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5.1. The analysis of associations of polymorphisms of genes-candidates FCER2, ADRB2, TNFA, GSTM1, NOS2, NOS3и GSDMB c predisposition to a bronchial asthma, change of clinico-laboratory parametres at the Buryat and the Russian living in Transbaikalian edge

Internal (congenital) factors cause genetic predisposition of the person to occurrence BA, atopies, giperreaktivyonosti bronchuses and for today remain uncontrollable. Influence of genetic factors on BA and its phenotype has shown their big geterogenyonost and communication with environment factors.

BA is multifaktori - alnoj a pathology and the genetic component is presented by complex effect of various genes, each of which is not capable to cause zaboyolevanie, but their certain combinations are responsible raised or poyonizhennuju for probability of individuals to be ill at action of corresponding factors of an environment [34, 79, 68, 80].

Research of associations of alleles and genotypes on 9 polymorphisms of 7 genes-candidates of development BA is spent by us on sample of 168 respondents the Buryat and 86 Russian.

Distribution of frequencies of genotypes of investigated polymorphisms FCER2 (T2206C), TNFA (-308G> A), GSTM1, NOS2A (VNTR), NOS3 (VNTR), ADRB2 (Gln27Glu), GSDMB (rs2305480) corresponds Hard-Vajnberga to balance (p> 0,05) (tab. 30).

At the analysis of distribution of frequencies of genotypes of polymorphism Arg16Gly in gene ADRB2у the Buryat in control group the deviation from ravnoyovesija by Hard-Vajnberga (HWE) (р=0,04), bound to a disadvantage geteroziyogot, and in frequency of genotypes of a gene rs7216389 GSDMBу the Buryat control grupyo is taped
py the deviation from Hard-Vajnberga balance (HWE), obuyoslovlennoe by excess of heterozygotes (p=0,001) also is taped.

Oksid the nitrogen, synthesised eNOS, has powerful influence on a ciliary epithelium of bronchuses, regulates mukotsiliarnyj a clearance, uchastyovuet in immune protection, participates in regulation of a tonus of vessels and bronchuses [35, 134, 171].

In gene NOS3проведен the analysis of minisatellite polymorphism, obuyoslovlennogo varying number tandemnyh 27 items n. Repetitions (VNTR) in 4 introne; it was defined two allelja *4 and *5. Higher frequency minor allelja *4 VNTR gene NOS3в to sample aginskih the Buryat, patients BA, in comparison with control group (0,103 against 0,045 is taped; p=0,04); OSH =2,44; 95%ДИ [1,0-5,8]. The parity of chances for carriers of genotypes *4/4 and *4/5 gene NOS3 (VNTR) is peer 2,72 (95%ДИ [1,1-7,0]; р=0,03), i.e. noyositelstvo allelja *4 VNTR gene NOS3является a marker raised risyoka developments BA in teenagers in studied group of the population. It is not established associations of the given polymorphism with development BA at Russian sick (tab. 30).

At studying of ethnic features of distribution of frequencies of alleles and genotypes it is shown, that among patients BA frequency minor allelja *4 at Russian teenagers (0,236) above, than at the Buryat (0,103); frequency allelja *5 at the Buryat (0,809) and Russian (0,764) (р=0,01). Total frequency of genotypes *4/4 + *4/5 NOS3 (VNTR) at Russian patients (0,472) also authentically above, than at the Buryat (0,191) (р=0,005) (tab. 31).

It is not taped authentically significant associations in frequency of alleles and geyonotipov polymorphism VNTR of gene NOS3со by disease severity level, the beginning of a manifestation of disease till 6 years, raised level IgE in blood serum at the Buryat and Russian patients BA (> 0,05).

Table 30.

Frequency of alleles and genotypes of genes-candidates, assotsiirovannyh with development of a bronchial asthma in the Buryat and Russian





Table 31. Significant interethnic differences in frequencies of alleles and geyonotipov genes NOS3 (VNTR), GSDMB rs 2305480, FCER2 (T2206C), THOI

(STR) at sick of a bronchial asthma


The data obtained by us at Russian patients BA will be compounded with dannyyomi the literatures, not taped association of gene NOS3 (VNTR) with development BA and level IgE in the British and Czech patients [93, 190, 211]; with tjazheyostju diseases [253].

