[Genetics of osteoporosis].

Osteoporosis is a common disease with a strong genetic componenet characterized by reduced bone mass and increased risk of fragility fractures. Twins and family studies have shown that the heritability of bone mineral density (BMD) and other determinants of fracture risk - such as ultrasound properties of bone, skeletal geometry, and bone turnover - are high, although heritability of fracture is modest. In this article, some important gene identifications of the last years such as vitamin receptor, estrogen receptor alpha, alpha 1 chain of type I collagen, low density lipoprotein receptor - related protein 5, bone morphogenic proteins 2 and 4, transforming growth factor beta 1, receptor activator of NF-kappa-B, receptor activator of NF-kappa-B ligand, osteoprotegerin and their contribution to the understanding of the genetic regulation of bone mass and susceptibility to osteoporosis are present.

[Allele polymorphism of alkaline phosphatase, acid soluble phosphatase, and vitamin D-binding protein genes in postmenopausal osteoporosis]. / Allel'nyi polimorfizm genov shchelochnoi fosfatazy, kisloi rastvorimoi fosfatazy i belka, sviazyvaiushchego vitamin D, pri postklimaktericheskom osteoporoze.

AIM: To study polymorphism of genes involved in mechanisms regulating metabolism of bone tissue: alkaline (ALPL) and acid (ACP1) phosphatases, vitamin D-binding protein (GC); to ascertain associations of their genotypes and alleles with osteoporosis (OP) and mineral density of spinal and femoral bone tissue (BTMD). MATERIAL AND METHODS: Relevant genetic examination was made in 70 females with OP diagnosed by the WHO criteria (1994) aged 60-79 years (mean age 71.0 +/- 6.2 years) and 51 OP-free females in the same age interval (mean age 69.0 +/- 5.6 years). Polymorphic sites of the genes were examined by polymerase chain reaction. Trinucleotide repeat, ARG105GLN polymorphism of restrictive fragment length (PRFL), [GC, TRH420LYS] PRFL were studied for ALPL gene, ACP1 gene and GC gene, respectively. RESULTS: Association was found between frequencies of genotypes SS, 2F and FS, F allele of GC gene with OP as well as between PRFL of the spine, femur and some GC genotypes in OP women. Genes ALPL and ACP1 were not associated with OP. CONCLUSION: It is suggested that genotypes SS, 2F and FS have marked functional differences in fixation and transport of vitamin D active metabolites involved in metabolism of bone tissue in OP.

[A search for genes of predisposition to rheumatoid arthritis]. / Poisk genov predraspolozhennosti k revmatoidnomu artritu.

Rheumatoid arthritis belongs to the group of autoimmune multifactor diseases with an essential involvement of genetic components in its genesis. The HLA DRB1* polymorphism was studied in 68 RA patients and in their 75 healthy relatives. 135 blood donors, who were tested at the Institute for Immunology of the Ministry of Health, Russian Federation, Moscow, were in the control group. The carrier-state of the HLA DRB1* 04 gene contributes to a higher probability of RA onset by 8.5 times, while the presence, in genotype, of genes HLADRB1* 02, 05, 06 reduces the risk of RA by 2.1, 2.3 and 7.2 times, respectively. Allele *0401 is encountered reliably more often in RA patients versus healthy controls. Within a sample of patients with familial RA, 43.9% turned out to be the carriers with various combinations of two alleles of genes coding the conservative amine acids of sequences QKRAA or QRRAA, which were named "shared epitope" (SE), versus 5.1% among the controls. The presence of homozygous "SE genotypes" among the RA patients contributed to a higher risk of morbidity by 5.8 times, while the carrier state of haplotypes with "duel SE positivity" enhanced the risk of morbidity by 17.8 times mainly due to the 01/0401 halotype. The RA linkage with two intragenic DNA markers, i.e. with the polymorphous micro-satellite replication of gene TCRA (CA)n and with the point-type changeability (localized in the coding area of the second variable region of V2 TCRD gene), was analyzed. The maximal possible value of the lod-point for (CA)n, i.e. replication of TCRA gene, was equal to +1.30 in males under the condition of zero recombination frequency, and to 16% of frequency recombination in females. The maximal possible value of the lod-point for the point-type changeability of gene TCRD was equal to +0.70 in males under the conditions of zero frequency recombination and to 40% of frequency recombination in females. The maximal lod-point value amounting to +1.20 in males and females in an identical frequency recombination of 5% was found on the basis of a three-point analysis of the linkage between RA and two intragenic markers from gene clusters coding the alpha- and beta-chains of T-cellular receptors. Therefore, our familial data are indicative of the opportunity of localizing the gene predisposed to RA is at a distance of 5 cM, in the direction of the telomere, from the locus of the examined (CA)n, i.e. replication of gene TCRA.

