Connors-BRI Symposium

Incorporating Sex as Biologic Variable to Advance Health

May 24, 2021 | 3-5PM

Virtual Event

Amélie Vromman, PhD

Brigham and Women’s Hospital
Cardiovascular Medicine


Clonal hematopoiesis of indeterminate potential (CHIP) describes somatic mutations of bone marrow derived blood cells in the absence of overt hematological disease.

CHIP correlates with aging and atherosclerotic cardiovascular diseases in humans. Tet2 mutations, common in CHIP, augment atherosclerosis. Tet2-deficient macrophages over-express Interleukin-(IL)1β mRNA in response to LDL. IL-1β neutralization reduces recurrent events in patients post myocardial infarction with residual inflammatory risk.

We previously showed that IL-1β neutralization reduces evolution of established mouse atherosclerosis. This study tested the hypothesis that IL-1β neutralization reduces accelerated atherosclerosis caused by Tet2 deficiency in hematopoietic cells.
To consider sex as a biological variable, we performed our experiments using female and male mice. We transplanted lethally irradiated LDL-R-/- atherosclerotic prone mice with either Tet2+/+ or Tet2-/- bone marrow cells. Chimeric mice consumed a western diet and received a selective anti-mouse IL-1β monoclonal antibody or isotype-matched control. After nine weeks of treatment, we analyzed atherosclerotic lesions morphologically and by single cell mRNA-sequencing analysis of the dissociated aortic arch.
IL-1β neutralization reduced accelerated atherosclerosis associated with myeloid Tet2 deficiency in female but not in male mice. Single cell mRNA analysis of aortic macrophage subpopulations revealed a higher pro-inflammatory profile of gene expression in female than in male chimeric mice. Anti-IL-1β treatment reversed this different pattern of gene expression yielding mechanistic insights about sex differences. Our results demonstrated that myeloid Tet2 deficiency leads to a greater pro-inflammatory gene expression profile in macrophages female mice in contrast to male mice. This heightened inflammatory status promotes responsiveness to IL-1β inhibition in female chimeric mice and leads to a decrease of atherogenesis.


3PM – Welcome Remarks
3:05PM – Keynote Address
3:45PM – Featured Short Talks
4:20PM – Lightning Talks
4:50PM – Closing Remarks

Keynote Speaker

Janine Austin Clayton, MD

Janine Austin Clayton, M.D., Associate Director for Research on Women’s Health and Director of the Office of Research on Women’s Health (ORWH) at the National Institutes of Health (NIH), is the architect of the NIH policy requiring scientists to consider sex as a biological variable across the research spectrum. This policy is part of NIH’s initiative to enhance reproducibility through rigor and transparency. As co-chair of the NIH Working Group on Women in Biomedical Careers with NIH Director Dr. Francis Collins, Dr. Clayton also leads NIH’s efforts to advance women in science careers.

Prior to joining the ORWH, Dr. Clayton was the Deputy Clinical Director of the National Eye Institute (NEI) for seven years. A board-certified ophthalmologist, Dr. Clayton’s research interests include autoimmune ocular diseases and the role of sex and gender in health and disease. She is the author of more than 120 scientific publications, journal articles, and book chapters.
Dr. Clayton, a native Washingtonian, received her undergraduate degree with honors from Johns Hopkins University and her medical degree from Howard University College of Medicine. She completed a residency in ophthalmology at the Medical College of Virginia. Dr. Clayton completed fellowship training in cornea and external disease at the Wilmer Eye Institute at Johns Hopkins Hospital and in uveitis and ocular immunology at NEI.

Dr. Clayton has received numerous awards, including the Senior Achievement Award from the Board of Trustees of the American Academy of Ophthalmology in 2008 and the European Uveitis Patient Interest Association Clinical Uveitis Research Award in 2010. She was selected as a 2010 Silver Fellow by the Association for Research in Vision and Ophthalmology. In 2015, she was awarded the American Medical Women’s Association Lila A. Wallis Women’s Health Award and the Wenger Award for Excellence in Public Service. Dr. Clayton was granted the Bernadine Healy Award for Visionary Leadership in Women’s Health in 2016. She was also selected as an honoree for the Woman’s Day Red Dress Awards and the American Medical Association’s Dr. Nathan Davis Awards for Outstanding Government Service in 2017.