However in a number of other researches association BA with VNTR polymorphism of gene NOS3 is taped. So, in Smirnovoj I.J.'s work with co-authors (2009) genotypes *4/4 and *4/5 met more often at BA in comparison with konyotrolem and susceptibility to illness was above at carriers of these genotypes (ОР=2,89; 95%ДИ [1,2-7,1]; р=0,01; ОР=4,11; 95%ДИ [1,4-11,6]; р=0,007, soyootvetstvenno).

The gene product indutsibelnoj sintazy oksida nitrogen regulates bayolans TH1/TH2, possesses antimicrobic and cytotoxic activity, influencing quantity produced NO, supports and strengthens vospayolitelnyj process in respiratory tracts [134].

Alleles with vosemju or nine repetitions CCTTT have lower levels transkriptsionnoj activity, than an allele from 12-15 repetitions. At inyodividov - carriers of alleles with lower number of repetitions it is produced less iNOS and, as consequence, it is developed less oksida nitrogen II (NO), than at individuals - carriers of alleles with higher number of repetitions [384].

At studying of microsatellite polymorphism (CCTTT) n in promoyotornoj areas of gene NOS2Aу the Buryat 11 alleles with number of repetitions CCTTT from *9 to *19 and 34 genotypes are identified; at Russian teenagers - 9 alleyolej from *10 to *18 and 22 genotypes. In view of the big number established genoyotipov on gene NOS2Aаллели with number of repetitions less than eleven oboyoznacheny as "short" alleles (S), alleles with number of repetitions more dvenayodtsati as "long" alleles (L), and genotypes - accordingly as SS, SL, LL.

By treating of everyone allelja gene NO2Aотдельно lower frequency allelja *11 in group of Buryats-patients BA in comparison with konyotrolnoj group (0,074 against 0,160 is taped; p=0,02; ОШ=0,42 [0,2-0,9]; fig. 7).

However, differences in frequency of alleles with low and high number of repetitions (CCTTT) n, as well as genotypes on gene NO2Aмежду samples of patients and zdoyorovyh the Buryat it is not established (tab. 30). Thus, the association of gene NO2Aс in the present research is not taped by development BA in teenagers of the Buryat nationality.

Fig. 7. Frequency of alleles NO2A (CCTTT) nу the Buryat, sick bronchial astyomoj and healthy.

At patients BA and healthy Russian teenagers static differences in frequency of alleles S of gene NOS2A (0,292 and 0,120, accordingly are taped; р=0,005, ОШ=3,02; 95%ДИ [1,4-6,6]). The relation of chances for carriers geyonotipov S/S and S/L gene NOS2A (CCTTT) nравно 3,96 (95%ДИ [1,6-10,1]; р=0,003), i.e. The carriage allelja S, containing short number tandemyonyh repetitions CCTTT in gene NOS2A, is a marker of the raised risk of development BA at Russian teenagers (fig. 8).


Fig. 8. Frequency of alleles NO2A (CCTTT) nу the Russian sick of a bronchial asthma and healthy.

At the analysis of frequency of everyone allelja (CCTTT) nгена NO2Aвыявлено statistically authentic difference in frequencies allelja *11 and *13 at Russian teenagers. Frequency allelja *11 above at patients BA in comparison with zdoroyovymi (0,167 and 0,060, accordingly; p=0,024; ОШ=3,11; 95%ДИ [1,1-9,4]). Frequency allelja *13 at patients has appeared more low (0,139) in comparison with zdoroyovymi (0,300) (p=0,014; ОШ=0,38; 95%ДИ [0,2-0,8]) (fig. 8).

At comparison vyborok sick BA interethnic differences in chastoyote alleles and genotypes of microsatellite polymorphism (CCTTT) n gene NO2Aотмечены of difference only in frequency allelja *11: at Russian patients alyolel *11 met more often (0,167) in comparison with Buryats (0,074; р=0,04) (tab. 31).

