Association between the gamma-aminobutyric acid A3 receptor gene and multiple sclerosis

Abstract

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.