Allelic variants in the GABA(A)alpha6 receptor subunit gene (GABRA6) is associated with abdominal obesity and cortisol secretion.
BACKGROUND
Cortisol is involved in the regulation of adipose-tissue differentiation, function and distribution, and in excess causes abdominal obesity. At the level of the brain, cortisol secretion is partly controlled by gamma-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the vertebrate brain, and acts by binding to GABA(A) receptors.


METHODS
We examined the potential impact of a 1519T>C polymorphism in the GABA(A)alpha6 receptor subunit (GABRA6) gene on obesity and obesity-related phenotypes as well as circulating hormones, including salivary cortisol in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using PCR amplification of the 3' non-coding region of the GABRA6 gene followed by digestion with the restriction enzyme AlwNI.


RESULTS
The frequency of allele T was 0.54 and 0.46 for allele C. Carriers for the T allele (n=211) had borderline significantly higher waist-to-hip ratio (P=0.094) and abdominal sagittal diameter (P=0.084) compared to homozygotes for the C allele (n=56). The homozygotes for the T allele had, in comparison to heterozygotes, significantly (P=0.004-0.024) higher mean cortisol levels at 11:45 am, and 30, 45 and 60 min after a standardized lunch and, finally, at 5:00 pm. In addition, T/T subjects had significantly (P=0.031) higher diurnal cortisol secretion compared to T/C subjects. Other hormones, glucose and serum lipids were not different across the genotype groups.


CONCLUSIONS
These findings suggest a role of the 1519T>C polymorphism in GABRA6 in the predisposition to hypercortisolism and perhaps abdominal obesity. The pathophysiology may involve various environmental factors, particularly stress, that destabilize the GABA-hypothalamic-pituitary-adrenal systems in those with genetic vulnerability.
Rosmond
R
R
Department of Clinical Chemistry, Sahlgrenska University Hospital, Göteborg, Sweden.
Bouchard
C
C
Björntorp
P
P
D000005:Abdomen; D000483:Alleles; D001786:Blood Glucose / Q000032:analysis; D001824:Body Constitution; D015992:Body Mass Index; D002940:Circadian Rhythm; D005787:Gene Frequency; D005838:Genotype; D006720:Homozygote; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D011110:Polymorphism, Genetic; D011963:Receptors, GABA-A / Q000235:genetics*; D012463:Saliva / Q000737:chemistry
D001786:Blood Glucose; D008055:Lipids; D011963:Receptors, GABA-A; D006854:Hydrocortisone