It is not taped authentically significant associations in frequency of alleles and geyonotipov polymorphism (CCTTT) nгена NO2Aсо by severity level zabolevayonija, age of a manifestation of disease (till 6 years), raised level IgE in blood serum at the Buryat and Russian patients BA (> 0,05).

The obtained data on absence of association of development BA with mikro - satellite polymorphism (CCTTT) nгена NO2Aу the Buryat will be compounded with literature data. At Chinese children of patients BA also it is not taped asyosotsiatsii polymorphism (CCTTT) nгена NO2Aс BA, with level sensibilizayotsii to aeroallergens and maintenance NO in exhaled air [258]. AnaYOlogichno at Indian children it is not established associations with BA and gravity zayobolevanija [135]. At Japanese, Chinese, English, Spanish and rossijyoskih (from Tomsk and Bashkorkostana) patients also association with BA not opreyodelena [89, 96, 190, 243, 258, 310].


According to Smirnovoj I.J. with co-authors [2009] at Russian children with BA it is not established associations (CCTTT) nNO2Aс by a controllable current of disease against treatment IGKS. But it is shown, that high maintenance IgE in blood serum at patients BA assotsiirovano with allelem *14 genes NO2A (р=0,02); the early beginning of illness (till 2 years) is characteristic for patients with BA, having a homozygous genotype *14/*14 on gene NO2A (р=0,02); pozdyonee the illness beginning (after 5 years) becomes perceptible at patients, not javljajuyoshchihsja carriers allelja *14 (р=0,04) [96] is more often.

Gene GSDMBкодирует gasdermin B, entering into family of fibers from hectares - sderminovym the domain. It is known, that the gene gasdermina In takes part in regulation of cellular differentiation, a cellular cycle and an expression of genes of cytokines [293, 332]. In view of taped associations are activly conducted issleyodovanija on studying of its role in development BA.

The analysis odnonukleotidnogo polymorphism rs7216389 gene GSDMBвы­явил of association of data of DNA-locus with a bronchial asthma at teenagers (aginskih the Buryat and Russian). Frequency allelja T polymorphism rs7216389 at the teenagers-Buryats suffering BA, it is appreciable above (78,7 %), than in konyotrolnoj to group (58,0 %; p=0,00011) (tab. 30). The relation indicator shanyosov (OSH) for allelja T polymorphism rs7216389 has made 2,66 (95%ДИ [1,6­4,4]), for allelja With - 0,38 (95%ДИ [0,2-0,6]). Homozygous genotype T/Т on polymorphism rs7216389 gene GSDMBвстречался in group of patients BA doyostoverno more often, than in the control (accordingly 0,662 and 0,230; p 0,05).

It is not taped authentically significant associations in frequency of alleles and geyonotipov polymorphism rs7216389 gene GSDMBсо by severity level zaboleyovanija, raised level IgE in blood serum at the Buryat and Russian, bolyonyh BA (> 0,05). Early beginning BA till 6 years at the Buryat assotsiirovano with alleyolem *С rs7216389 GSDMB (0,276 against 0,133; р=0,04; ОШ=2,48; 95%ДИ [1,0-6,1]) (tab. 32).

The obtained data on association rs7216389 gene GSDMBс at aginskih the Buryat and Russian of Transbaikalia will be compounded by development BA with data literatuyory. So, the association rs7216389 gene GSDMBс by formation detyoskoj BA at evropeoidov is proved: Englishmen (61,7 % against 49,7 %), Germans (57,0 % proyotiv 47,3 %), Scots (56 % against 46 %), Americans severoyoevropejskogo parentages (54,9 % against 50,9 %) [293, 348, 366], in obyoedinennoj to sample of Tatars, the Bashkir, Russian - inhabitants Volgo-Ural reyogiona (59,6 % against 45,0 %) [53]; and also at Japanese (78,2 % and 71,3 %) [209].

It is not established also assoatsiii with raised level IgE and poliyomorfizmom rs7216389 gene GSDMBу of Englishmen, Koreans, Chineses with BA [144, 236, 259, 398].

