[Nozological Heterogeneity, Molecular Genetics and Immunology of Autoimmune Diabetes Mellitus].

Article is devoted to the review of literature data, and also the analysis of results of own researches concerning genetics, molecular genetics and immunological violations at various forms of the autoimmune diabetes (DM) including classical T1DM, LADA type and an autoimmune polyglandular syndrome of 1 type (APS1). In case of T1DM more than 80% of patients are carriers of one or two strongest predisposing haplotypes: DRB1*04-DQA1*0301-DQB1*0302 and DRB1*03-DQA1*0501-DQB1*0201 designated as DQ2 and DQ8. HLA genes can model a clinical features of disease. In Russian population, the children with diabetes manifestation up to 5-year age has significantly often high risk genotypes (DQ2/ DQ8) and significantly less the low risk genotypes in comparison with children, who had manifestation of T1DMin 10 years and later. The long-term 16-yearsfamily studies showed the maximum frequency of TJDMin high risk group, constantly accruing in process of increase in term of supervision, and in groups of an average and low risk lower and invariable. The highest risk of T1DM manifestation, reaching 90% at 10 years of supervision is defined by existence of HLA high risk genotypes and many antibodies, revealedfrom early age. LADA - the hybridform of autoimmune DM having signs of T1DM and T2DM in the basis. The development of autoimmune process against ß-cells can be caused by only gene mutation (APS1). The part of T1DM cases which doesn't have the contributing HLA genes and autoimmune markers in process of studying of the importance of various genes and their biological value can be attributed to new, yet unknown forms of DM.

[Immunogenetics of type 1 diabetes mellitus--from fundamental ideas to medical practice].

The review of studies of Russian researchers on theoretical and practical aspects of genetic predisposition to type 1 diabetes associated with immunity: HLA and not HLA genes. Most important for practical public health outcomes are evidence that HLA-genetic predisposition to type 1 diabetes is associated with the DRB1-genotype, consisting entirely of variants DRB1-genes associated with the development of T1D. It was also established that CTLA4 gene has an independent predictive value for T1D.

[Molecular genetics and clinical aspects of monogenic diabetes mellitus].

The paper is dedicated to clinical and laboratory aspects of Diabetes Mellitus non-immune forms, such as neonatal Diabetes Mellitus, Maturity Onset Diabetes of young (MODY), DIDMOAD-syndrome, Wolframe syndrome, Alstrom syndrome and its determinating genes. The analysis of proper clinical results are present in this paper.

[Association of the polymorphisms of the ERBB3 and SH2B3 genes with type 1 diabetes].

To study the association with diabetes mellitus type 1 we performed analysis of the distribution of frequencies of alleles and genotypes of polymorphic marker rs2292239 of ERBB3 gene, encoding epidermal growth factor receptor type 3 and polymorphic marker rs3184504 of SH2B3 gene, encoding adaptor protein LNK. The study included groups of T1DM patients and unrelated controls of Russian origin. Genotyping was performed using methods of RFLP and real-time amplification. For the polymorphic marker rs2292239 of ERBB3 gene was not found statistically significant associations with type 1 diabetes, while analysis of the distribution of frequencies of alleles and genotypes of the polymorphic marker rs3184504 of SH2B3 gene showed the presence of association with T1DM in Russian population.

[Association of the T(-365)C POLG1, G(-25)A ANT1 and G(-605)T PEO1 gene polymorphisms with diabetic polyneuropathy in patients with type 1 diabetes mellitus].

The aim of this study was the search of association of polymorphic markers T(-365)C of POLG1 gene, G(-25)A of ANT1 gene and G(-605)T of PEO1 gene with diabetic polyneuropathy (DPN) in type 1 diabetes mellitus (T1DM) patients. All patients were ethnic Russians from Moscow, with a T1DM record of no more than 5 years and DPN or a T1DM record of more than 10 years but without DPN. We have found that polymorphic marker T(-365)C of POLG1 gene was associated with DPN in Russian patients with T1DM. The carriers of C allele and CC genotype had higher risk of DPN development (OR = 1.62; CI = 1.11-238; and OR = 1.76; CI = 0.99-3.13; relatively). On the contrary, the carriage of T allele and TT genotype were associated with the lower risk of DPN development (OR = 0.62, CI = 0.42-0.90; and OR = 0.61; CI = 035-1.07; relatively). We have not found any association of polymorphic markers G(-25)A of ANT1 gene and G(-605)T of PEO1 gene with DPN in Russian patients with T1DM living in Moscow.

