TPSAB1

Researchers reported for the first time that a genetic biomarker may be able to help predict the severity of food allergy reactions. Currently there is no reliable or readily available clinical biomarker that accurately distinguishes patients with food allergies who are at risk for severe life-threatening reactions versus more mild symptoms. Researchers from Ann & Robert H. Lurie Children's Hospital of Chicago and colleagues reported for the first time that a genetic biomarker may be able to help predict the severity of food allergy reactions. Currently there is no reliable or readily available clinical biomarker that accurately distinguishes patients with food allergies who are at risk for severe life-threatening reactions versus more mild symptoms. Findings were published in the Journal of Allergy and Clinical Immunology. Dr. Lang and colleagues found that the presence of an enzyme isoform called α-tryptase, which is encoded by the TPSAB1 gene, correlates with increased prevalence of anaphylaxis or severe reaction to food as compared to subjects without any α-tryptase. "Determining whether or not a patient with food allergies has α-tryptase can easily be done in clinical practice using a commercially available test to perform genetic sequencing from cheek swabs," said lead author Abigail Lang, MD, MSc, attending physician and researcher at Lurie Children's and Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine. "If the biomarker is detected, this may help us understand that the child is at a higher risk for a severe reaction or anaphylaxis from their food allergy and should use their epinephrine auto-injector if exposed to the allergen. Our findings also open the door to developing an entirely new treatment strategy for food allergies that would target or block α-tryptase. This is an exciting first step and more research is needed." Tryptase is found mainly in mast cells, which are white blood cells that are part of the immune system. Mast cells become activated during allergic reactions. Increased TPSAB1 copy number which leads to increased α-tryptase is already known to be associated with severe reactions in adults with Hymenoptera venom allergy (or anaphylaxis following a bee sting). Dr. Lang's study included 119 participants who underwent TPSAB1 genotyping, 82 from an observational food allergy cohort at the National Institute of Allergy and Infectious Diseases (NIAID) and 37 from a cohort of children who reacted to peanut oral food challenge at Lurie Children's. "We need to validate our preliminary findings in a much larger study, but these initial results are promising," says Dr. Lang. "We also still need a better understanding of why and how α-tryptase makes food allergy reactions more severe in order to pursue this avenue for potential treatment." Rajesh Kumar, MD, MSc, from Lurie Children's is the co-senior author on the study. Dr. Kumar is the Interim Division Head of Allergy and Immunology and Professor of Pediatrics at Northwestern University Feinberg School of Medicine. This work was supported in part by the Midwest Allergy Research Institute (MARI) Food Allergy Pilot Research Award and NIAID-sponsored T32 grant AI083216. This project was funded in part with federal funds from the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH. This project has also been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024.

Researchers have published an assessment of 13 studies that took a genotype-first approach to patient care. This approach contrasts with the typical phenotype-first approach to clinical research, which starts with clinical findings. A genotype-first approach to patient care involves selecting patients with specific genomic variants and then studying their traits and symptoms; this finding uncovered new relationships between genes and clinical conditions, broadened the traits and symptoms associated with known disorders, and offered insights into newly described disorders. National Institutes of Health researchers have published an assessment of 13 studies that took a genotype-first approach to patient care. This approach contrasts with the typical phenotype-first approach to clinical research, which starts with clinical findings. A genotype-first approach to patient care involves selecting patients with specific genomic variants and then studying their traits and symptoms; this finding uncovered new relationships between genes and clinical conditions, broadened the traits and symptoms associated with known disorders, and offered insights into newly described disorders. The study was published in the American Journal of Human Genetics. "We demonstrated that genotype-first research can work, especially for identifying people with rare disorders who otherwise might not have been brought to clinical attention," says Caralynn Wilczewski, Ph.D., a genetic counselor at the National Human Genome Research Institute's (NHGRI) Reverse Phenotyping Core and first author of the paper. Typically, to treat genetic conditions, researchers first identify patients who are experiencing symptoms, then they look for variants in the patients' genomes that might explain those findings. However, this can lead to bias because the researchers are studying clinical findings based on their understanding of the disorder. The phenotype-first approach limits researchers from understanding the full spectrum of symptoms of the disorders and the associated genomic variants. "Genomics has the potential to change reactive medicine into preventative medicine," said Leslie Biesecker, M.D., NIH distinguished investigator, director of NHGRI's Center for Precision Health Research and a senior author of the article. "Studying how taking a genotype-first approach to research can help us learn how to model predictive and precision medicine in the future." The study documents three types of discoveries from a genotype-first approach. First, the researchers found that this approach helped discover new relationships between genomic variants and specific clinical traits. For example, one NIH study found that having more than two copies of the TPSAB1 gene was associated with symptoms related to the gastrointestinal tract, connective tissues, and the nervous system. Second, this approach helped researchers find novel symptoms related to a disorder that clinicians previously missed because the patient did not have the typical symptoms. NHGRI researchers identified a person with a genomic variant associated with a known metabolic disorder. Further testing found that the individual had high levels of certain chemicals in their body associated with the disorder, despite having only minor symptoms. Third, this approach allowed researchers to determine the function of specific genomic variants, which has the potential to help clinicians understand newly described disorders. For example, in one study, NHGRI researchers and their collaborators found that a genomic variant was associated with immune dysfunction at the molecular level in blood cells. The 13 studies that implemented a genotype-first approach used genomic data from NHGRI's Reverse Phenotyping Core in the Center for Precision Health Research. The core aggregates genomic data from programs such as ClinSeq(R) and the National Institute of Allergy and Infectious Disease (NIAID) Centralized Sequencing Protocol, which together allowed analyses to be performed on more than 16,000 research participants who have undergone genome or exome sequencing. Exome and genome sequencing data from participants who consented to broad genomic data sharing and recontact for future research studies are currently available to NIH intramural researchers through the Reverse Phenotyping Core Genomic Data Browser to identify genomic variants of interest for their own research. "Importantly, we provide a framework for other institutions to build research programs that allow for genotype-first studies. With more programs taking this approach, we can better study the predictive potential of genomic medicine," said Clesson Turner, M.D., director of NHGRI's Reverse Phenotyping Core and a senior author of the article. The framework includes broad genomic data sharing with the ability to recontact participants explicitly stated during the informed consent process. NHGRI researchers recommend institutions aiming to establish genotype-first centers create strategic plans, especially for deciding what genomic findings will be returned, which may involve genetic counseling services. Importantly, according to the study, researchers must actively communicate with study participants to build informed and trusting long-term relationships. "In the future, as more researchers adopt this approach, we hope to identify more people who may be helped by the availability of their genome sequence, especially as more diverse populations join genome-sequencing studies," says Dr. Wilczewski.