Multiomics and Systematic Analyses Reveal the Roles of Hemoglobin and the HIF‐1 Pathway in Polycystic Ovary Syndrome DOI Creative Commons
Guiquan Wang,

Weian Mao,

Yurong Zhang

и другие.

Advanced Science, Год журнала: 2025, Номер unknown

Опубликована: Фев. 14, 2025

Polycystic ovary syndrome (PCOS) affects reproductive and cardiometabolic health, yet its pathogenesis remains unclear. Emerging evidence links hemoglobin levels to metabolic disorders, suggesting a potential role in PCOS development. Here, we integrated large-scale cohort study, Mendelian randomization (A genetic tool infer causal relationships), bioinformatics analyses, vitro experiments investigate the relationship between PCOS. In of 20 602 women, each 10 g L-1 elevation is associated with 22% higher odds (adjusted ratio: 1.22, 95% confidence interval: 1.15-1.29, P < 0.001) manifestations, particularly hyperandrogenism. analysis confirms that are increased risk elevated testosterone levels. The hypoxia-inducible factor 1 (HIF-1) pathway enriched, identifying three testosterone-associated genes (nuclear kappa B (NFKB1), insulin receptor (INSR), protein kinase C alpha. Colocalization druggability supports shared regions confirmed these as druggable targets. Upregulation NFKB1 INSR both blood ovarian granulosa cells patients. findings demonstrate higher-end normal risk, potentially through mechanism elevating involving HIF-1 pathway.

Язык: Английский

Refining the impact of genetic evidence on clinical success DOI Creative Commons
Eric Vallabh Minikel, Jeffery L. Painter,

Coco Chengliang Dong

и другие.

Nature, Год журнала: 2024, Номер 629(8012), С. 624 - 629

Опубликована: Апрель 17, 2024

Abstract The cost of drug discovery and development is driven primarily by failure 1 , with only about 10% clinical programmes eventually receiving approval 2–4 . We previously estimated that human genetic evidence doubles the success rate from to 5 In this study we leverage growth in over past decade better understand characteristics distinguish failure. estimate probability for mechanisms support 2.6 times greater than those without. This relative varies among therapy areas phases, improves increasing confidence causal gene, but largely unaffected effect size, minor allele frequency or year discovery. These results indicate are far reaching peak insights aid targets more effective drugs.

Язык: Английский

Процитировано

88
RNAi-based drug design: considerations and future directions DOI
Qi Tang, Anastasia Khvorova

Nature Reviews Drug Discovery, Год журнала: 2024, Номер 23(5), С. 341 - 364

Опубликована: Апрель 3, 2024

Язык: Английский

Процитировано

71
Genetic and molecular architecture of complex traits DOI Creative Commons
Tuuli Lappalainen, Yang Li, Sohini Ramachandran

и другие.

Cell, Год журнала: 2024, Номер 187(5), С. 1059 - 1075

Опубликована: Фев. 1, 2024

Язык: Английский

Процитировано

21
A DNA language model based on multispecies alignment predicts the effects of genome-wide variants DOI
Gonzalo Benegas,

Carlos Albors,

Alan J. Aw

и другие.

Nature Biotechnology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 2, 2025

Язык: Английский

Процитировано

5
Large-scale multi-omics identifies drug targets for heart failure with reduced and preserved ejection fraction DOI
Danielle Rasooly, Claudia Giambartolomei, Gina M. Peloso

и другие.

Nature Cardiovascular Research, Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

Язык: Английский

Процитировано

2
Refining the impact of genetic evidence on clinical success DOI Creative Commons
Eric Vallabh Minikel, Jeffery L. Painter,

Coco Chengliang Dong

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июнь 29, 2023

Abstract The cost of drug discovery and development is driven primarily by failure, with just ∼10% clinical programs eventually receiving approval. We previously estimated that human genetic evidence doubles the success rate from to In this study we leverage growth in over past decade better understand characteristics distinguish failure. estimate probability for mechanisms support 2.6 times greater than those without. This relative varies among therapy areas phases, improves increasing confidence causal gene, but largely unaffected effect size, minor allele frequency, or year discovery. These results suggest are far reaching peak insights aid targets more effective drugs.

Язык: Английский

Процитировано

23
Genetic factors associated with reasons for clinical trial stoppage DOI Creative Commons
Olesya Razuvayevskaya,

Irene Lopez,

Ian Dunham

и другие.