[Association of the C1858T polymorphism of the PTPN22 gene with type 1 diabetes].

To study the association with diabetes mellitus type 1 (T1DM) we performed TDT analysis and analysis of the distribution of frequencies of alleles and genotypes of polymorphic marker C1858T of the PTPN22 gene, encoding tyrosine phosphatase of non-receptor type (LYP). Groups of concordant (27 families) and discordant (62 families) sibpairs and groups of T1DM patients and unrelated controls of Russian origin were recruited in Endocrinology Research Center, Moscow and Center of Diabetes, Samara. For a given polymorphic marker was not found statistically significant associations with type 1 diabetes in the transmission disequilibrium test, while analysis of the distribution of frequencies of alleles and genotypes showed the association with T1DM. Thus, the polymorphic marker C1858T of the PTPN22 gene is associated with T1DM in Russian patients.

[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.

[The use of achievements in human molecular immunogenetics in the management of type 1 diabetes mellitus].

New original data are presented on the use of achievements in human molecular immunogenetics in the management of type 1 diabetes mellitus. They include materials allowing for the prediction of the development of the disease at the population, family, and individual levels along with novel approaches to its radical treatment by the reconstitution of the lost glucose tolerance. The reported data may find wide application in current clinical practice. They open up new prospects for the enhancement of efficacy of prognosis, diagnosis, and treatment of type 1 diabetes mellitus and other autoimmune diseases.

Evidence for a type 1 diabetes susceptibility locus (IDDM10) on chromosome 10p11-q11 in a Russian population.

Around 20 susceptibility loci for type 1 diabetes mellitus (T1DM) have been mapped. One of these loci, IDDM10, was found on chromosome 10p11-q11. Here, we investigated whether the IDDM10 locus contributes in the susceptibility to T1DM in a Russian family dataset. One hundred and fourteen simplex Russian families, each containing two siblings (one affected with T1DM diagnosed and one nondiabetic sibling), and 97 multiplex families, containing 106 affected full sibling pairs, were studied. Genomic DNA from the venous blood of the patients was genotyped by PCR using 12 microsatellites (D10S193, D10S548, D10S565, D10S586, D10S588, D10S675, D10S1243, D10S1426, D10S1733, D10S1772, D10S1780 and D10S1783) located on chromosome 10p11-q11. Using the multipoint linkage analysis, the region of suggestive linkage, with a multipoint logarithm of odds (LOD) ratio (MLS) value of more than 2.2, was found between markers D10S1733 and D10S1780, an area of 9.0 cM on the genetic map. The maximum linkage peak (MLS = 2.85 and nonparametric logarithm = 2.68) was observed between markers D11S565 and D11S1243. Using the transmission disequilibrium test, an association of these markers, D10S565 (P overall = 0.0082) and D10S1243 (P overall = 0.017), with T1DM was shown. These results suggest the evidence for the IDDM10 susceptibility locus on chromosome 10p11-q11.

A new type 1 diabetes susceptibility locus containing the catalase gene (chromosome 11p13) in a Russian population.

BACKGROUND: Oxidative stress is involved in the origin of type 1 diabetes. Low efficiency of the scavenging antioxidant system has been shown to be related to the pathogenesis of the disease. This, therefore suggests that genes encoding catalase and other antioxidant enzymes may implicate in the development of type 1 diabetes. METHODS: Nine microsatellite markers that cover about 10 megabases around the catalase (CAT) gene on chromosome 11p13 were analyzed using polymerase chain reaction (PCR) and fluorescence-based genotyping on an automatic DNA sequencer. We also evaluated three single-nucleotide polymorphisms (SNP) within genes encoding catalase (T1667T and C(-262)T dimorphism) and ETS homologous factor (EHF) (C255T SNP) using a PCR-restriction fragment-length polymorphism approach. Multipont linkage analysis in 37 affected sibling pairs was performed using GENEHUNTER 2.1. We examined the markers for association with the disease by transmission disequilibrium tests in 57 discordant sibling pairs and by a case-control study in 258 unrelated healthy donors and 247 affected patients. RESULTS: We obtained close-to-suggestive evidence of linkage to type I diabetes, with the maximum linkage peak between markers D11S907 and D11S2008. Analysis of three SNPs at the CAT and EHF gene located within the region of maximum linkage showed that T1667T and C(-262)T markers of the CAT gene are strongly associated with the disease. CONCLUSION: Our findings support evidence of a new putative type 1 diabetes susceptibility locus on chromosome 11p13 and suggest that the CAT gene may play a role in conferring susceptibility to the disorder in Russian patients.