Table 32. Significant differences in frequencies of alleles and genotypes of genes

GSDMB rs 7216389, THOI (STR), assotsiirovannyh with the beginning manifeyostatsii a bronchial asthma

According to GWAS, the united 23 researches the significant association rs 2305480 genes GSDMBс by development of a children's asthma (ОШ=0,76 is taped statiyosticheski; r 0,05) (tab. 30).

Interethnic differences of frequencies of alleles and genotypes on polymorphism rs 2305480 genes GSDMBсреди of patients BA are established. So, at Russian patients BA frequency minor allelja G has made 0,583; at the Buryat - 0,434 (р=0,04), frequency of homozygous genotype AA above at the Buryat (0,382), than at Russian (0,111), totally frequencies of genotypes AG+GG rs 2305480 genes GSDMBпревалировали at Russian (0,889) in comparison with Buryats (0,618; р=0,004) (tab. 31).

It is not taped authentically significant associations in frequency of alleles and geyonotipov polymorphism rs 2305480 genes GSDMBсо by severity level zaboleyovanija, the beginning of a manifestation of disease (till 6 years), raised level IgE in blood serum at the Buryat and the Russian sick BA (p> 0,05).

Activation of cells of an inflammation by products of degranulate of mast cells induces nizkoafinnyj an IgE-receptor (FceRII, CD23), responsible for cytotoxicity of cells of the inflammation, IgE-dependent representation of antigen T-limfotsitam, adhesion V-limfotsitov to each other, participates in an apoptosis, regulation of synthesis IgE in vivo [342].

Gene FCER2увеличивает risk of development of an uncontrollable asthma, asyosotsiirovan with the raised risk of hospitalisation of patients, with serious exacerbations of an asthma and the raised requirement in IGKS [275, 363].

At the analysis of polymorphism T2206C of gene FCER2у the Buryat and Russian it is not taped associations with a bronchial asthma. Differences of frequency minor allelja *C polymorphism T2206C of gene FCER2между samples of patients BA and control group statistically are not significant: accordingly at buyorjat - 0,176 and 0,205 (> 0,05), at Russian - 0,347 and 0,220 (р=0,06) (tab. 30).

Interethnic differences at patients BA are taped. At Russian patients BA frequency minor allelja *C polymorphism T2206C (0,347 against 0,176; р=0,006) and a genotype *CC on gene FCER2 (0,139 against 0,029; р=0,03) above, than at the Buryat. At the Buryat with BA on frequency prevailed an allele *T polymorphism
T2206C Gene FCER2 - 0,824 in comparison with Russian - 0,653 (р=0,006) and geyonotip T/T - 0,676 against 0,444 (р=0,02) (tab. 31).

It is not established authentically significant associations in frequency of alleles and genotypes of polymorphism T2206C of gene FCER2со by severity level zaboleyovanija, the beginning of a manifestation of disease (till 6 years) at the Buryat and Russian bolyonyh BA, raised level IgE in blood sera at the Buryat, patients BA (p> 0,05).

The association of gene FCER2 (T2206C) at Russian patients BA with raised level IgE is established. Frequency minor allelja C gene FCER2 (T2206C) at patients with raised IgE has made 0,471, that significantly above, than at patients BA with normal level IgE - 0,237 (р=0,04; ОШ=0,86; 95%ДИ [1,1-7,8]) (tab. 33).

The obtained data, will be compounded with earlier published rezultayotami about absence of association of gene FCER2 (T2206C) with development BA in children [244, 275, 330, 363]; and shown association of three odnonukleotidnyh poyolimorfizmov gene FCER2 (T2206C) with the raised level serumal IgE [363].

Table 33. Significant differences in frequencies of alleles and genotypes of genes FCER2 (T2206C), THOI (STR), asssotsiirovannyh with level of the general IgE at Russian sick of a bronchial asthma


The gene of a v2-adrenergic receptor (ADRB2) is one of osyonovnyh and the most proved genes of predisposition to BA. It otvechayoet for sensitivity of patients to therapy v2-adrenomimetikami, assotsiiyorovan also with presence or absence of night symptoms of illness, bronyohialnoj a hyperreactivity [174, 189, 214].

