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Abdurakhmanov Mamur Mustafayevich,
DM., professor, professor of the department of surgical Diseases, Resuscitation and Anesthesiology of the Bukhara State Medical Institute Abdullayeva Muslima Akhadovna, senior lecturer of the department of physiology and pathological physiology of the Bukhara State Medical Institute Bukhara, Uzbekistan E-mail: [email protected]
CONGENITAL RISK FACTORS IN UZBEK POPULATION WITH NONSPECIFIC AORTOARTERIITIS
Abstract: The distribution of HLA antigens in patients with aortoarteriitis in the Uzbek population (UP) was studied. 42 patients with nonspecific aortoarteriitis (NAA) were examined, the control group consisted of 100 healthy donors of Uzbek nationality. The results of the studies demonstrate that the most frequently identified antigens are HLA-B13, B40 and DR2. These antigens play an important role in predisposition to NAA. The more rarely identified antigens are: HLA-A10 and B35 playing the role of protectors in predisposition to NAA. HLA-B40 antigen has the highest relative risk (RR = 6.7). Combinations of these antigens in the individuals' phenotype increase the risk of NAA. The most frequently demonstrated haplotypes are: HLA-A11/B40, B40/DR2, A3/B13.
Keywords: nonspecific aortoarteriitis, HLA antigens, Uzbek population, phenotype, risk, haplotypes.
The recent decades saw the rise of the incidence of NAA agnosed to have chronic NAA. 26 patients had a continuously in different countries of the world including CIS countries. In recurrent and 16 a latent disease pattern.
the 30s-50s NAA was classified with a casuistic disease but today it ranks second in frequency of involvement of aortic arch branches, yielding only to atherosclerosis [4].
The etiology and, in many respects, the pathogenesis of this disease have not been specified until now and thus remain the point at issue.
The majority of the research workers think that NAA is an autoimmune disease marked by primary involvement of the intima and media of the aorta and main vessels [5]. On account of the key role the immune mechanisms play in the pathogenesis of NAA it should be assumed that certain allelic genes of the HLA system are implicated in it. As established, the HLA system controls the immune system of man. However, in the literature there are only single controversial communications about the relationship between some HLA-antigens and NAA [1; 6].
The purpose of the present study was to examine distribution of HLA-antigens in the UP presenting with NAA.
Materials and methods. The present work is based on an analysis of the data on 42 UP aged 15 to 36 years (medium age 22.3 years) who were examined at the Department ofAngiol-ogy of Bukhara regional Multidisciplinary Medical Center. There were 18 men and 24 women. All the patients were di-
The diagnosis was established on the basis of the disease history, objective examination, physical and instrumental studies (volumetric sphygmography, rheoencephalography, Doppler ultrasound, contrast aortography). All the patients were found to have aortic arch syndrome. In 15 patients, it was associated with vasorenal hypertension, and in 4 patients with vasorenal hypertension and aortic bifurcation syndrome. Class I and II HLA-typing was performed using the 2-step mi-crolymphocytotoxic test with a panel of typing sera provided by the Saint-Petersburg Research Institute of Hematology and Blood Transfusion, Ministry of Public Health and Medical Industry of the RF. On analysis account was taken of12 locus A HLA-antigens: A1, A2, A3, A9, A10, A11, Awl9, A25, A28, A32, Aw33, Aw34; 16 locus B antigens: B5, B7, B12, B13, B14, B15, B16, B17, B18, Bw22, B27, B35, B40, B50, B51, B60; 4 locus C antigens: Cwl, Cw2, Cw3, Cw4; 14 locus DR antigens: DR1, DR2, DR3, DR4, DR7, DRw8, DR9, DRwlO, DRwll, DR12, DRwl3, Drwl4, DRwl5, DRwl6; 5 locus DQantigens: DQw2, DQw3, DQw4, DQw7.
Distribution of HLA-antigens in the patients' population was studied as compared to distribution of the same antigens in the healthy Uzbeks (n-100) living in the Bukhara region. The reliability of the frequency of HLA-antigens distribution
CONGENITAL RISK FACTORS IN UZBEK POPULATION WITH NONSPECIFIC AORTOARTERIITIS
in the groups under comparison was computed with the aid of the x2 criterion (criterion of correspondence). The association force was expressed via the relative risk (RR), the value indicates how many times more often or more seldom the individuals with the given HLA phenotype may develop the disease as compared to those lacking this phenotype. The RR was calculated according to the formula Woolf:
a •b
RR =
d • c
where a, b, c, d are values of the four-pole table: a - the number of patients with the given antigen, b - the number of patients lacking this antigen, c - the number of healthy individuals with the given antigen, d - the number of individuals without this antigen.
Results and discussion. Studies have shown that in the Uzbek population there were antigens of the HLA-F locus in the compared groups, such antigens as Al, A2, A3, A9, A28, A32. HLA=B5, B7, B8, B12, B50 are among specificities of the HLA-B locus, Cw2, Cw4 among those of C locus, DR1, DR3, DR4, DR7, DRw8, DR9, DRwlO, DRwl 1, DRwl3, DRwl4 among those of DR locus, and DQ2, DQ4, DQw7 among those of locus DQ. However, together with uniform distribution of HLA-antigens in the group of NAA patients, the frequency of which noticeably exceeds that identified in the controls. These are All (25% versus 13.7% in the controls), B13 (55% and 19.6%), B40 (30 and 5.9%). Among class II HLA antigens, these are DR2 (45% versus 21.1% in controls, DRwl 6 (7.5 and 1.1%).