Nature Genetics, Год журнала: 2024, Номер 56(9), С. 1862 - 1867

Опубликована: Июль 29, 2024

Many drug discovery projects are started but few progress fully through clinical trials to approval. Previous work has shown that human genetics support for the therapeutic hypothesis increases chance of trial progression. Here, we applied natural language processing classify free-text reasons 28,561 stopped before their endpoints were met. We then evaluated these classes in light underlying evidence and target properties. found more likely stop because a lack efficacy absence strong genetic from populations or genetically modified animal models. Furthermore, certain safety if gene is highly constrained broadly expressed across tissues. These results growing use evaluate targets programs.

Язык: Английский

Процитировано

10
Drug-target Mendelian randomization analysis supports lowering plasma ANGPTL3, ANGPTL4, and APOC3 levels as strategies for reducing cardiovascular disease risk DOI Creative Commons
Fredrik Landfors, Peter Henneman, Elin Chorell

и другие.

European Heart Journal Open, Год журнала: 2024, Номер 4(3)

Опубликована: Апрель 30, 2024

Abstract Aims APOC3, ANGPTL3, and ANGPTL4 are circulating proteins that actively pursued as pharmacological targets to treat dyslipidaemia reduce the risk of atherosclerotic cardiovascular disease. Here, we used human genetic data compare predicted therapeutic adverse effects inactivation. Methods results We conducted drug-target Mendelian randomization analyses using variants in proximity genes associated with protein levels drug targets. obtained exposure outcome from large-scale genome-wide association studies generalized least squares correct for linkage disequilibrium-related correlation. evaluated five primary cardiometabolic endpoints screened potential side across 694 disease-related endpoints, 43 clinical laboratory tests, 11 internal organ MRI measurements. Genetically lowering reduced odds coronary artery disease (CAD) [odds ratio, 0.57 per s.d. (95% CI 0.47–0.70)] Type 2 diabetes (T2D) 0.73 0.57–0.94)]. APOC3 also CAD 0.90 0.82–0.99)]. lowered ANGPTL3 via common were not CAD. However, meta-analysis protein-truncating revealed inactivation protected against (odds 0.71 allele [95%CI, 0.58–0.85]). Analysis ANGPTL4, did identify important safety concerns. Conclusion Human evidence suggests therapies aimed at reducing may T2D.

Язык: Английский

Процитировано

8
Pharmacological treatment for metabolic dysfunction–associated steatotic liver disease and related disorders: Current and emerging therapeutic options DOI Creative Commons
Xiang Zhang, Harry Cheuk-Hay Lau, Jun Yu

и другие.

Pharmacological Reviews, Год журнала: 2025, Номер 77(2), С. 100018 - 100018

Опубликована: Янв. 7, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as nonalcoholic fatty disease) is a chronic affecting over billion individuals worldwide. MASLD can gradually develop into more severe pathologies, including metabolic steatohepatitis (MASH), cirrhosis, and malignancy. Notably, although being global health problem, there are very limited therapeutic options against its related diseases. While thyroid hormone receptor agonist (resmetirom) recently approved for MASH treatment, other efforts to control these diseases remain unsatisfactory. Given the projected rise in incidence, it urgent novel effective strategies prevalent In this article, pathogenic mechanisms of MASH, insulin resistance, dysregulated nuclear signaling, genetic risk factors (eg, patatin-like phospholipase domain-containing 3 hydroxysteroid 17-β dehydrogenase-13), introduced. Various interventions then explored, medication (resmetirom), drugs that currently clinical trials glucagon-like peptide 1 agonist, fibroblast growth factor 21 analog, PPAR agonist), those failed previous obeticholic acid stearoyl-CoA desaturase antagonist). Moreover, given role gut microbes increasingly acknowledged, alterations microbiota microbial development elucidated. Therapeutic approaches target dietary intervention probiotics) further explored. With better understanding multifaceted mechanisms, innovative therapeutics root causes greatly facilitated. The possibility alleviating achieving patient outcomes within reach. SIGNIFICANCE STATEMENT: (MASLD) most common worldwide, progress steatohepatitis, cancer. Better has facilitated strategies. increasing evidence illustrated crucial pathogenesis It may be clinically feasible alleviate future.

Язык: Английский

Процитировано

1
Discovery of drug targets for heart failure with preserved and reduced ejection fraction DOI
Scott C. Ritchie

Nature Cardiovascular Research, Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

Язык: Английский

Процитировано

1