Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a previously unrecognized, potent, age-related, and common risk factor for atherosclerosis. Somatic mutations in certain known leukemia driver genes give rise to clones of mutant cells in peripheral blood. The increased risk of developing hematologic malignancy does not, on its own, explain excess mortality in individuals with CHIP. Cardiovascular disease accounts for much of this gap. Experimental evidence supports the causality of certain CHIP mutations in accelerated atherosclerosis. CHIP due to mutations in different driver genes varies in their promotion of atherosclerotic events and in the region of augmented atherosclerotic involvement. For example, CHIP due to mutations in DNMT3a appears less atherogenic than CHIP that arises from TET2 or JAK2, forms of CHIP that incite inflammation. The recognition of certain CHIP mutations as promoters of atherosclerotic risk has opened new insights into understanding of the pathophysiology of this disease. The accentuated cardiovascular risk and involvement of distinct pathways of various forms of CHIP also inform novel approaches to allocation of targeted therapies, affording a step toward personalized medicine.
Ohad Oren, Aeron M. Small, Peter Libby
Therapy-related clonal hematopoiesis (t-CH) is defined as clonal hematopoiesis detected in individuals previously treated with chemotherapy and/or radiation therapy. With the increased use of genetic analysis in oncological care, the detection of t-CH among cancer patients is becoming increasingly common. t-CH arises through the selective bottleneck imposed by chemotherapies and potentially through direct mutagenesis from chemotherapies, resulting in a distinct mutational landscape enriched with mutations in DNA damage-response pathway genes such as TP53, PPM1D, and CHEK2. Emerging evidence sheds light on the mechanisms of t-CH development and potential strategies to mitigate its emergence. Due to its unique characteristics that predominantly affect cancer patients, t-CH has clinical implications distinct from those of CH in the general population. This Review discusses the potential mechanisms of t-CH development, its mutational landscape, mutant-drug relationships, and its clinical significance. We highlight the distinct nature of t-CH and call for intensified research in this field.
Koichi Takahashi, Daisuke Nakada, Margaret Goodell
Clonal hematopoiesis (CH), the expansion of hematopoietic stem cells and their progeny driven by somatic mutations in leukemia-associated genes, is a common phenomenon that rises in prevalence with advancing age to affect most people older than 70 years. CH remains subclinical in most carriers, but, in a minority, it progresses to a myeloid neoplasm, such as acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm. Over the last decade, advances in our understanding of CH, its molecular landscape, and the risks associated with different driver gene mutations have culminated in recent developments that allow for a more precise estimation of myeloid neoplasia risk in CH carriers. In turn, this is leading to the development of translational and clinical programs to intercept and prevent CH from developing into myeloid neoplasia. Here, we give an overview of the spectrum of CH driver mutations, what is known about their pathophysiology, and how this informs the risk of incident myeloid malignancy.
William G. Dunn, Matthew A. McLoughlin, George S. Vassiliou
Autoimmune diseases are a leading cause of disability worldwide. Most autoimmune diseases occur more often in women than men, with rheumatic autoimmune diseases being among those most highly expressed in women. Several key factors, identified mainly in animal models and cell culture experiments, are important in increasing autoimmune disease in females. These include sex hormones, immune genes including those found on the X chromosome, sex-specific epigenetic effects on genes by estrogen and the environment, and regulation of genes and messenger RNA by microRNAs found in extracellular vesicles. Evidence is also emerging that viruses as well as drugs or toxins that damage mitochondria may contribute to increased levels of autoantibodies against nuclear and mitochondrial antigens, which are common in many autoimmune diseases. The purpose of this Review is to summarize our current understanding of mechanisms that may determine sex differences in autoimmune disease.
DeLisa Fairweather, Danielle J. Beetler, Elizabeth J. McCabe, Scott M. Lieberman
Globally, the majority of people living with HIV are women or girls, but they have been a minority of participants in clinical trials and observational studies of HIV. Despite this underrepresentation, differences in the pathogenesis of HIV have been observed between men and women, with contributions from both gender- and sex-based factors. These include differences in the risk of HIV acquisition, in viral load set point and immune activation in responses to viremia, and differences in HIV reservoir maintenance. These differences obligate adequate study in both males and females in order to optimize treatments, but also provide a powerful leverage point for delineating the mechanisms of HIV pathogenesis. The shifts in exposure to sex steroid hormones across a lifespan introduce additional complexity, which again can be used to focus on either genetic or hormonal influences as the driver of an outcome. In this Review, we discuss consistent and reproducible differences by sex across the spectrum of HIV, from acquisition through pathogenesis, treatment, and cure, and explore potential mechanisms and gaps in knowledge.