In the sample of children investigated by us of Aginsky Buryat district of Transbaikalian edge it is not received associations of polymorphisms Arg16Gly and Gln27Glu gene ADRB2с BA neither at the Buryat, nor at Russian (tab. 30). At patients with BA also it is not defined interethnic differences in frequency of alleles both genoyotipov Arg16Gly and Gln27Glu gene ADRB2 (> 0,05).

It is not defined authentically significant associations in frequency of alleles and genotypes of polymorphism Arg16Gly and Gln27Glu gene ADRB2со by degree tjayozhesti diseases, age of a manifestation of disease (till 6 years), povyyoshennym level IgE in blood serum at the Buryat and the Russian sick BA (> 0,05).

The data obtained by us will be compounded with the results received as at the Taiwan teenagers with BA at which it has not been taped associations of disease with genotypes on gene ADRB2, and at Chineses, Japanese, korejyotsev, Yakuts [97, 174, 186, 241, 245, 255, 266, 340, 402]. At them also it has not been taped associations with gravity of disease [113] and level of the general IgE [241].

The necrosis factor opuholeja (TNFA), is powerful provospali - telnym a cytokine which is responsible for a late phase allergic vospaleyo
nija which defines remodelirovanie walls of respiratory tracts and proyognoz illnesses [334].

At the polymorphism analysis-308G> A gene TNFAне it is taped assotsiayotsii data of DNA-locus with development of a bronchial asthma in the Buryat and rusyoskih. Statistically significant differences of frequency of occurrence allelja *А polymorphism-308G> A gene TNFAу the Buryat, patients BA, and in control group (0,125 and 0,075;> 0,05) it is not established. Frequency minor allelja *А in sample of Russian patients BA has made 0,125, in the control - 0,110 (0,05) (tab. 30).

Interethnic differences in frequency of alleles and genotypes (-308G> A) geyona TNFAу patients BA it is not established (0,05).

It is not taped authentically significant associations in frequency of alleles and geyonotipov polymorphism (-308G> A) gene TNFAсо by severity level zabolevayonija, age of a manifestation of disease (till 6 years), raised level IgE in blood serum at the Buryat and the Russian sick BA (0,05).

The received results will be compounded with data of the researchers who have not found out associations of polymorphism of gene TNFAс by development BA at kiyotajtsev and malazijtsev; Taiwan and Korean children and teenagers with BA [215, 267, 360], not defined association with severity level of disease at Englishmen, Belgians [143, 271], with raised level IgE at the Asian - kitajyotsev and Koreans [215, 267, 247], at evropeoidov - Australians, Belgians, cheyohov [153, 271, 291], that dictates expediency of carrying out of the analysis assoyotsiatsy polymorphic variants of gene TNFAотдельно in each ethnic group.

Gljutationtransferaza М1, coded by gene GSTM1, concerns enzymes of the second phase of a biotransformation of xenobiotics. High soderyozhanie glutationa it is defined in the slime covering cylindrical epiyotely of bronchuses which basic function is mukotsiliarnyj kliyorens [60]. Glutation ^-transferazy besides detoxicating participate in bioyosinteze and a metabolism lejkotriena B4 and prostoglandina Е2, possessing
hemotaksicheskim action for neutrophils [318].

At the analysis of a polymorphic variant of gene GSTM1не it is defined assoyotsiatsii data of DNA-locus with a bronchial asthma at surveyed podyorostkov, the Buryat and Russian. The comparative analysis of frequency of zero genotype GSTM1 (0/0) at patients BA and in control group at the Buryat (0,353 and 0,420) and at Russian (0,472 and 0,420) statistical differences has not taped (> 0,05) (tab. 30). Interethnic differences in frequency of genotypes on gene GSTM1у of patients BA it is not established (0,05).

It is not taped authentically significant associations in frequency of alleles and geyonotipov gene GSTM1со by disease severity level, age manifeyostatsii diseases (till 6 years), raised level IgE in blood serum at the Buryat and the Russian sick BA (> 0,05).

The results received by us about absence of association zero geyonotipa GSTM1с BA, with gravity of disease will be compounded with data of other researchers [54, 55, 182, 213, 254, 276, 339].

Thus, by us it is shown, that a bronchial asthma at the Buryat assoyotsiirovana with genes NOS3 (VNTR) and GSDMB (rs7216389), at Russian - with genes NOS2 (CCTTT) n and GSDMB (rs7216389).

