[The hypothalamic-pituitary-adrenal axis and genetic variants affecting its reactivity].

The hypothalamic-pituitary-adrenal (HPA) axis plays a primary role in the body response to stresses. Activation of the HPA axis results in the production ofcorticosteroid hormones that influence a wide variety of body functions, including immunity, metabolism, ion exchange, and behavior. A well-balanced regulation of stress responses is pivotal for maintaining intrabody homeostasis. The HPA axis is regulated at several levels, including stimulatory or inhibitory signals from the brain mediated through neurotransmitter systems and the suppressive feedback influence of corticosteroids themselves. Corticosteroids affect the HPA axis through binding to the glucocorticoid and mineralocorticoid receptors located in the hippocampus. Genes encoding these receptors have several polymorphic regions in which the alleles are associated with different basal and stress-induced levels of hormones secreted in the course of HPS axis stimulation. Additionally, genetic variants of neurotransmitter systems involved in the activation or suppression of the HPA axis have been found. Thus, the given genetic variations are major contributors to the HPA axis-mediated individual resistance or susceptibility to stresses.

[Association of the chromosomal region 2q35 with type 1 diabetes mellitus in the Russian patients from Moscow].

To map human chromosome 2 region associated with type 1 diabetes mellitus, 89 families with concordant and discordant sib pairs were analyzed. Linkage and association with type 1 diabetes were examined using polymorphic microsatellite markers spanning the region of about 4 Mb. The linkage plot was constructed, and association of the five microsatellite markers within the chromosomal region 2q35 was examined. Polymorphic marker D2S137 (Z' = 3.225, p(c) = 0.0048) demonstrated maximum linkage and association with type 1 diabetes.

[Polymorphic markers Val762Ala and Leu54Phe of the ADPRT1 gene associated with chronic glomerulonephritis in Russian patients from the city of Moscow].

A comparative analysis of allelic and genotype distribution of polymorphic markers Val762Ala and Leu54Phe of ADPRT1 gene encoding poly(ADP-ribose)polymerase I has been performed in chronic glomerulonephritis patients compared to normal controls. This has shown a significant difference in the ADPRTI gene polymorphic marker Val762Ala allelic and genotype frequency distribution between chronic glomerulonephritis patients and healthy controls (according to Fisher's exact test). At the same time the allelic and genotype frequency for a polymorphic marker Leu54Phe distribution did not show significant difference between these groups. Therefore, we have concluded that the ADPRTI gene polymorphic marker Val762Ala is associated with the development of chronic glomerulonephritis in Russian patients of the Moscow region.

[Search for the association of polymorphic markers for genes coding for antioxidant defense enzymes, with development of diabetic polyneuropathies in patients with type 1 diabetes mellitus]. / Poisk assotsiatsii polimorfnykh markerov genov, kodiruiushchikh fermenty antiokislitel'noi zashchity, s razvitiem diabeticheskoi polineiropatii u bol'nykh sakharnym diabitom tipa 1.

The allele and genotype frequency distributions of polymorphic markers of genes coding for antioxidant enzymes were compared for type 1 diabetes mellitus patients with or without diabetic polyneuropathy (DPN). The groups (total 180 patients) had nonoverlapping (polar) phenotypes. Group DPN+ included 86 patients with DPN and diabetic record no more than 5 years. Control group DPN- included patients without DPN and diabetic record of at least 10 years. Comparative analysis with Fisher's exact test revealed a significant difference in allele and genotype frequency distributions of the T(-262)C polymorphic marker of the CAT gene. Polymorphic markers C1167T of the CAT gene, Pro/Leu of the GPX1 gene, 0/+ of the GSTT1 gene, and 0/+ of the GSTM1 gene showed no significant difference in allele or genotype frequency distribution. On this evidence, these markers were not associated with DPN in the sample examined.

[Association of the SOD2 Ala(-9)Val and SOD3 Arg213Gly polymorphisms with diabetic polyneuropathy in patients with diabetes mellitus type 1]. / Assotsiatsiia polimorfnykh markerov Ala(-9)Val gena SOD2 i Arg213Gly gena SOD3 s diabeticheskoi polineiropatiei u bol'nykh sakharnym diabetom tipa 1.

Single-nucleotide polymorphisms of the genes for mitochondrial (SOD2) and extracellular (SOD3) superoxide dismutases were tested for association with diabetic polyneuropathy (DPN) in diabetes mellitus (DM) type 1. Patients (n = 180) were divided into two groups with nonoverlapping (polar) phenotypes. Group DPN+ included 86 individuals with DPN and DM type 1 record of no more than 5 years. Group DPN-included 94 patients with DM type 1 record of more than 10 years but without clinical signs of DPN. Fisher's exact test revealed significant differences in allele and genotype frequencies for the two groups. Higher frequencies of SOD2 allele Val and genotype Val/Val and of SOD3 allele Arg and genotype Arg/Arg were established for group DPN+. On this evidence, SOD2 and SOD3 were associated with DPN in DM type 1.

[Identification of the locus associated with diabetic nephropathy in type 1 diabetes mellitus]. / Identifikatsiia lokusa assotsiirovannogo s diabeticheskoi nefropatiei pri sakharnom diabete tipa 1.