[Polymorphism of Fc gamma RIIIA-158F/V gene and promoter region of IL-10 gene in systemic lupus erythematosus in Kazakhs]. / Polimorfizm gena FcgammaRIIIA-158F/V i promotornoi oblasti gena IL-10 pri sistemnoi krasnoi volchanke u kazakhov.

AIM: To assess the role of allele polymorphism of genes Fc gamma RIII and IL-10 in systemic lupus erythematosus (SLR) in a homogeneous (stratified by nationality) Kazakh population sample. MATERIAL AND METHODS: Polymorphism of genes Fc gamma RIIIA and IL-10 was studied in 49 patients SLE patients and 81 healthy subjects (control group). Detection of two allele variants of gene Fc gamma RIIIA (alleles F and V) caused by point mutation in position 559 was performed by polymerase chain reaction (PCR) in the amplification refractory mutation system. Genetic changeability of IL-10 gene promotion site due to point mutation in position 627 (alleles 1 and 2) was investigated by polymorphism of restricted fragment lengths using restrictase RsaI. RESULTS: Significant differences in the distribution rates of genes Fc gamma RIIIA and IL-10 were revealed in SLE patients versus controls. Alleles F and -627A (1), including homozygous ones, are genes predisposing to development of SLE while variants of the markers V and -627 (2) are protecting genes. If a SLE patient's genotype combines alleles F of gene Fc gamma RIII and alleles 1 of gene IL-10 (F/F + 1/1), this patient has an 8 times higher risk to develop SLE. CONCLUSION: Polymorphism of genes Fc gamma RIIIA and IL-10 is associated with predisposition to development of SLE in Kazakh population. The analysis of combined genotypes of the studied genes suggests a synergic action of genes Fc gamma RIIIA and IL-10 on the risk to develop SLE.

[An analysis of the linkage of hypertrophic cardiomyopathy and the delta locus of the T-cell receptor (TCRD) chain in the family of P]. / Analiz stsepleniia gipertroficheskoi kardiomiopatii i lokusa del'ta tsepi T-kletochnogo retseptora (TCRD) v sem'e P.

AIM: To estimate probability of location of the gene determining family hypertrophic cardiomyopathy (HCMP) in family P. on the 14th chromosome in segment 14q11 using parametric method "lod score". MATERIALS AND METHODS: The family of proband P. had multiple cases of HCMP. Dinucleotide GT repeat and NT 256 point variation located in the cluster of genes coding synthesis of TCRD (14q11 chromosome segment) were used as markers of HCMP gene (FHC-1 gene 14q1 chromosome segment). Allele polymorphism of the two markers was defined at polymerase chain reaction, restriction of the amplificate by restrictase BamHI (for NT 256 point variation) and vertical electrophoresis in polyacrylamide and agar gels. RESULTS: Basing on the distribution of the above markers in P. family, lod score estimates in all the standard values of recombination frequency were determined (0-0,45, step 0.05). The maximal estimate corresponded to zero recombination frequency and was equal to 1.17 (this was below the critical value 3). However, the obtained lod score value satisfied the chance ratio 15:1 in favor of the link presence. CONCLUSION: The data obtained evidence for the presence of the link of HCMP gene with marker locus TCRD which is nearby the identified locus of the disease (FHC-1-14q11.2 segment). This suggests that HCMP in family P may be due to mutant allele of the gene coding synthesis of beta-polypeptide chains of cardial myosin.

[Genetic aspects of rheumatic diseases]. / Geneticheskie aspekty revmaticheskikh boleznei.

