Affiliations: Department of Molecular Diagnostics, National Research
Center GosNIIgenetika, Moscow, Russia | Department of Endocrinology and Diabetology, Russian
Academy for Advanced Medical Studies, Moscow, Russia
Note: [] Corresponding author: Dimitry A. Chistiakov, Ph.D., Associate
Professor, Department of Molecular Diagnostics, National Research Center
GosNIIgenetika, 1st Dorozhny Proezd 1, 117545 Moscow, Russia. Tel.: +7 495 3150
329; Fax: +7 495 3150 501; E-mail: dimitry. chistiakov@eudoramail.com
Abstract: Abnormalities in G protein-mediated signal transduction could be
involved in the pathogenesis of diabetic polyneuropathy (DPN). Here we test
whether the GNB3 C825T variant confers susceptibility to DPN in type 1 diabetes
(T1D) mellitus. The C825T marker of GNB3 was genotyped in genomic DNA from
blood isolated from a total of 213 Russian T1D patients 100 of whom had DPN.
Compared to carriers of the wild-type genotype C/C, diabetic subjects with
genotypes T/T had significantly increased risk to develop DPN (Odds Ratio (OR)
of 4.4 (p = 0.001). The adjustment for confounders (age, sex, body mass index,
cigarette smoking, and level of reduced glutathione) resulted in increase of
the OR value up to 4.72 (p = 8.9 × 10^{-3}). The
further adjustment for hypertension abolished the association between the GNB3
C825T variant and DPN (OR = 1.95, p = 0.18). Non-complicated subjects
homozygous for T/T showed decreased levels of reduced glutathione (T/T: 69
± 19 vs. C/T: 74 ± 19 vs. C/C: 77 ± 17 μmol/l, p =
0.009). Compared to other GNB3 variants, carriers of the T/T genotype had
elevated systolic blood pressure (SBP) in complicated (T/T: 115.8 ± 9.1
vs. C/T: 113.3 ± 8.2 vs. C/C: 109.5 ± 8.7 mm/Hg, p = 0.036) and
non-complicated T1D patients (T/T: 118.1 ± 8.4 vs. C/T: 116.9 ±
7.9 vs. C/C: 112.1 ± 7.2 mm/Hg, p = 0.02). However, the significance of
association between the C825T polymorphism was lost after adjustment for
confounding risk factors. In conclusion, the 825T allele of GNB3 is likely to
accelerate the development of DPN through primary effects to SBP and
hypertension in subgroups of diabetic patients with impaired neurovascular
function and advanced oxidative stress.
Keywords: GNB3, C825T polymorphism, peripheral polyneuropathy, type 1 diabetes, susceptibility