Erin Mihealsick, Anna Word, Eileen P. Scully
Depression and multiple musculoskeletal disorders are overrepresented in women compared with men. Given that depression is a modifiable risk factor and improvement of depressive symptoms increases positive outcomes following orthopedic intervention, efforts to improve clinical recognition of depressive symptoms and increased action toward ameliorating depressive symptoms among orthopedic patients are positioned to reduce complications and positively affect patient-reported outcomes. Although psychosocial factors play a role in the manifestation and remittance of depression, it is also well appreciated that primary biochemical changes are capable of causing and perpetuating depression. Unique insight for novel treatments of depression may be facilitated by query of the bidirectional relationship between musculoskeletal health and depression. This Review aims to synthesize the diverse literature on sex, depression, and orthopedics and emphasize the potential for common underlying biological substrates. Given the overrepresentation of depression and musculoskeletal disorders among women, increased emphasis on the biological drivers of the co-occurrence of these disorders is positioned to improve women’s health.
Mackenzie Newman, Henry J. Donahue, Gretchen N. Neigh
Half of adults in the United States have hypertension as defined by clinical practice guidelines. Interestingly, women are generally more likely to be aware of their hypertension and have their blood pressure controlled with treatment compared with men, yet hypertension-related mortality is greater in women. This may reflect the fact that the female sex remains underrepresented in clinical and basic science studies investigating the effectiveness of therapies and the mechanisms controlling blood pressure. This Review provides an overview of the impact of the way hypertension research has explored sex as a biological variable (SABV). Emphasis is placed on epidemiological studies, hypertension clinical trials, the genetics of hypertension, sex differences in immunology and gut microbiota in hypertension, and the effect of sex on the central control of blood pressure. The goal is to offer historical perspective on SABV in hypertension, highlight recent studies that include SABV, and identify key gaps in SABV inclusion and questions that remain in the field. Through continued awareness campaigns and engagement/education at the level of funding agencies, individual investigators, and in the editorial peer review system, investigation of SABV in the field of hypertension research will ultimately lead to improved clinical outcomes.
Michael J. Ryan, John S. Clemmer, Roy O. Mathew, Jessica L. Faulkner, Erin B. Taylor, Justine M. Abais-Battad, Fiona Hollis, Jennifer C. Sullivan
Testosterone (T) and 17β-estradiol (E2) are produced in male and female humans and are potent metabolic regulators in both sexes. When E2 and T production stops or decreases during aging, metabolic dysfunction develops and promotes degenerative metabolic and vascular disease. Here, we discuss the shared benefits afforded by E2 and T for metabolic function human females and males. In females, E2 is central to bone and vascular health, subcutaneous adipose tissue distribution, skeletal muscle insulin sensitivity, antiinflammatory immune function, and mitochondrial health. However, T also plays a role in female skeletal, vascular, and metabolic health. In males, T’s conversion to E2 is fundamental to bone and vascular health, as well as prevention of excess visceral adiposity and the promotion of insulin sensitivity via activation of the estrogen receptors. However, T and its metabolite dihydrotestosterone also prevent excess visceral adiposity and promote skeletal muscle growth and insulin sensitivity via activation of the androgen receptor. In conclusion, T and E2 are produced in both sexes at sex-specific concentrations and provide similar and potent metabolic benefits. Optimizing levels of both hormones may be beneficial to protect patients from cardiometabolic disease and frailty during aging, which requires further study.
Franck Mauvais-Jarvis, Sarah H. Lindsey
Alcohol use disorder (AUD) is a prominent contributor to global morbidity and mortality. Its complex etiology involves genetics, epigenetics, and environmental factors. We review progress in understanding the genetics and epigenetics of AUD, summarizing the key findings. Advancements in technology over the decades have elevated research from early candidate gene studies to present-day genome-wide scans, unveiling numerous genetic and epigenetic risk factors for AUD. The latest GWAS on more than one million participants identified more than 100 genetic variants, and the largest epigenome-wide association studies (EWAS) in blood and brain samples have revealed tissue-specific epigenetic changes. Downstream analyses revealed enriched pathways, genetic correlations with other traits, transcriptome-wide association in brain tissues, and drug-gene interactions for AUD. We also discuss limitations and future directions, including increasing the power of GWAS and EWAS studies as well as expanding the diversity of populations included in these analyses. Larger samples, novel technologies, and analytic approaches are essential; these include whole-genome sequencing, multiomics, single-cell sequencing, spatial transcriptomics, deep-learning prediction of variant function, and integrated methods for disease risk prediction.
Hang Zhou, Joel Gelernter
Stress has long been associated with substance misuse and substance use disorders (SUDs). The past two decades have seen a surge in research aimed at understanding the underlying mechanisms driving this association. This Review introduces a multilevel “adaptive stress response” framework, encompassing a stress baseline, acute reaction, and recovery with return-to-homeostasis phase that occurs at varying response times and across domains of analysis. It also discusses evidence showing the disruption of this adaptive stress response in the context of chronic and repeated stressors, trauma, adverse social and drug-related environments, as well as with acute and chronic drug misuse and with drug withdrawal and abstinence sequelae. Subjective, cognitive, peripheral, and neurobiological disruptions in the adaptive stress response phases and their link to inflexible, maladaptive coping; increased craving; relapse risk; and maintenance of drug intake are also presented. Finally, the prevention and treatment implications of targeting this “stress pathophysiology of addiction” are discussed, along with specific aspects that may be targeted in intervention development to rescue stress-related alterations in drug motivation and to improve SUD treatment outcomes.
Rajita Sinha
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