The paper presents the results of the long-term studies of the pattern of hereditary predisposition to rheumatism, rheumatoid arthritis (RA), ankylosing spondyloarthritis (AS), osteoarthrosis which have been conducted at the Institute of Rheumatology, Russian Academy of Medical Sciences. It gives data on the type of inheritance of these diseases, the affliction heritability ratio, the penetrance of three genotypes within the model of an autosomal one-allele locus (SAL-2) for rheumatism and RA. The contribution of additive and dominant components in the determination of rheumatism and RA, the results of tests of their genetic heterogeneity, associations with HLA antigens are assessed. The paper outlines the results of tests of the candidate genes COLIA2, TCRB, TCRD as major RA predisposition genes via analysis of adherence and DNA polymorphism.

[Analysis of linkage of HLA antigens and rheumatoid arthritis]. / Analiz sovmestnogo nasledovaniia antigenov HLA i revmatoidnogo artrita.

Based on consistent associations of rheumatoid arthritis (RA) with some HLA antigens several authors hypothesized the existence of a gene of susceptibility to RA, linked closely with the HLA loci and in disequilibrium with associated alleles. Data on six pedigrees (four of these involved three generations) with recurrent diseases (in total, 45 individuals, 13 of whom were affected with RA) were used in the linkage analysis. The data on allelic typing of HLA-A and -B loci were combined to form a "superlocus" that enabled more accurate determination of an individual genotype for the marker. Previously obtained parameters of disease inheritance were used to test the locus: a frequency of the abnormal allele of 2.14%, and the penetrances of abnormal homozygotes, heterozygotes, and normal homozygotes of 100, 2.1, and 0% in men and 100, 6, and 0.3% in, respectively. A softwares package developed in the Department of Epidemiology and Genetics of the Institute of Rheumatology, Russian Academy of Medical Sciences, was used in the linkage analysis. This work resulted in two-dimensional tables of Lod score values at different recombination frequencies (RF), changing with a step of 0.05 in men and women. The minimal Lord score value at RF = 0 is -2.11, which is higher than the critical value (-2.0) and serves as an indication of the absence of close linkage between the analyzed loci.

[The pattern of predisposition to rheumatism]. / Struktura predraspolozhennosti k revmatizmu.

The present study was based on the results of many-year studies of the Mongoloid populations the Tofalars (793 and 661 persons in 1973 and 1984, respectively), the Dolgans (n = 952) the Taimyr Yakuts (n = 452), the Todji Tuvins (n = 819) and a sample from 200 families of rheumatic patients in Moscow and Moscow Region. The interpopulation gene differentiation expressed through the generalized genetic distance (8) and the prevalence of rheumatism correlated (r = 0.63). There was also a correlation between the mean heterozygocity of the populations and the spread of rheumatism-the determination rate was 72%. Therefore, structural features of the populations have a definite impact on the prevalence of rheumatism and suggest that there is a genetic component in the determination of the disease. A segregative analysis indicated the adequacy of a multifactorial model for the majority of the studied populations, the contribution of a genetic component to the determination of varying susceptibility to rheumatism ranged from 71% in the population of the Tofalars to 100% in the populations of the Dolgans and the Tuvins. The results of testing the type of rheumatism inheritance using a SAL-2 model, the data of a regression analysis of susceptibility heritability and inbreedity of the populations, and a component resolution of phenotypic dispersion of susceptibility are indicative of its involvement, along with an additive component, in the determination of rheumatism. Clinical and genetic findings also suggest that there is a genetic heterogeneity both of rheumatism as a whole (verified +likely) and verified rheumatism (without and with cardiac diseases).

[Genetic variants of acid erythrocytic phosphatase as a risk factor of rheumatic fever]. / Geneticheskie varianty kisloi éritrotsitarnoi fosfatazy kak faktor riska revmatizma.

