Association between a variant at the GABA(A)alpha6 receptor subunit gene, abdominal obesity, and cortisol secretion

In the present study, we examined the potential impact of a T-to-C substitution at nucleotide 1519 of the GABA(A)alpha6 receptor subunit gene (GABRA6) 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 followed by digestion with the restriction enzyme AlwNI. The frequency of allele T was 0.54 and that of allele C was 0.46. Carriers for the T allele (n = 211) had 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; at 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. Leptin, insulin, and glucose were not different across the genotype groups. In conclusion, these findings suggest a role of the point substitution (T-to-C) at nucleotide 1519 of 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.