (UK Biobank: n=122 224; Women's Health Initiative: n=8030), of whom 4809 (3.7%) had experienced menopause before age 40. Earlier menopause was associated with shorter LTL (meta-analyzed ß=-0.02 SD/5 years of earlier menopause [95% CI, -0.02 to -0.01]; P=7.2×10^-12). This association was stronger and significant in both cohorts for women with natural/spontaneous menopause (meta-analyzed ß=-0.04 SD/5 years of earlier menopause [95% CI, -0.04 to -0.03]; P<2.2×10^-16) and was independent of hormone therapy use. Mendelian randomization supported a causal association of shorter genetically predicted LTL with earlier age at natural menopause. LTL and age at menopause were independently associated with incident coronary artery disease, and mediation analyses indicated small but significant mediation effects of LTL in the association of menopausal age with coronary artery disease.

Conclusions: Earlier age at menopause is associated with shorter LTL, especially among women with natural menopause. Accelerated telomere shortening may contribute to the heightened cardiovascular risk associated with premature menopause.

Keywords: aging; cardiovascular disease; menopause; telomere; women.

Publication types

Research Support, U.S. Gov't, P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Coronary Artery Disease* / epidemiology
Coronary Artery Disease* / genetics
Female
Humans
Leukocytes
Menopause / genetics
Menopause, Premature*
Postmenopause / genetics
Telomere / genetics

Abstract

Publication types

MeSH terms

Grants and funding