genetic factors Archives - Amazing Health Advances

Researchers Discover Genetic Connections to Alcohol Consumption

The AHA! Team — Fri, 14 Jun 2024 08:22:49 +0000

University of California San Diego via News-Medical – A research group centered at the University of California San Diego School of Medicine has drilled deep into a dataset of over 3 million individuals compiled by the direct-to-consumer genetics company 23andMe, Inc., and found intriguing connections between genetic factors influencing alcohol consumption and their relationship with other disorders. A research group centered at the University of California San Diego School of Medicine has drilled deep into a dataset of over 3 million individuals compiled by the direct-to-consumer genetics company 23andMe, Inc., and found intriguing connections between genetic factors influencing alcohol consumption and their relationship with other disorders. The study was recently published in the Lancet eBioMedicine. Sandra Sanchez-Roige, Ph.D., corresponding author and associate professor at UC San Diego School of Medicine Department of Psychiatry, explained that the study used genetic data to broadly classify individuals as being European, Latin American and African American. Such classifications “are needed to avoid a statistical genetics pitfall called population stratification,” noted co-author Abraham A. Palmer, Ph.D., professor and vice chair for basic research in the psychiatry department. Researchers analyzed genetic data from the 3 million 23andMe research participants The researchers analyzed genetic data from the 3 million 23andMe research participants, focusing on three specific little snippets of DNA known as single-nucleotide polymorphisms, or SNPs. Sanchez-Roige explained that variants, or alleles, of these particular SNPs are “protective” against a variety of alcohol behaviors, from excessive alcohol drinking to alcohol use disorder. One of the alcohol-protective variants they considered is very rare: the most prevalent among the three alleles found in the study showed up in 232 individuals of the 2,619,939 European cohort, 29 of the 446,646 Latin American cohort and in 7 of the 146,776 African American cohort; others are much more common. These variants affect how the body metabolizes ethanol – the intoxicating chemical in alcoholic beverages. “The people who have the minor allele variant of the SNP convert ethanol to acetaldehyde very rapidly. And that causes a lot of negative effects.” – Sandra Sanchez-Roige, Ph.D., corresponding author and associate professor at UC San Diego School of Medicine Department of Psychiatry She went on to say that the resulting nausea eclipses any pleasurable effects of alcohol – think of a bad hangover that sets in almost immediately. “These variants are primarily associated with how much someone may consume alcohol,” she said. “And they also tend to prevent alcohol use disorder, because these variants are primarily associated with the quantity of alcohol someone may drink.” Sanchez-Roige explained that the SNP variants’ influence on alcohol consumption are well researched, but her group took a “hypothesis-free” approach to the 23andMe dataset, which contains survey data on thousands of traits and behaviors. The researchers wanted to find out if the three SNP variants might have any other effects beyond alcohol consumption. Sanchez-Roige and Palmer noted that their group has developed a 10-year partnership with 23andMe that has focused on numerous traits, especially those with relevance for addiction. This work is the basis of an academic collaboration through the 23andMe Research Program. They data-mined the analyses of DNA from saliva samples submitted by consenting 23andMe research participants, as well as the responses to the surveys of health and behavior available from the 23andMe database, and found a constellation of associations, not necessarily connected with alcohol. Individuals with the alcohol-protecting alleles had generally better health, including less chronic fatigue and needing less