[Analysis of nuclear families with two or more patients with insulin-dependent diabetes mellitus with diabetic siblings]. / Analiz iadernykh semei s dvumia i bolee bol'nymi insulinzavisimym sakharnym diabetom sibsami.

HLA haplotype distribution was analyzed in nuclear families of patients with insulin-dependent diabetes mellitus. Sixteen families with two or more diabetic siblings were examined, a total of 69 subjects, 33 of these diabetic siblings and 36 normal subjects (siblings and parents). The data were processed using the involved sibling pairs method based on a mixed model making use of a conditional probability approach. The ratio of diabetic sibling pairs concordant by 2 haplotypes, 1 haplotype, and discordant by 2 haplotypes was 9:5:2 vs. 1:2:1 expected according to Mendel's accidental distribution (p < 0.025). Increased incidence of siblings concordant by 2 haplotypes proves the presence in the HLA domain of one or several genes responsible for the development of diabetes mellitus. Siblings identical by two HLA haplotypes with the diabetic proband are at a higher risk of developing this disease.

[Limited mobility of the joints: A complication of diabetes mellitus in children and adolescents]. / Ogranichenie podvizhnosti sustavov--oslozhnenie sakharnogo diabeta u detei i podrostkov.

The incidence of a specific complication, limited mobility of the joints (mainly of interphalangeal joints of the hand), was estimated in 108 patients aged 6 to 22 with insulin-dependent diabetes of 5 and more years duration. It was found to be high: 44%. This complication more frequently develops in cases of poor metabolic control and longer disease duration. Limited mobility of the joints in children and adolescents with insulin-dependent diabetes permits predict in them with a 50% probability early manifestations of retinopathy and nephropathy. A classification of this complication by three degrees is offered.

Frequency analysis of HLA-DQA1 and HLA-DQB1 gene alleles and susceptibility to type 1 diabetes mellitus in Russian patients.

The HLA-DQA1 and DQB1 genes have recently been recognized to be strong genetic markers of susceptibility to type 1 (insulin-dependent) diabetes mellitus. The Arg52 DQA1 and non-Asp57 DQB1 alleles of these genes correlate with the disease predisposition and the Asp57 DQB1 and non-Arg52 DQA1 alleles with disease protection. We investigated 113 patients with type 1 diabetes and 121 healthy subjects from the Russian population of Moscow using DNA amplification and dot-blot hybridization with sequence-specific oligonucleotides (SSO). Using conventional statistical methods we confirmed previous observations indicating the important role of the above-mentioned amino acid residues in susceptibility and resistance to type 1 diabetes. Relative risk values for all alleles and absolute risk for carriers of most predisposing allele combinations were calculated. The absolute risk for carriers of DQA1 and DQB1 gene alleles allowing for the formation of four possible 'diabetogenic' heterodimers on the surface of immunocompetent cells, regardless of the type of coding (cis or trans), was 2.54%, which is 13 times greater than the background risk for the Russian population--0.2% up to 30 years of age.

[Constitutional and dermatoglyphic characteristics of children with diabetes mellitus]. / Konstitutsional'no-dermatoglificheskaia kharakteristika detei s sakharnym diabetom.

A group of Russian children with clinically diagnosed diabetes mellitus were examined using a comprehensive constitutional dermatoglyphic program. Pattern asymmetry was observed in children of both sexes. On the whole the examined population was characterized by reduced incidence of loop patterns and increased incidence of double-delta patterns. In boys the incidence of arches and coils was higher and that of loops lower than in controls, in girls there were no arches and the incidence of radical and ulnar loops was low. Analysis of genetically determined signs, both anthropometric and dermatoglyphic ones, and use of other criteria will help assess the significance of these signs as markers of risk of development of type I diabetes.

[Diabetes mellitus incidence and its prevalence in Moscow]. / Zabolevaemost' sakharnym diabetom i ego rasprostranennost' v Moskve.