A study was made of the genetic variants (isoenzymes, phenotypes) of acid erythrocytic phosphatase (AcP) in 120 patients with rheumatic fever. There were 78 women and 42 men aged 16 to 57 years. The population data concerned with distribution of the AcP variants among the population of Moscow were used as control. As compared with control, the patients suffering from rheumatic fever demonstrated the accumulation of the rarely occurring variants of AcP (AC, BC and CC, in particular). A significant direct correlation was established between the activity of isoenzymes and relative risk of rheumatic fever incidence. The definite regularities in the distribution of AcP variants were found to depend on the disease clinical patterns (the articular syndrome, the times of the formation of heart diseases, the character of recurrent rheumocarditis). The data obtained can used for distinguishing the rheumatic fever risk groups and forecasting the rheumatic process (to a certain degree of probability).

[The genetics of rheumatic diseases: genetic basis of the classification of multifactorial diseases]. / Genetika revmaticheskikh zabolevanii: geneticheskie osnovy klassifikatsii mul'tifaktorial'nykh zabolevanii.

Examination of the pattern of hereditary predisposition allows a more precise determination of pathogenetic relationships between individual clinical forms and variants of multifactorial diseases (MFD), as well as assessment of the possibilities and approaches to a genetic classification to be made. The construction of genetic classifications is based on the identification of differences in the type of inheritance, the study of the progeny in families where both parents have the same or different forms of the disease, the results of the marker adhesion test, and the genetic correlation coefficients. The study has made use of some clinical forms of rheumatic diseases, whose relationships are a subject of controversy among the clinicians, as splitting phenotypes. Segregation analysis of the selected clinical forms of rheumatic diseases and genetic correlation coefficients obtained within the framework of a quasi-continuous model provide no indication that these forms can be isolated as independent nosologic entities. Possible phenotype splitting into individual subtypes and the potentialities of a marker approach to the construction of genetic MFD classifications are demonstrated, with rheumatoid arthritis associated with HLA antigen Dr 4 taken as an example.

[Dermatoglyphics in patients with rheumatism]. / Dermatoglifika u bol'nykh revmatizmom.

Dermatoglyphic parameters were studied in 163 patients with rheumatic fever (111 women and 52 men aged 16 to 58) and in 200 controls (131 women and 69 men) in the Moscow population. Quantitative parameters of the patients did not differ from those of the controls. An analysis of the qualitative parameters showed statistically significant differences in the whole group of the patients as well as in relation to the presence and topical character of heart disease as compared to the controls. Differences in dermatoglyphic indices in particular clinical types of rheumatic fever were mainly associated with a type of phenotypical pattern on the fingers, the presence or absence of a pattern on thenar and hypothenar, a pattern type on the fourth and fifth fingers. The authors have been of opinion that the results obtained make it possible to predict, with a positive degree of probability, a possibility of development of disease as well as its outcome (the formation of heart disease).

[The HLA system and its contribution to the genetics of rheumatic diseases]. / Izuchenie sistemy HLA i ee vklad v genetiku nekotorykh revmaticheskikh boleznei.

The results of the study of histocompatibility antigens at loci A, B and Dr in patients with RA and SLE, and their first degree relatives are presented. HLA antigens B12. B18, B27, Dr2 and Dr4 were associated with RA. The antigens HLA A11, B7, B35, Dr2 and Dr3 were associated with SLE. The influence of HLA antigens on formation of clinical picture of RA and SLE was determined. Evaluation of interallelic and interloci antigens interaction in a relative risk of disease suggests that, in some cases, there is a "superdominance" effect. Some combinations of HLA antigens at loci B and Dr increase the disease risk for RA and SLE. Analysis of test-marker linkage to genes predisposed to RA and SLE provides no direct confirmation of the hypothesis of their location on the short arm of the sixth chromosome between loci B and Dr, though this possibility cannot be completely excluded.

[Population genetics study of rheumatism in the Dolgans of the Taimyr]. / Populiatsionno-geneticheskoe izuchenie revmatizma u dolgan Taimyra.

The results of medical-genetic examination of population in five villages of Taimir have been presented. Among them 824 dolgans (aborigines) have been inspected. The prevalence of rheumatism is in average 3,23%. The frequency of rheumatism in the southern subpopulation was higher, than in the North. Analysis of pedigrees has shown family aggregation of rheumatism which correlated with theoretically expected according to recessive hypothesis. Investigations of genetic markers have shown important distinction of rheumatic patients from population on ABC and Hp.