Study Narrows List of Genetic Suspects Behind Adolescent Idiopathic Scoliosis
核心洞察
University of Florida Health (搜索) researchers identified 92 genetic variants that may contribute to adolescent idiopathic scoliosis (搜索), a spinal curvature affecting 3% of children worldwide.
The team narrowed an initial pool of 1,664 variants across 26 genomic regions using a massively parallel reporter assay in living cartilage cells.
The findings could eventually enable genetic tests to identify children at high risk, allowing closer monitoring and timely intervention before curvature requires surgery.
University of Florida Health (搜索) researchers have identified 92 genetic variants that might contribute to adolescent idiopathic scoliosis (搜索) (AIS), a spinal curvature affecting 3% of children worldwide. The findings, published Aug. 17 in Genome Research, represent a milestone that could, with further research, eventually allow genetic tests to identify those at high risk of developing the condition.
"Earlier risk identification could allow closer monitoring and timely intervention before a spinal curve progresses to the point of requiring surgery," said Nadja Makki, Ph.D., the study's senior author and an assistant professor in the UF College of Medicine's Department of Physiology and Aging.
UF Health researchers collaborated with Anat Kreimer, Ph.D., and her bioinformatics lab at Rutgers University on the study. UF doctoral student Darius Ramkhalwan also played a key role in the investigation.
Narrowing the Field of Genetic Suspects
Scientists began with 1,664 variants in 26 regions of the human genome previously associated with scoliosis risk. They narrowed the pool to 92 and ranked them by the extent to which each variant altered DNA's control of gene activity. More change provided stronger evidence that the variant might be important in scoliosis.
"This is quite a big deal in the scoliosis research community," Makki said. "This allows us to focus on very specific regions in the genome that we can now analyze in more detail."
Previous genetic studies compared the DNA of people with and without scoliosis and identified 26 regions of DNA associated with increased risk. However, those studies could not tell scientists which DNA variations in those regions were important or what they did.
"Genome-wide studies gave us the neighborhood where a risk variant might be located," Makki said. "Our study helps identify the specific address and begins to explain what is happening there."
A Massively Parallel Reporter Assay Approach
The relatively new method used in the study is called a massively parallel reporter assay, which enables simultaneous testing of thousands of genetic sequences. Researchers created short DNA fragments containing either the common or the scoliosis-associated version of each variant and introduced them into living cartilage cells in the lab. They then measured whether the two versions differed in their ability to increase or decrease gene activity.
By comparing the results, researchers could identify genetic variants that might interfere with the normal activity of genes tied to cartilage and spinal development. Most variants in the study involved a difference of just a single DNA letter.
Makki was particularly encouraged by one variant located near a gene essential for cartilage health and spinal alignment. Loss of the gene can lead to a condition in mice similar to scoliosis. More research is needed to confirm whether any of the variants affect scoliosis development.
Connecting DNA Changes to Gene Activity
The study comes on the heels of another landmark scoliosis paper by Makki and UF Health researchers, published in June in Human Genetics and Genomics Advances. That earlier research began with spinal cartilage and muscle tissue samples collected from people with and without scoliosis and compared gene activity between the two groups, focusing on which genes are unusually active or inactive in scoliosis.
The new study starts at the other end of the problem—with inherited variants already statistically linked to scoliosis—and asks which of them can alter the switches that control gene activity. Together, the studies begin to connect DNA changes with abnormal gene activity.
The earlier tissue-based work, which relied on a tissue biobank created by UF Health researchers, found that each tissue in AIS patients exhibited a distinct pattern of abnormal gene activity, suggesting scoliosis might arise from multiple biological processes occurring at once. Researchers identified important differences in genes involved in cartilage development, particularly those that help specialized cartilage cells form properly, as well as abnormal activity in muscle genes that help muscles contract and maintain strength.
The Clinical Need for Earlier Detection
AIS is the most common type of pediatric spinal deformity, affecting up to 3% of children worldwide. The condition usually occurs during the child's most rapid growth period, with spinal curvature for some progressing even into adulthood, with curves of greater than 60 degrees in some individuals, according to the Scoliosis Research Society. The disease occurs in both boys and girls, but progressive cases are far more common in girls.
Current scoliosis treatment largely begins only after spinal curvature has already developed, leaving physicians focused on slowing progression rather than preventing the condition altogether.
"If we could identify these patients prior to them developing that large curvature, then we could put that child in a brace, or we could do scoliosis-specific exercises," said study co-author Jessica McQuerry, M.D., a pediatric orthopaedic surgeon and an assistant professor in the UF College of Medicine's Department of Orthopaedic Surgery and Sports Medicine. "We have preventive therapies that do work, but we don't know who to use them on."
"Adolescent idiopathic scoliosis (搜索) is a condition that we're very reactive to," said study co-author Stephanie Ihnow, M.D., an associate professor and surgeon in orthopaedics. "And what we're trying to do is to be more proactive instead of reactive."
The research opens the possibility of identifying children at risk before spinal curvature progresses enough to require highly invasive and costly surgery.