Polymorphic tetranucleotide microsatellites D3S1512, D3S1744, D3S1550, and D3S232 were used to study the association of chromosome region 3q21-q25 neighboring the angiotensin II receptor type 1 gene (AT2R1) with diabetic nephropathy (DN) in diabetes mellitus type 1 (DM1). Allele and genotype frequencies were compared for DM1 patients with (N = 39) or without (N = 62) DN. Fisher's exact test with Bonferroni's correction revealed significant differences in frequencies of two D3S2326 alleles, one D3S1512 allele, and one allele and one genotype of D3S1550. No significant difference was observed with D3S1744. Thus, region 3q21-q25 proved tightly associated with DN in ethnic Russians with DM1 from Moscow.

[Polymorphic locus D6S392 near the Mn-dependent superoxide dismutase gene is associated with diabetes mellitus in the Moscow population]. / Polimofnyi lokus D6S392 riadom s genom Mn-zavisimoi superoksiddismutazy sviazan s sakharnym diabetom v Moskovskoi populiatsii.

AIM: Distribution of alleles of tetranucleotide microsatellite D6S392 located nearby the gene of Mn-dependent superoxide dismutase (SOD2) was studied in healthy donors (n = 143), patients with insulin-dependent (n = 166) and insulin-independent (n = 101) diabetes mellitus (IDDM and IIDM). MATERIALS AND METHODS: Alleles of the polymorphic locus D6S392 were amplified using polymerase chain reaction (PCR) on the basis of genome DNA isolated from the venous blood of the examinees. PCR products were analysed with gel-electrophoresis in polyacrylamide gel. Significance of differences of allele and genotypes distribution in the population control and patients were assessed with Fisher's criterion and Bonferroni's corrections. RESULTS: Locus D6S392 contains 31 allele from 210 to 330 pn in length and 37 to 67 tandem repeats. Compared to controls, IDDM patients had less frequent incidence of low molecular allele 41 and 42 as well as allele 62. CONCLUSION: Polymorphic locus D6S392 is closely associated with development of DM in Moscow population. This may indicate possible participation of the gene SOD2 in development of this pathology.

[Associative analysis of the connection between mutation C1167T in the catalase gene and polymorphic marker D6S392 nearby the Mn-dependent superoxide dismutase gene with diabetic microangiopathies]. / Assotsiativnyi analiz sviazi mutatsii C1167T v gene katalazy i polimorfnogo markera D6S392 riadom s genom Mn-zavisimoi superoksiddismutazy s diabeticheskimi mikroangiopatiiami.

AIM: To study allele polymorphism of two variable regions [C1167T substitution in the catalase (CAT) gene D6S392 microsatellite near the Mn-dependent superoxide dismutase (SOD2) gene] was studied in insulin-dependent diabetic (IDDM) patients with (n = 36) or without (n = 56) diabetic nephropathy, and with (n = 30) or without (n = 44) diabetic retinopathy. MATERIAL AND METHODS: Both polymorphic regions were amplified using polymerase chain reaction (PCR). PCR products were separated using polyacrylamide (D6S366) or agarose (C1167T) gel electrophoresis. In a case of C1167, PCR-amplified products were digested with BstXI restriction endonuclease before electrophoresis. A significance of the difference between allele distributions in complicated and uncomplicated IDDM patients was estimated using the exact Fisher's test. RESULTS: No significant difference was observed in allele and genotype frequencies in complicated and uncomplicated IDDM subjects. CONCLUSION: C1167 polymorphism in the CAT gene and D6S366 near the SOD2 gene are not associated with the development of diabetic nephropathy and diabetic retinopathy in IDDM.

[Polymorphic markers of endothelial NO-synthase and angiotensin II vascular receptor genes and predisposition to ischemic heart disease]. / Polimorfnye markery genov éndotelial'noi NO-sintazy i sosudistogo retseptora angiotenzina II i predraspolozhennost' k ishemicheskoi bolezni serdtsa.

Allele and genotype frequency distribution patterns of the polymorphic regions at the genes for human endothelial NO-synthase (NOS3) (the ecNOS4a/4b VNTR and the Glu298Asp substitution) and the angiotensin II type 1 receptor (AT1)(the A1166C substitution) were compared in 83 unrelated healthy individuals and 88 patients with ischemic heart disease (IHD). In the group of patients statistically significantly higher frequencies of the NOS3 allele 4a (45.5 versus 19.3%), as well as the 4a/4a (15.9 versus 2.4%) and 4a/4b (59.1 versus 33.7%) genotypes were observed. Frequencies of the allele 4b (54.5% versus 80.7%) and the 4b/4b homozygotes (25.0 versus 63.9%) were statistically significantly lower in the group of IHD patients than in healthy individuals. The IHD patients were statistically significantly different from the healthy subjects also in the distributions of the AT1 genotypes. In the former group, a significantly decreased frequency of the AA homozygotes (51.1 versus 65.1%) and an increased frequency of AC heterozygotes (40.9 versus 27.7%) were observed. Thus, in the Moscow population the ecNOS4a/4b VNTR of the NOS3 gene and the A1166C polymorphism of the AT1 gene are associated with the IHD development. Furthermore, the correlation with the IHD revealed was much stronger for the NOS3 VNTR locus.