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.
Genomic and phenomic landscape of clonal hematopoiesis in over a million ancestrally diverse participants
Uddin, Md Mesbah , Weinstock, Joshua S. , Niroula, Abhishek , Vlasschaert, Caitlyn , Koyama, Satoshi , Nakao, Tetsushi , Urbut, Sarah , Paruchuri, Kaavya , Silver, Alexander J. , Mack, Taralynn , Wong, Megan , Bhattacharya, Romit , Jorshery, Saman Doroodgar , Raddatz, Michael A. , Hornsby, Whitney , Kresge, Hailey A. , Cho, Kelly , Sun, Yan V. , Pyarajan, Saiju , Chen, Yii‐Der Ida , Sheu, Wayne H-H , Hung, Yi‐Jen , Hidalgo, Bertha , Fornage, Myriam , Kaplan, Robert C., Williams, L. Keoki , Province, Mike , Kardia, Sharon, Peyser, Patricia A., Yanek, Lisa R. , Becker, Lewis C. , Meyers, Deborah A. , Naseri, Take, Barnes, Kathleen C. , Redline, S S, Schwartz, D A, Shoemaker, M. Benjamin , Palmer, Nicholette D., Bowden, Donald W., Kumar, Rajesh, Nj, Smith, Floyd, James, Tracy, Russell, Bis, Joshua C. , SS, Rich, Boerwinkle, Eric, Wang, Zhe, Silverman, Edwin K. , Auer, Paul L. , Reiner, Alexander P. , Ebert, Benjamin L. , Natarajan, Pradeep , Uddin, Md M , Niroula, Abhishek , Weinstock, Joshua S , Bhattacharya, Romit , Ebert, Benjamin L , Natarajan, Pradeep , Yu, Zhi , Zekavat, Seyedeh M , Truong, Buu Minh Thanh , Haidermota, Sara , Honigberg, Michael C. , Zhang, Martin Jinye , Dron, Jacqueline S. , Heimlich, Jonathan Brett , Sankaran, Vijay G. , Griffin, Gabriel K. , Gibson, Christopher James , Wilson, Peter W.F. , Genovese, Giulio , Xu, Yaomin , Savona, Michael R. , Raffield, Laura M. , Arnett, Donna K. , Konkle, Barbara A. , Peyser, Patricia A. , Smith, Jennifer A. , Mathias, Rasika A. , Andrade, Mariza de , Darbar, Dawood , He, Jiang , Blangero, John , Weiss, Scott T. , Custer, Brian , Minster, Ryan L , Viali, Satupaitea , Mitchell, Braxton D. , Palmer, Nicholette D , Freedman, Barry I. , Bowden, Donald W. , Albert, Christine M. , Smith, Nicholas, Tracy, Russell P. , Psaty, Bruce M. , Taylor, Kent D. , Rotter, Jerome I. , Boerwinkle, Eric , Vasan, Ramachandran S. , Lubitz, Steven A. , Ellinor, Patrick T. , Loos, Ruth J. F. , Yun, Jeong H. , Cho, Michael H. , Abecasis, Gonçalo R. , Kooperberg, Charles , Reiner, Alex P. , Jaiswal, Siddhartha , Bick, Alexander G.
No container title available | July 31, 2022 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract With aging, somatic mutations in hematopoietic stem and progenitor cells (HSPC) can give rise to clonal hematopoiesis of indeterminate potential (CHIP), a premalignant state associated with diverse age-related diseases. Here we report the largest multi-ancestry genome-wide analysis of CHIP to date (N = 1,018,305), including individuals of African (N = 85,978), Admixed American (N = 191,371), East Asian (N = 13,532), European (N = 694,015), and South Asian (N = 13,193) ancestry. Multi-ancestry meta-analyses identified 72 genome-wide significant loci, including 44 novel associations implicating genes such as AFF1 , ATF7IP , ATP8B4 , BCL2 , CEBPA , CYRIA , DNM2 , ELF1 , NKX2-3 , PIK3CB , PRDM16 , RPN1 , TERC , and TRIM4 . Notably, variants at MECOM and PHF20L1 showed opposite allelic effects between DNMT3A - and non- DNMT3A -driven CHIP, highlighting driver-specific germline influences. Implicated loci converge on pathways regulating telomere maintenance, cell-cycle control, hematopoietic transcription, DNA damage response and immune signaling. These findings support a model in which germline variation both expands the HSPC pool and biases clonal selection in a driver-dependent manner, providing a mechanistic basis for inter-individual heterogeneity in CHIP. Phenome-wide association analyses further linked CHIP to hematologic, neoplastic, and circulatory traits, with enrichment across hematopoietic and non-hematopoietic cell types. Together, this work expands the genomic and phenomic landscape of CHIP and reveals germline–somatic interactions that shape clonal evolution during aging.