Changes in various genes tied to key processes affect SMA’s course: Study
Disease severity, onset affected by variations in a gene's DNA building block
Variations in more than a dozen genes related to inflammation, neurodevelopment, and oxidative stress associate with the severity of spinal muscular atrophy (SMA) and disease type, as well as person’s age at onset and their motor and lung function, researchers report.
“Further exploration of these pathways offers a promising avenue for developing personalized therapeutic strategies for SMA patients,” they wrote. The team also considered how these variations might affect disease risk.
The study, “Genetic Variability in Oxidative Stress, Inflammatory, and Neurodevelopmental Pathways: Impact on the Susceptibility and Course of Spinal Muscular Atrophy,” was published in Cellular and Molecular Neurobiology.
Changes seen in 18 genes tied to inflammation, neurodevelopment, cell stress
SMA largely is caused by mutations in the SMN1 gene that lead to progressive muscle weakness and wasting due to the loss of spinal cord motor neurons, the specialized nerve cells that control movement. Disease severity is generally determined by the number of copies of a second SMN2 gene, which can partly compensate for the loss of SMN1.
Still, the disease’s severity and progression can vary widely, even among individuals with identical SMN2 copy numbers.
A research team at the University of Ljubljana, in Slovenia, sought to determine whether changes in other genes influence the susceptibility to and progression of SMA.
They enrolled 54 SMA patients and 163 healthy individuals who served as controls. Of the patients, 24 (46.2%) were diagnosed with SMA type 2, 25 (48.1%) with SMA type 3, and three (5.8%) with SMA type 4. A total of 26 (53.1%) patients had three SMN2 copies, 20 (40.8%) had four copies, two (4.1%) had five copies, and one (2%) had two copies.
From blood samples, the researchers analyzed 18 genes for single nucleotide polymorphisms, or SNPs, which are changes in a single DNA building block within a gene. Two genes were involved in neurodevelopment, nine were related to inflammation, and seven were involved in oxidative stress, a type of cell damage where reactive oxygen species outweigh the body’s antioxidant defenses.
The presence of SNPs then was compared to demographic and clinical data that included motor and lung function assessments. At the study’s start, all patients had yet to receive treatment.
Single nucleotide polymorphism in CARD8 gene raised odds of SMA type 3
Analysis revealed that patients with an SNP in the IL-6 gene (rs1800795), associated with inflammation, had an increased risk of SMA by at least threefold. In contrast, a SNP in the inflammation-related TNF gene (rs1800629) and the neurodevelopment BDNF gene (rs6265) had a protective effect against SMA.
A single nucleotide polymorphism in the CARD8 gene (rs2043211) involved in inflammation was associated with increased odds of having SMA type 3, while one in the BDNF gene (rs6265) lowered the odds. These results remained significant after adjusting for SMN2 copy number.
Older age at symptom onset was associated with three genetic variants: SOD2 (rs4880) and CAT (rs1001179), both genes involved in oxidative stress, and MIR146A (rs2910164), a gene related to inflammation.
SNPs in the NOTCH gene (rs367398), involved in neurodevelopment, linked with better motor function, as indicated by higher scores on the Revised Hammersmith Scale, even after adjusting for age, SMN2 copy number, and disease duration. Higher scores on this scale also associated with SNPs in the GPX1 gene (rs1050450), related to oxidative stress, and the MIR146A gene (rs2910164), involved in inflammation. Conversely, single nucleotide polymorphisms in two genes related to oxidative stress — NFE2L2 (rs6721961) and HMOX1 (rs2071747) — were linked to worse motor function.
Variations in 2 genes affected upper body strength, and 2 others lung function
Better upper limb function, as indicated by higher scores on the Revised Upper Limb Module scale, was associated with SNPs in two genes, MIR146A (rs2910164) and NOTCH (rs367398), including after adjustments. In contrast, a deletion in the GSTM1 gene, involved in inflammation, was associated with poorer scores on this scale.
Carriers of at least one SNP in the HMOX1 gene (rs2071747) and the BDNF gene (rs6265) had poorer lung function, as assessed by the vital capacity, the amount of air that can be forcibly exhaled after taking a deep breath.
In another assessment of lung function, peak expiratory flow (which measures the speed of exhaled air), the GPX1 gene SNP (rs1050450) was associated with faster exhalation. The HMOX1 gene SNP (rs2071747) was linked with slower air flow, consistent with vital capacity data.
“These findings emphasize the potential of genetic variability in oxidative stress, inflammatory processes, and neurodevelopmental pathways to elucidate the complex course of SMA,” the researchers wrote. “We believe our findings have profound implications for future therapies and highlight the potential of recent genomic advances in customizing treatment approaches to improve outcomes for SMA patients.”
About the Author