daily assistance with daily tasks. But the paper notes individuals with the alcohol-protective alleles also had worse health outcomes in certain areas: more lifetime tobacco use, more emotional eating, more Graves’ disease and hyperthyroidism. Individuals with the alcohol-protective alleles also reported totally unexpected differences, such as more malaria, more myopia and several cancers, particularly more skin cancer and lung cancer, and more migraine with aura. Sanchez-Roige acknowledged that there is a chicken-and-egg aspect to their findings. For example: Cardiovascular disease is just one of a number of maladies known to be associated with alcohol consumption. “So is alcohol consumption leading to these conditions?” she asks. Palmer finishes the thought: “Or do these genetic differences influence traits like malaria and skin cancer in a manner that is independent of alcohol consumption?” Sanchez-Roige said that such broad, hypothesis-free studies are only possible if researchers have access to very large sets of data. Many datasets, including the one used in the study, rely heavily on individuals with European ancestry. “It is important to include individuals from different ancestral backgrounds in genetic studies because it provides a more complete understanding of the genetic basis of alcohol behaviors and other conditions, all of which contributes to a more inclusive and accurate understanding of human health,” she said. “The study of only one group of genetically similar individuals (for example, individuals of shared European ancestry) could worsen health disparities by aiding discoveries that will disproportionately benefit only that population.” She said their study opens numerous doors for future research, chasing down possible connections between the alcohol-protective alleles and conditions that have no apparent connection with alcohol consumption. “Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine,” Sanchez-Roige noted. Co-authors on the paper from the University of California San Diego School of Medicine Department of Psychiatry are Mariela V. Jennings, Natasia S. Courchesne-Krak, Renata B. Cupertino and Sevim B. Bianchi. Sandra Sanchez-Roige is also associated with the Department of Medicine, Division of Genetic Medicine, Vanderbilt University. Other co-authors are: José Jaime Martínez-Magaña, Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine; Laura Vilar-Ribó, Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; Alexander S. Hatoum, Department of Psychology & Brain Sciences, Washington University in St. Louis; Elizabeth G. Atkinson, Department of Molecular and Human Genetics, Baylor College of Medicine; Paola Giusti-Rodriguez, Department of Psychiatry, University of Florida College of Medicine; Janitza L. Montalvo-Ortiz, Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, National Center of Posttraumatic Stress Disorder, VA CT Healthcare Center; Joel Gelernter, VA CT Healthcare Center, Department of Psychiatry, West Haven CT; and Departments of Psychiatry, Genetics & Neuroscience, Yale Univ. School of Medicine; María Soler Artigas, Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Mental Health, Hospital Universitari Vall d’Hebron, Barcelona; Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid; and Department of Genetics, Microbiology, and Statistics, Faculty of Biology, Universitat de Barcelona; Howard J. Edenberg, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine; and the 23andMe Inc. Research Team, including Sarah L. Elson and Pierre Fontanillas. The study was funded, in part, by Tobacco-Related Disease Research Program grants T32IR5226 and 28IR-0070, National Institute of Health (NIH) National Institute of Drug Abuse (NIDA) DP1DA054394, and NIH National Institute of Mental Health (NIMH) R25MH081482. Source: University of California San Diego Journal reference: Jennings, M. V., et al. (2024) A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals. Lancet eBioMedicine. doi.org/10.1016/j.ebiom.2024.105086. To read the original article click here.

