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Association between the gamma-aminobutyric acid A3 receptor gene and multiple sclerosis
R Gade-Andavolu1, J P MacMurray, H Blake
1Department of Medical Genetics, City of Hope Medical Center, Duarte, Calif 91910, USA.
Background:
In a prior study we observed an association between the dopamine D2 receptor gene (DRD2) and the age of onset and/or diagnosis of multiple sclerosis (MS). We hypothesized that this effect was mediated through the dopaminergic control of the release of prolactin, a modulator of immune response. Since gamma-aminobutyric acid also modulates the release of prolactin, we examined the possible association between alleles of the GABRA3 (gamma-aminobutyric acid A3 receptor) gene and MS.
Design:
We examined the GABRA3 alleles of 189 subjects with MS who died of their disease. They were divided into test group 1 (n=64) and retest group 2 (n=56). Each group had a separate set of controls (group 1, n=109; group 2, n=430). All subjects were white. All were tested at a dinucleotide cytosine-adenosine repeat polymorphism with 6 alleles representing 11 to 16 repeats.
Results:
In the first group there was a significant difference in the frequency of the GABRA3 alleles (P<.002), with the most notable difference being an increase in the frequency of the 16-repeat allele in subjects with MS and a relative decrease in the other alleles. In the replication group there was again a significant difference in the distribution of the GABRA3 alleles (P<.001), and again the greatest difference was an increase in the frequency of the 16-repeat allele in subjects with MS. For both groups combined, a significant difference in the frequency of the 16-repeat allele was noted (chi2=46.30; P<.001).
Conclusions:
These results suggest the GABRA3 gene may be a risk factor for MS. As with the DRD2 gene, the effect may be mediated through its regulation of prolactin release.
Insights
The gamma-aminobutyric acid A3 receptor (GABRA3) gene may be a risk factor for multiple sclerosis (MS). A specific GABRA3 allele (16-repeat) was significantly more frequent in MS patients, suggesting a role in disease development.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Prior research linked dopamine D2 receptor gene (DRD2) to multiple sclerosis (MS) onset.
- This association may involve dopaminergic control of prolactin, an immune modulator.
- Gamma-aminobutyric acid (GABA) also influences prolactin release.
Purpose of the Study:
- To investigate the association between gamma-aminobutyric acid A3 receptor (GABRA3) gene alleles and multiple sclerosis (MS).
- To explore if GABRA3 gene variations contribute to MS risk, potentially via prolactin regulation.
Main Methods:
- Genotyping of GABRA3 alleles in 189 deceased multiple sclerosis (MS) patients and control groups.
- Analysis focused on a dinucleotide cytosine-adenosine repeat polymorphism within the GABRA3 gene.
- Subjects were categorized into test and replication groups for validation.
Main Results:
- Significant differences in GABRA3 allele frequencies were observed in both test and replication groups (P<.002 and P<.001, respectively).
- The 16-repeat allele of GABRA3 showed a notably increased frequency in MS patients compared to controls.
- Combined analysis confirmed a significant association between the 16-repeat GABRA3 allele and MS (P<.001).
Conclusions:
- The GABRA3 gene is suggested as a potential risk factor for multiple sclerosis (MS).
- The mechanism may involve GABRA3's regulation of prolactin release, similar to the previously observed DRD2 gene effect.
- These findings highlight the role of GABAergic pathways in MS pathogenesis.