Epidemiologic survey of two diabetes mellitus types in Moscow has shown that the incidence of type I diabetes markedly increases from birth (0.012-0.013%) to the age of 10-14 (0.04-0.045%), after which somewhat reduces (0.02-0.03%) and thus persists up to 40. Type I diabetes prevalence increases from 0.002-0.004% at the age of 0 to 4 years to 0.14-0.092% by the age of 35-39 in men and women, respectively. Type II diabetes is diagnosed after the age of 20. At the age of 20 to 24 this diabetes incidence is lower than that of type I condition; at the age of 25-34 the incidence of both is approximately the same, and after 35 the incidence of type II is much higher than that of type I diabetes. Type II diabetes prevalence by the age of 40 is 0.074 and 0.122% in men and women, respectively. Prevalence of diabetes cases treated with diets and oral sugar-reducing drugs at the age 75 and older is 4.3% in men and 5.5% in women, of insulin-treated cases 1.2 and 0.5%, respectively. The true prevalence of type II diabetes is however higher and that of type I condition lower than the resultant values; this is explained by a frequent prescription of insulin to elderly patients with type II diabetes because of complications or concomitant diseases.

[Probability of an association between HLA- and DR-antigens in nuclear families of patients with insulin-dependent diabetes mellitus]. / Veroiatnost' assotsiatsii mezhdu HLA- i DR-antigenami v iadernykh sem'iakh bol'nykh insulinzavisimym sakharnym diabetom.

Insulin dependent diabetes mellitus (IDDM) is known to associate with various antigens and alleles of the HLA-system: DR3, DR4, and DQ-determinants. However penetration of the HLA-genes, predisposing to disease, is low, suggesting a possible role of additional genes outside the HLA-system in IDDM development. Among such genes there can be a group of heavy chain Ig genes (the Gm-system). The frequency of antigens of the Gm-system C1m(1) and C1m(2) and antigens of loci A, B, C and DR of the HLA-system was investigated in 92 Russians divided into 3 groups: 1 - IDDM patients from nuclear families (n = 35); 2 - their relatives of the 1st degree of kinship (n = 34); 3 - a random sampling (n = 23). The results obtained by A. A. Lopatenok and O. S. Budyakov (1973) were used as control data. No significant difference (p greater than 0.05) was found while comparing the frequency of Gm-phenotypes in IDDM patients from nuclear families with DR 4/X and in IDDM patients from nuclear families with another DR-phenotype, nor any significant difference was noted while comparing the frequency of Gm-phenotypes in IDDM patients from nuclear families and in patients from a random sampling with the HLA-phenotype DR 4/X. Thus the relationship of the Gm-system with IDDM through interrelationship with the HLA-DR-genes was undetectable. A conclusion was made that factors of the Gm-system played no significant role in predisposition to IDDM and could not be used as its genetic markers.

[Glycemia as a risk factor of reduced tolerance of hypoxic hypoxia in flight personnel]. / Glikemiia kak faktor riska ponizhennoi perenosimosti gipoksicheskoi gipoksii u letnogo sostava.

The glycemic level was measured in 61 people exposed to hypoxic hypoxia. Three major types of glycemic responses were identified: type I--no change (15.79%); type II--hypoglycemia (49.12%), and type III--hyperglycemia (35.09%). The subjects with a low resistance to hypoxic hypoxia typically showed a low glycemic level (57.5 +/- 2.5 mg%. P < 0.05). It is suggested that three types of glycemic responses to hypoxia reflect three major pathways of biochemical adaptation of the body. It is recommended to study hormonal changes in people with hyperglycemic responses to hypoxia. This will help determine hormonal levels responsible for hyperglycemia and, consequently, develop methods of early detection of susceptibility to cardiovascular diseases and diabetes mellitus. This approach may contribute to medical expertise and rehabilitation of the flying personnel.

[Medico-genetic counselling of the relatives of patients with type I diabetes mellitus]. / Mediko-geneticheskoe konsul'tirovanie rodstvennikov bol'nykh sakharnym diabetom I tipa.

Population-genetic surveys show that for the relatives of patients with type I diabetes mellitus (the 1st degree of kinship) a risk of developing the same type of diabetes is 2-5%. Tables of repeated risk of developing diabetes mellitus (DM) of type I for persons with a different number of relatives affected by this type of DM were calculated on the basis of analysis of 2000 family histories of DM patients (a random sampling). A risk of developing this disease is in direct correlation with the number of sick and healthy relatives and their age. The presence of patients with type II DM in a family does not influence the risk of developing type I DM. Risk assessments are of prognostic rather than diagnostic value. The effectiveness of medico-genetic counselling can be increased with the help of various genetic markers, associated with type I DM. Risk assessment must lay the basis of a follow-up of persons with aggravated heredity by investigating immunological, hormonal and metabolic derangements in them.