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Association Between the -Aminobutyric Acid A₃ Receptor Gene and Multiple Sclerosis

Radhika Gade-Andavolu, PhD; James P. MacMurray, PhD; Hezekiah Blake; Donn Muhleman, MS; Wallace Tourtellotte, MD; David E. Comings, MD

Arch Neurol. 1998;55:513-516.

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 -aminobutyric acid also modulates the release of prolactin, we examined the possible association between alleles of the GABRA3 (-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 (²=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.

From the Department of Medical Genetics, City of Hope Medical Center, Duarte, Calif (Drs Gade-Andavolu, Blake, Muhleman, and Comings); the Department of Psychiatry, Loma Linda University, Loma Linda, Calif (Dr MacMurray); and the Department of Neurology, Los Angeles Veterans Affairs Medical Center, Los Angeles, Calif (Dr Tourtellotte).

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