titin

THURSDAY, June 27, 2024 -- Rare predicted loss-of-function (pLOF) variants and a polygenic risk score (PRS) are associated with increased atrial fibrillation (AF) risk, according to a study published online June 26 in JAMA Cardiology . Oliver B. Vad, M.D., from Copenhagen University Hospital–Rigshospitalet in Denmark, and colleagues examined rare pLOF variants associated with AF and elucidated their role in risk of AF, cardiomyopathy, and heart failure in combination with a PRS in a genetic association and nested case-control study. Data were included for 403,990 individuals from the U.K. Biobank (median age, 58 years). Over a median follow-up of 13.3 years, 24,447 participants were diagnosed with incident AF. The researchers identified associations for rare pLOF variants in six genes ( TTN , RPL3L , PKP2 , CTNNA3 , KDM5B , and C10orf71 ) with AF. In an external cohort, TTN , RPL3L , PKP2 , CTNNA3 , and KDM5B were replicated. Rare pLOF variants combined with high PRS conferred an odds ratio of 7.08 for AF. PRS carriers also had a considerable 10-year risk of AF (16 and 24 percent in women and men older than 60 years, respectively). There was an association seen for rare pLOF variants with increased risk of cardiomyopathy before and subsequent to AF (hazard ratios, 3.13 and 2.98, respectively). "These findings may contribute to possible future genetic risk stratification and improved clinical practice," the authors write. Several authors disclosed ties to the biopharmaceutical and medical device industries. Abstract/Full Text Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

Rich longitudinal clinical and genomic data through a network of diverse U.S. health systems. SAN MATEO, Calif.--(BUSINESS WIRE)-- Helix the leading population genomics company, is launching new clinico-genomic datasets to enable life science companies to drive precision medicine drug discovery and development. Built through Helix’s extensive health system partnerships, these population-scale cohorts consist of full longitudinal clinical and genomic records that span multiple therapeutic areas including Cardiovascular, Immunology & Inflammation, Metabolic conditions and more. “Life science researchers can utilize Helix’s diverse clinico-genomic cohorts to better understand genetic factors associated with disease progression and clinical outcomes, as well as validating therapeutic candidates of interest,” said Hylton Kalvaria, Chief Commercial Officer of Helix. “Organizations can also rapidly identify targeted patient populations based on specific genetic and phenotypic criteria to optimize discovery and clinical development.” Helix’s precision cohorts consist of longitudinal clinical data combined with the company’s proprietary Exome+® sequencing data for over 125,000 patients across the US, all of whom have been consented for recontact. With regular data refreshes, partners receive access to structured EHR fields including clinical diagnosis, procedures, lab results, and prescriptions. As an illustrative example, Helix’s new Cardiometabolic cohort consists of over 50k patients with major Cardiovascular Disease diagnoses, patient vitals and demographics, and key lab results including triglycerides, HbA1c and cholesterol. All of these fields are linked to exome sequencing data with deep and uniform coverage of TTN, MYH7, and hundreds of other Cardiovascular genes. “As the number of precision therapies in development continues to rapidly expand, clinico-genomic data provide incredible opportunities to develop targeted therapeutics with better safety and efficacy pro ” said James Lu, M.D., Ph.D., CEO and co-founder of Helix. “Using real-world data and genomics, precision medicine has the potential to revolutionize drug development and bring us closer to a future of personalized, tailored treatments.” About Helix Helix is the leading population genomics company, enabling health systems, life sciences organizations and payers to accelerate the integration of genomic data into patient care and therapeutic development. Learn more at .

Uncertainty surrounding how truncated titin proteins (TTNtvs) cause dilated cardiomyopathy (DCM) and peripartum cardiomyopathy (PPCM) led to investigations that could better inform therapies for these conditions. Advancements in the study of two rare heart conditions -- peripartum cardiomyopathy (PPCM), and dilated cardiomyopathy (DCM) -- contributed by researchers at the Perelman School of Medicine at the University of Pennsylvania may serve as critical guides in future work toward developing therapies for the conditions. The lab of Zoltan Arany, MD, PhD, the Samuel Bellet Professor of Cardiology and a professor of Cell and Developmental Biology, published their findings this month in the New England Journal of Medicine (NEJM), adding to separate research they recently published in the Journal of Clinical Investigation (JCI). PPCM is a severe cardiac condition affecting approximately 1 in 1,000 pregnant or recently pregnant women, characterized by the weakening of the heart muscle, leading to reduced cardiac function. Certain factors increase the risk of developing PPCM, including advanced maternal age, multiple gestations (twins or more), anemia, and hypertensive disorders of pregnancy. Black women in the United States are at a much higher risk compared to White women, for reasons that remain unclear. Treatment for PPCM generally involves standard heart failure management strategies, including medications like diuretics, beta-blockers, and ACE inhibitors. In severe cases, advanced therapies such as LVADs or heart transplantation may be considered. Unlike PPCM, DCM can occur at any age and is not specifically related to pregnancy and affects about 1 in 100 people. Risk factors for DCM can include a family history of heart disease, certain infections, exposure to toxins, and other underlying heart conditions. The recent JCI study focused on the role of genetic variants in the TTN gene, which encodes for a crucial protein called titin. Titin acts like a spring, playing a vital role in the assembly and regulation of heart muscle contraction. The study sheds light on how specific genetic variants, known as truncating variants (TTNtvs), in the TTN gene may contribute to DCM. Arany and his team developed a patient-specific antibody to detect these TTNtvs in human heart tissue. Using this novel approach, they found that TTNtvs are present in hearts affected by DCM, indicating a potential link between these genetic variants and the development of the disease. The study also revealed that the truncated titin proteins associated with TTNtvs integrate into the heart's muscle structure. This suggests that these genetic variants may impact the sarcomere, the basic unit of heart muscle, influencing its structure and function. Meanwhile, the recent article in the NEJM consolidates the current state of knowledge about PPCM, while providing a roadmap for navigating the complexities of the disease. Past research from the Arany lab has highlighted the racial disparities in PPCM, with Black women in the US being four times more likely than White women to develop the disease. The NEJM article emphasizes the critical need for early diagnosis and the development of effective management strategies, given that PPCM is now a leading cause of maternal mortality in many parts of the world. "There is a great need for further research into long-term outcomes, racial disparities, and the underlying mechanisms of PPCM," said Arany. "We hope our recent research signals a call to action for the medical community to address this critical issue affecting young women, their families, and newborns." There is a profound lack of research in peripartum cardiomyopathy (PPCM), which limits expert's ability to find the best way to treat, and ultimately prevent it. In order to make important discoveries, doctors at the Perelman School of Medicine created PPCM-R, the first patient-focused registry about PPCM. Among the goals of the PPCM-R is to create a database of PPCM survivor medical records driven by patients, and to answer important research questions and ultimately prevent PPCM. The work was supported by grants from the National Heart, Lung, and Blood Institute (HL152446, HL126797, HL149891), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-53461-12), the Children's Hospital of Philadelphia Frontier Program, Foundation Leducq Research Grant no. 20CVD01, and by the Center for Engineering Mechanobiology through a grant from the National Science Foundation's Science and Technology program (15-48571).