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Genetic Mutations Predispose Individuals to Severe COVID-19

AHA Publisher — Mon, 27 Jul 2020 07:00:16 +0000

Rabound University Medical Center via EurekAlert – Current observations suggest that the coronavirus SARS-CoV-2 causes severe symptoms mainly in elderly patients with chronic disease. However when two pairs of previously healthy young brothers from two families required mechanical ventilation at the intensive care unit in rapid succession, doctors and researchers at Radboud University Medical Center were inclined to consider that genetic factors had a key role in compromising their immune system. Their research identified the gene TLR7 as an essential player in the immune response against SARS-CoV-2. A finding with potentially major consequences for understanding and possibly treatment of COVID-19. During the wave of COVID-19 patients that flooded Dutch hospitals in the first half of 2020, two young brothers became seriously ill with the SARS-CoV-2 virus and had to be mechanically ventilated in the ICU. One of them died from the consequences of the infection, the other recovered. The severe course of disease in otherwise healthy young brothers was a relatively rare occurrence, especially because the virus mainly affects the elderly. This observation triggered the curiosity of an attentive physician from the MUMC+ department of clinical genetics. She contacted her colleagues in Nijmegen who then investigated why these two young brothers were so severely affected. Genetic Factors “In such a case, you immediately wonder whether genetic factors could play a role,” says geneticist Alexander Hoischen. “Getting sick from an infection is always an interplay between – in this case – the virus and the human immune system. It may be a mere coincidence that two brothers from the same family become so severely ill. But it is also possible that an inborn error of the immune system has played an important role. We investigated this possibility, together with our multidisciplinary team at Radboudumc.” One X-Chromosome All genes (collectively called the exome) of both brothers were sequenced, after which the investigators combed through the data searching for a possible shared cause. Cas van der Made, PhD student and resident at the department of Internal Medicine: “We mainly looked at genes that play a role in the immune system. We know that several of these genes are located on the X-chromosome, and with two brother pairs affected X-chromosomal genes were most suspicious. Women carry two X-chromosomes, while men possess a Y-chromosome apart from the X. Therefore, men have only one copy of the X-chromosomal genes. In case men have a defect in such a gene, there is no second gene that can take over that role, as in women.” Gene Identification That search quickly revealed mutations in the gene encoding for the Toll-like receptor 7, TLR7 for short. There are multiple TLR-genes, which belong to a family of receptors with an important role in the recognition of pathogens (such as bacteria and viruses) and the activation of the immune system. Hoischen: “A few letters were missing in the genetic code of the TLR7 gene. As a result, the code cannot be read properly and hardly any TLR7 protein is produced. TLR7 function has so far never been associated with an inborn error of immunity. But unexpectedly we now have an indication that TLR7 is essential for protection from this coronavirus. So it seems that the virus can replicate undisturbed because the immune system does not get a message that the virus has invaded. Because TLR7, which must identify the intruder and subsequently activate the defense, is hardly present. That could be the reason for the severity of the disease in these brothers.” Additional Confirmation Then, quite unexpectedly, the doctors and researchers at Radboudumc come across another pair of brothers who have fallen seriously ill with COVID-19. Again, they are both under 35 years of age. Both of them were also in the ICU for mechanical ventilation. “Then the question of the role of genetics became even more obvious.” says Hoischen. “We also investigated the genetic code of these two brothers, again via the ‘rapid-clinical exome’ method. This time we saw no deletion, no loss of letters, but a single spelling mistake of one DNA-letter of the TRL7 gene. The effect on the gene is the same, however, because these brothers also do not make sufficient functional TLR7 protein. Suddenly we had four young people with a defect in the same gene, all of whom had fallen seriously ill from the SARS-CoV-2 virus.” Essential Role in the Defense Van der Made and colleagues have investigated the consequences of improper functioning of the TLR7 receptor. “Once activated, TLR7 triggers the production of so-called interferons, signaling proteins that are essential in the defense against virus infections,” says van der Made. “This immune response is perhaps all the more important in the fight against the SARS-CoV-2 virus, because we know from the literature that the virus has tricks to reduce the production of interferons by immune cells. When we mimic an infection with the coronavirus, we see that immune cells of the patients without properly functioning TLR7 hardly respond, and that minimal amounts of interferons are produced. These tests make it clear that the virus appears to have free rein in people without properly functioning TLR7 because it [the virus] is not recognized by the immune system.” Consequences “Due to the serious illness of four brothers in two families, so serious that it cost one of the young men his life, we have discovered this condition,” says Hoischen. “It seems to be a very specific abnormality, an immunodeficiency, which is mainly related to this coronavirus. None of the four men have previously suffered from immune-related diseases. It is the first time that we can connect a clinical phenomenon so strongly with TLR7.” “This discovery not only provides us with more insight into the fundamental workings of the immune system, but it may also have important consequences for the treatment of severely ill COVID-19 patients,” says Frank van de Veerdonk, immunologist and infectiologist. “The substance interferon can be given as a therapy. It is currently being investigated whether administering interferon in COVID-19 can indeed help.” To read the original article click here.

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