Meanwhile the statistically significant difference in the frequency of HLA-antigen identification in NAA patients and healthy individuals was established for antigens such as B13 (X2 = 4.08; p < 0.05; RR = 3.54); B40 (x2 = 5.35; p < 0.05; RR = = 6.7); DR2 (x2 = 7.0; p < 0.05; RR = 3.8). As seen from the data obtained, the highest relative risk is discovered in Uzbeks having HLA = rB40 phenotype; on combination in the HLA-phenotype of the above-indicated antigens (B13, B40, DR2), the RR appreciably rises, increasing the disease risk in its carriers. It follows from the data presented that HLA=B13, B40and DR2 antigens may be regarded as unfavourable antigens determining predisposition to NAA in the Uzbek population. As compared to the healthy population, the frequency of identification of certain antigens in NAA patients was, on the contrary, considerably lowered. These are HLA = A10 (50% versus 21.6% in the control) and B35 (5 and 23.5%) antigens.
Therefore, these antigens determine the resistance to NAA in the UP and can be classified with protective genetic factors of NAA.
Analysis of the antigenic combinations has demonstrated that HLA-phenotypes, namely B13 = B40; A2 = A3 and haplo-types: A1/B7; A1/B13; A2/B13; A11 /B40; B40/DR2 occur-
ring at an increased rate in the patients are most significant for NAA occurrence in the UP. As seen from, six HLA haplotypes were identified most frequently in patients with NAA. Of these, 3 were found to be of statistical power. The highest reliability was marked for B40/DR2 haplotype (x2 = 6.05; p < 0.01), then there follow A11/B40 haplotype (x2 = 5.07; p < 0.01) and A3/ B13 haplotype (x2 = 3.89; p < 0.05).
The data obtained allow the conclusion to be drawn that predisposition to NAA in the UP is associated precisely with these HLA haplotypes. The positive importance of the gene linkage nonequilibrium was established for all these haplotypes. For instance, as far as HLA = A3/B13 haplotype is concerned, the observed frequency was 2.3 times higher than theoretically expected and that for HLA-B40/DR2 haplotype was 2.1 times higher. The greatest difference between the observed and theoretically expected frequency was noted for HL A = A11 haplotype, constituting 4.9. The data presented evidence the significance of these haplotypes for predisposition to NAA in the UP. We are thus confident that NAA is marked by the genetic factors of predisposition to NAA associated with the HLA system.
The HLA markers identified point to the polygenous nature of the hereditary factors of predisposition to NAA. The genetic markers of predisposition to NAA in the Uzbek population are HLA = B13, B40and DR2 antigens.
Khraishi M. M. et al. [6] who studied class I and II HLA-antigens in europeoids in the USA failed to reveal any significant difference in the frequency of their identification in NAA patients and healthy subjects. At the same time they discovered a statistically significant decrease in the frequency of DR1 antigen which may indicate its protective role in the pathogenesis of NAA.
The other research workers [7] identified in Japanese patients with NAA an association with HLA = Bw51, Bw52 related to a group of HLA = B5 antigen crossovers.
Our findings evidence the presence of HLA- associated genetic predisposition to NAA in the UP. HLA-B40, B13 and DR2 antigens appeared markers of predisposition to NAA. The relations discovered indicate the polygenous nature of the hereditary factors of predisposition to NAA in the Uzbek population. It should be noted that the data on the relationship between HLA-DR2 and NAA in the UP coincide with those obtained by Japanese authors. Mechanisms of the impairment of the genetic control of immune response are likely to underlie predisposition to NAA in Uzbeks with DR2 antigen. This is confirmed by the deficiency of T lymphocytes and subpopulation of T-suppressors in the patients with NAA [8; 9] Of note, the identified associations (HLA = B40, B13, DR2) in the Uzbek population with NAA were established for the first time. Nevertheless the association with HLA = B13
antigen was determined previously in the Uzbek population presenting with infectious allergic bronchial asthma and pol-lenosis whereas the association with HL A = B40 antigen was recognized in patients suffering from atopic bronchial asthma. This points to the presence of the common pathogenetic mechanisms underlying these diseases.
It has been demonstrated recently [2; 3; 8] that in Uzbeks, the presence of HLA = B13 antigen is associated with a high level of mitogen-induced proliferative activity whereas the presence of HLA-B40 antigen with the reduced spontaneous level of lymphocyte proliferation. Therefore, the presence of these antigens in individuals and alterations in lymphocyte immune responsiveness may also be initially unfavourable
factors that form the basis for the development of the autoimmune process associated with NAA.
Thus, the data presented indicate that investigation of the HLA-antigenic composition of the tissues is a research priority and is badly needed organization of the goal-oriented examination of the population. Determination of the HLA phenotype permits identification of the subjects predisposed to NAA by screening a group of subjects at high risk for the disease, thereby enabling early prophylaxis of the pathology to be carried out. Our investigations make a definite contribution to the understanding of the mechanisms of the relationship between the HLA system and predisposition to autoimmune diseases in the UP.
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