Citations 2
Age at Menopause, Leukocyte Telomere Length, and Coronary Artery Disease in Postmenopausal Women
Schuermans, Art , Nakao, Tetsushi , Uddin, Md Mesbah , Hornsby, Whitney , Ganesh, Shriienidhie , Liu, Simin , Haring, Bernhard , Shufelt, Chrisandra , Taub, Margaret A. , Reiner, Alex P. , Bick, Alexander G. , Natarajan, Pradeep , Liu, Simin , Haring, Bernhard , Shufelt, Chrisandra L , Taub, Margaret A , Mathias, Rasika A , Kooperberg, Charles , Reiner, Alexander P , Bick, Alexander G , Manson, JoAnn E , Natarajan, Pradeep , Honigberg, Michael C , Uddin, Md M , Shadyab, Aladdin H , Mathias, Rasika A. , Kooperberg, Charles , Manson, JoAnn E. , Honigberg, Michael C.
Circulation Research | July 25, 2023 | Volume: 133 | Issue: 5 | Pages: 376-386
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.
Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential
Nakao, Tetsushi , Bick, Alexander G. , Taub, Margaret A. , Uddin, Md Mesbah , Niroula, Abhishek , Carty, Cara L. , Lane, John , Honigberg, Michael C. , Weinstock, Joshua S. , Pampana, Akhil , Griffin, Gabriel K. , Bhattacharya, Romit , Assimes, Themistocles L. , Emery, Leslie S. , Wong, Quenna , Broome, Jai , Laurie, Cecelia , Khan, Alyna , Smith, Albert V. , Blackwell, Thomas W. , Nelson, Christopher P. , Yoneda, Zachary T. , Peralta, Juan M. , Bowden, Donald W. , Irvin, Marguerite R. , Boorgula, Meher Preethi, Zhao, Wei , Yanek, Lisa R. , Roden, Dan M. , Reupena, Muagututi‘a Sefuiva , DeMeo, Dawn L. , Kelly, Shannon , Musani, Solomon K., Bis, Joshua C. , Lloyd‐Jones, Donald M. , Peyser, Patricia A. , Qiao, Dandi , Tiwari, Hemant K., Smith, Jennifer A. , Smith, Nicholas L. , Kelly, Tanika N. , Hidalgo, Bertha , Weeks, Daniel E. , Group, The Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA), Deka, Ranjan , Naseri, Take, Fuentes, Lisa de las , Raffield, Laura M. , Morrison, Alanna C. , Vries, Paul S. de , Shoemaker, M. Benjamin , Palmer, Nicholette D. , Barnes, Kathleen C. , Redline, Susan , Kardia, Sharon L.R., Becker, Lewis C. , Heckbert, Susan R. , He, Jiang , Post, Wendy S. , Arnett, Donna K. , McGarvey, Stephen T. , Chen, Yii‐Der Ida , Kaplan, Robert C. , Meyers, Deborah A. , Fornage, Myriam , Boerwinkle, Eric , Loos, Ruth J. F. , Silverman, Edwin K. , Danesh, John , Samani, Nilesh J. , Jaiswal, Siddhartha , Ebert, Benjamin L. , Reiner, Alex P. , Mathias, Rasika A. , Do, Ron , Natarajan, Pradeep , Zhao, Wei , Zekavat, Seyedeh M , Uddin, Md M , Niroula, Abhishek , Lane, John , Honigberg, Michael C , Weinstock, Joshua S , Pampana, Akhil , Griffin, Gabriel K , Clarke, Shoa L , Bhattacharya, Romit , Assimes, Themistocles L , Emery, Leslie S , Stilp, Adrienne M , Wong, Quenna , Broome, Jai , Khan, Alyna T , Smith, Albert V , Codd, Veryan , Nelson, Christopher P , Yoneda, Zachary T , Peralta, Juan M , Yanek, Lisa R , Wiggins, Kerri L , Gu, C Charles , Peloso, Gina M , Roden, Dan M. , Hwu, Chii-Min , North, Kari E. , Bis, Joshua C , Lloyd-Jones, Donald M , Johnsen, Jill M , Preuss, Michael , Tracy, Russell P , Peyser, Patricia A , Qiao, Dandi , Curran, Joanne E , Freedman, Barry I , Chavan, Sameer , Smith, Jennifer A , Kelly, Tanika N , Hidalgo, Bertha , Weeks, Daniel E , Hawley, Nicola L , Minster, Ryan L , de las Fuentes, Lisa , Raffield, Laura M , Ballantyne, Christie M , Kenny, Eimear E , Rich, Stephen S , Whitsel, Eric A , Cho, Michael H , Palmer, Nicholette D , Mitchell, Braxton D , Shuldiner, Alan R , Redline, Susan , Heckbert, Susan R , He, Jiang , Post, Wendy , Arnett, Donna K , Vasan, Ramachandran S , Weiss, Scott T , McGarvey, Stephen T , Custer, Brian S , Correa, Adolfo , Manson, JoAnn E , Konkle, Barbara A , Loos, Ruth J F , Rotter, Jerome I , Silverman, Edwin K , Kooperberg, Charles , Samani, Nilesh J , Jaiswal, Siddhartha , Libby, Peter , Ellinor, Patrick T , Pankratz, Nathan , Ebert, Benjamin L , Mathias, Rasika A , Do, Ron , Natarajan, Pradeep , Morrison, Alanna C , Bick, Alexander G , Gibson, Christopher James , Clarke, Shoa L. , Codd, Veryan , Wiggins, Kerri L. , Hixson, James E. , Peloso, Gina M. , Tracy, Russell P. , Desai, Pinkal , Curran, Joanne E. , Freedman, Barry I. , Cupples, L. Adrienne , Group, The Samoan Obesity, Lifestyle and Genetic Adaptations Study (OLaGA), Naseri, Take K. , Ballantyne, Christie M. , Rich, Stephen S. , Cho, Michael H. , Pace, Betty S. , Blangero, John , Mitchell, Braxton D. , Shuldiner, Alan R. , Abecasis, Gonçalo R. , Vasan, Ramachandran S. , Darbar, Dawood , Weiss, Scott T. , Andrade, Mariza de , Custer, Brian , Psaty, Bruce M. , Manson, JoAnn E. , Konkle, Barbara A. , Rotter, Jerome I. , Kooperberg, Charles , Libby, Peter , Ellinor, Patrick T. , Pankratz, Nathan
Science Advances | April 6, 2022 | Volume: 8 | Issue: 14 | Pages: No page available
Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( n = 63,302) and UK Biobank ( n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.