Latest news with #geneticvariant
Medscape
2 days ago
- Health
- Medscape
Dog Exposure Affects Genetic Risk in Eczema, Study Finds
Children with a genetic variant linked to atopic eczema (rs10214237) appeared less likely to develop the condition if they were exposed to dogs in their early years, according to a large European study. METHODOLOGY: Researchers analyzed 16 European cohorts (n = 25,339) and replicated findings in 10 more (n = 254,532). They tested for an interaction between 24 atopic eczema-associated genetic loci and 18 early-life environmental exposures. In vitro experiments assessed IL-7R expression in keratinocytes of known rs10214237 genotype after exposure to dog allergen using cells from multiple donors. TAKEAWAY: The discovery analysis revealed 14 significant interactions ( P < .05 for all) between at least one gene variant for eczema and seven environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking, and washing practices). < .05 for all) between at least one gene variant for eczema and seven environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking, and washing practices). The interaction between dog exposure and rs10214237 was confirmed in the replication analysis (odds ratio [OR], 0.91; P = .025). = .025). The T allele of rs10214237 increased the risk for atopic eczema only in individuals not exposed to dogs (OR, 1.14; 95% CI, 1.08-1.22) but not in those with dog exposure (OR, 0.99; 95% CI, 0.93-1.05). Keratinocytes with the T:T genotype demonstrated higher IL-7R mRNA expression than those with the C:C genotype. mRNA expression than those with the C:C genotype. Dog allergen exposure downregulated IL-33 and TSLP but upregulated CXCL8 , CSF2 , CCL2 , and TNF , suggesting enhanced IL-10 signaling, which plays a suppressive role in atopic eczema. IN PRACTICE: 'We know that genetic make-up affects a child's risk of developing eczema and previous studies have shown that owning a pet dog may be protective, but this is the first study to show how this may occur at a molecular level,' study author Sara J. Brown, MD, PhD, of the Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland, said in a press release from Wiley, the publisher of Allergy . 'More work is needed, but our findings mean we have a chance to intervene in the rise of allergic disease, to protect future generations.' SOURCE: The study was led by Marie Standl, Institute of Epidemiology, Helmholtz Zentrum München — German Research Center for Environmental Health, Neuherberg, Germany, and was published online on June 4 in Allergy . LIMITATIONS: Genome-wide interaction analysis was not conducted. Replication samples sizes were not powered for some interactions. Detailed data on environmental factors were not available. The inclusion of predominantly White population may limit generalizability of findings. DISCLOSURES: The study received funding from the Innovative Medicines Initiative 2 Joint Undertaking, which was supported by the European Union's Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations. Many authors reported receiving research funding, honoraria, grants, and compensations for lectures and consulting from various organizations and pharmaceutical companies, including Wellcome Trust, UK Research and Innovation, Medical Research Council, Unilever, Pfizer, and AbbVie.
The Independent
24-05-2025
- Health
- The Independent
Sperm donor with cancer-causing gene passes on disease to 10 children
A sperm donor who has been used to conceive at least 67 children across Europe had a rare cancer -causing mutation, with 10 of the children developing the disease. Twenty-three of the children, conceived between 2008 and 2015 across eight countries, have now been found to carry the variant, while some have been diagnosed with cancers such as leukaemia and non-Hodgkin lymphoma. The case has raised concerns about the lack of internationally agreed limits on the use of a single sperm donor, and the difficulty in tracing a large number of families to inform them of a serious medical issue. The news was uncovered after two separate families contacted their fertility clinics becaues their children had developed cancers that were linked to a genetic variant called TP53. An analysis by the European Sperm Bank, who supplied the sperm, confirmed that the variant was present but was not known to be linked to cancer at the time of donation in 2008. Dr Edwige Kasper, a biologist at Rouen university hospital in France, said: 'We need to have a European limit on the number of births or families for a single donor. 'We can't do whole-genome sequencing for all sperm donors – I'm not arguing for that,' she added. 'But this is the abnormal dissemination of genetic disease. Not every man has 75 children across Europe.' She continued: 'I analysed the variant using population and patient databases, computer prediction tools and the results of functional trials and came to the conclusion that the variant was probably cancer-causing and that children born from this donor should receive genetic counselling.' Children who have been shown to have the gene are advised to have whole body and brain MRI scans. They are also recommend to have breast and abdomen ultrasounds as adults. Julie Paulli Budtz, a spokesperson for the European Sperm Bank, told The Guardian: 'We are deeply affected by this case.' She said the donor had been thoroughly tested but that 'it is scientifically simply not possible to detect disease-causing mutations in a person's gene pool if you don't know what you are looking for'. She added: 'We welcome continued dialogue on setting an internationally mandated family limit and have advocated for this on several occasions. This is also why we have proactively implemented our own international limit of 75 families per donor.'