Alleles and genotypes of the raised risk formations BA identical to both studied ethnic groups - a carriage allelja T are taped and homozygous genotype T/T of polymorphism rs7216389 gene GSDMB.В too time ethnic differences are established also. So, markers of the raised risk of disease by a bronchial asthma were at the Buryat - a carriage alyolelja *4 and genotypes 4/4 and 4/5 genes NOS3 (VNTR), and at Russian - alleles, soyoderzhashchih short number tandemnym repetitions (CCTTT) n gene NOS2.

Interethnic differences between patients BA are shown at comparison of genes. Frequency of minor (mutant) alleles and genotypes NOS3 (VNTR), NOS2 (CCTTT) n, GSDMB rs 2305480, FCER2 (T2206C) has appeared above at rusyoskih, patients BA.

It is not taped authentically significant associations of studied genes - of candidates with gravity of disease at the Buryat and the Russian sick BA (> 0.05).

The association allelja rs7216389*C GSDMBс early nachayolom (till 6 years) a bronchial asthma at the Buryat is established.

The association minor allelja C gene FCER2 (T2206C) with raised level IgE in blood serum at the Russian sick BA is defined.

The received interethnic differences of associations of genes-candidates with formation BA, with the years manifestations of disease and raised level IgE can cause features of regulation immune mehayonizmov, playing a role in pathogenesis BA.

5.2

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Scientific source BATOZHARGALOVA BAIRMA TSYDENDAMBAEVNA. CLINICO-EPIDEMIOLOGICAL, GENETIC And ETHNIC FEATURES of the BRONCHIAL ASTHMA At TEENAGERS of Transbaikalia. The dissertation on competition of a scientific degree of the doctor of medical sciences. Moscow - 2013. 2013

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Other medical related information 5.1. The analysis of associations of polymorphisms of genes-candidates FCER2, ADRB2, TNFA, GSTM1, NOS2, NOS3и GSDMB c predisposition to a bronchial asthma, change of clinico-laboratory parametres at the Buryat and the Russian living in Transbaikalian edge:

  1. THE TABLE OF CONTENTS
  2. INTRODUCTION
  3. the Bronchial asthma and a tobacco smoking
  4. Genetic aspects of predisposition to a bronchial asthma and formation of nicotinic dependence
  5. Modern approaches to the analysis intergene and a gene-sredovyh of interactions at a bronchial asthma
  6. Molekuljarno-genetic methods of research.
  7. CHAPTER 3. EPIDEMIOLOGIJA THE BRONCHIAL ASTHMA AT THE TEENAGERS LIVING IN THE COUNTRYSIDE OF TRANSBAIKALIAN EDGE
  8. CHAPTER 5. THE ANALYSIS OF THE INTERNAL RISK FACTORS CAUSING GENETIC predraspolozhenyonost TO DEVELOPMENT OF THE BRONCHIAL ASTHMA AT TEENAGERS IN TRANSBAIKALIAN EDGE
  9. 5.1. The analysis of associations of polymorphisms of genes-candidates FCER2, ADRB2, TNFA, GSTM1, NOS2, NOS3и GSDMB c predisposition to a bronchial asthma, change of clinico-laboratory parametres at the Buryat and the Russian living in Transbaikalian edge
  10. the Analysis of interrelations of genes-candidates of predisposition to tobacco smoking THOIи CHRNA5у sick of a bronchial asthma and zdoyorovyh teenagers the Buryat and Russian
  11. 5.3. Modelling of intergene interactions at patients bronyohialnoj an asthma the Buryat and the Russian living in Transbaikalian edge
  12. the Analysis of associations of genes-candidates of development of a bronchial asthma and predisposition to a tobacco smoking at the teenagers living in Transbaikalia: gender differences
  13. CHAPTER 6. ANALYSIS SOCHETANNOGO OF INFLUENCE GENETIC AND SREDOVYH FACTORS, predraspolagajuyoshchih TO THE BRONCHIAL ASTHMA (WITH THE ACCOUNT OF INTERGENE INTERACTIONS)