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


METHODS
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.
Gade-Andavolu
R
R
Department of Medical Genetics, City of Hope Medical Center, Duarte, Calif 91910, USA.
MacMurray
J P
JP
Blake
H
H
Muhleman
D
D
Tourtellotte
W
W
Comings
D E
DE
D000483:Alleles; D016009:Chi-Square Distribution; D016207:Cytokines / Q000378:metabolism; D005260:Female; D008040:Genetic Linkage; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics*; D011388:Prolactin / Q000502:physiology*; D011963:Receptors, GABA-A / Q000235:genetics*; D012307:Risk Factors; D018433:Twin Studies as Topic; D014960:X Chromosome; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D016207:Cytokines; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D011388:Prolactin; D005968:Glutamate Decarboxylase