Medscape
19-05-2025
- Health
- Medscape
Novel Genetic Variant May Drive MASLD
A novel genetic variant may be a driving force behind the development of metabolic dysfunction–associated steatotic liver disease (MASLD) in some cases, according to researchers at the Mayo Clinic in Rochester, Minnesota. In an article published in Hepatology , Filippo Pinto e Vairo, MD, PhD, and colleagues described their discovery of a single inherited variant of the mesenchymal-epithelial transition ( MET ) gene in a familial case of MASLD involving a father and daughter with no apparent additional risk factors. MASLD remains one of the world's most common diseases and will likely become the leading cause of liver cirrhosis worldwide, the researchers wrote. MASLD, formerly known as nonalcoholic fatty liver disease (NAFLD), likely stems from a combination of genetic and environmental factors, they said. Their discovery of the gene variation prompted the researchers to investigate whether that variation and others on the MET gene were linked to steatotic liver disease. They used Mayo Clinic's Tapestry study, a large-scale genetic sequencing project, to analyze the exome sequencing data of 3904 adults with MASLD to identify other cases and analyze them. About 1% (45 individuals) had rare variants of the MET gene potentially associated with MASLD, and 8 of the 45 (18%) had genetic variants in the same area as the index patient and her father. Pinto e Vairo, medical director of the Program for Rare and Undiagnosed Diseases in the Mayo Clinic's Center for Individualized Medicine, explained the potential implications of the findings in a Q&A with Medscape Medical News . What prompted you to conduct this research? How did you identify the original patient? Pinto e Vairo: The original patient was identified through clinical care and underwent liver biopsy due to elevated liver enzymes. Her histology confirmed MASH [metabolic dysfunction–associated steatohepatitis], and subsequent exome sequencing revealed a novel heterozygous MET variant, inherited from her affected father, which led to a deeper investigation into the genetic basis of her condition. Were you surprised by any of the findings? Why or why not? Pinto e Vairo: The findings were surprising in several ways. First, variants in MET had not previously been implicated as a germline monogenic cause of MASLD or MASH in humans. Its known roles had largely been confined to cancer. Second, the discovery that rare, loss-of-function variants in the MET kinase domain could underlie liver steatosis and inflammation ran counter to the usual oncogenic MET variants, which are typically gain-of-function. The confirmation that the MET variants impaired downstream signaling further reinforced a novel mechanism. The lack of high polygenic risk scores in patients with these MET variants also highlighted that monogenic drivers might be underrecognized contributors to MASLD/MASH. Based on your research and other research, how might genetics play into MASLD? Pinto e Vairo: Genetics play a significant role in MASLD by modulating both susceptibility and disease progression. While large-scale genome-wide association studies have identified common variants — such as those in PNPLA3 , TM6SF2 , GCKR , MBOAT7 , and HSD17B13 — that confer risk or protection, this study adds evidence that rare monogenic variants can also independently drive the disease. This suggests a genetic spectrum in MASLD, ranging from polygenic, environmentally modulated forms to monogenic cases with high penetrance. The interplay between these rare variants and broader metabolic context will be crucial to understand personalized risk. Is there a practical application for this research now? What might the future clinical applications be? Pinto e Vairo: The immediate practical application lies in the potential for early identification of individuals at high risk for MASLD/MASH through exome or genome sequencing, particularly in families with a strong history of liver disease. Clinically, this could justify enhanced surveillance or earlier lifestyle and therapeutic interventions in at-risk individuals. In the future, this research may support the development of targeted therapies that can restore or bypass defective MET signaling. Moreover, it opens the door to personalized medicine strategies that consider a patient's unique genetic profile when choosing interventions or preventive strategies. What are the next steps? Pinto e Vairo: The next steps include functional validation of other rare MET variants to better understand their pathogenic potential and variability in phenotypic expression; longitudinal cohort studies to monitor disease progression in individuals with MET variants and to define genotype-phenotype correlations more precisely; and ultimately therapeutic exploration, including in vitro and in vivo modeling, to determine whether restoring MET signaling could reverse or mitigate disease.
