“ The epigenetic work is really exciting because epigenetics provides almost like a record of environmental exposures over the lifetime of an individual .”
-PATRICK CARRY , PHD
causes AIS and increases spinal curve severity . Dr . Hadley-Miller explains that with diseases like diabetes , researchers have the benefit of narrowing their search to just one organ , the pancreas . But with orthopedic conditions such as AIS , it ’ s a bit like finding a needle in a haystack .
“ Bones are everywhere . Cartilage is everywhere . That ’ s what makes it overwhelming to figure out what the problem is ,” she says . “ I ’ ve been studying this for more than 30 years and sometimes I feel like we ’ re further away than we were when I started .”
With her latest study though , Dr . Hadley-Miller shrunk the haystack and inched closer to the needle . Working alongside Patrick Carry , PhD , Dr . Hadley-Miller recently published new research utilizing the largest known set of monozygotic ( identical ) twins with AIS in the world to better understand whether and how epigenetic , or environmental , factors play a role in disease onset .
Dr . Carry says the use of epigenetic research methods in studying musculoskeletal diseases is novel and presents new opportunities for critical breakthroughs as they represent an interesting bridge between nature and nurture . Epigenetics are a set of mechanisms that have numerous biological functions , including modifying gene expression . These mechanisms are set in motion by external factors , including hormone exposure , smoking , pollution and other environmental exposures .
“ We know there isn ’ t one gene that causes scoliosis ,” Dr . Carry says . “ The epigenetic work is really exciting because epigenetics provides almost like a record of environmental exposures over the lifetime of an individual . This information can help us to understand the role of external factors in the onset of complex musculoskeletal diseases .”
DNA methylation is considered the most easily measurable epigenetic mechanism and occurs when a methyl group is added to the cytosine nucleotide in a DNA sequence . This can alter the way the body interprets that gene . For this study , Drs . Hadley-Miller and Carry examined DNA methylation in blood samples from eight sets of twins with AIS .
Because identical twins are near perfect genetic matches , utilizing this population for study allowed Drs . Hadley-Miller and Carry to compare variations in each twin ’ s spinal curvature and to trace them to specific areas of the genome by correlating differences in curve severity to differences in DNA methylation .
This comparison of twins with AIS uncovered 58 sites where DNA methylation differed between sets of twins and four sites that are specifically related to curve severity . To narrow the pool of 58 possibilities even further , Dr . Hadley Miller collaborated with a researcher at Sweden ’ s Lund University to identify which of these genome sites , measured in blood , were similar in bones . That brought the total number of suspected regions down to just 21 .
Though the work is not done and Dr . Hadley Miller says she doesn ’ t expect to find her “ holy grail ,” — the specific genomic cause of AIS — in her lifetime , she says this work has brought us closer than ever before .
“ I think it ’ s very important ,” she says . “ Is this going to lead to some therapeutic targets ? I don ’ t know . But it certainly gives us a hint as to where we may go next .” •
1 . Carry , Patrick M et al . “ Severity of Idiopathic Scoliosis Is Associated with Differential Methylation : An Epigenome-Wide Association Study of Monozygotic Twins with Idiopathic Scoliosis .” Genes vol . 12,8 1191 . 30 Jul . 2021 , doi : 10.3390 / genes12081191
NANCY HADLEY-MILLER , MD
Orthopedic Surgery , Children ’ s Hospital Colorado
Professor , Orthopedics , University of Colorado School of Medicine
PATRICK CARRY , PHD
Research Associate , Musculoskeletal Research Center , Children ’ s Hospital Colorado
Department of Orthopedics , University of Colorado Anschutz Medical Campus
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