Modern approaches to the analysis intergene and a gene-sredovyh of interactions at a bronchial asthma

At the heart of formation BA lay intergene and a gene-sredovye vzaimodejyostvija which need to be considered at individual forecasting of risk of development BA and working out of preventive actions [220].

Studying of a role a gene-gene of interactions at BA where change in one locus of a gene influences the second locus, reflects epistaticheskie interactions between two or more genes [206].

Intergene interactions

Intergene interactions are caused by mutual influence of genetic variants in a context of one physiological way. At BA as multifakto - rialnom the disease, the separate genetic variant has weak individuyoalnyj effect concerning a phenotype, however in a synergy with others variantayomi this effect can significantly be enlarged. At the analysis genetic kompoyonenty susceptibility BA convincing examples of importance of genetic interactions in development of disease [105] are received some.

For modelling of intergene interactions use now statistical programs: logistical regress; MDR (Multifactor Dimentionality Reduction) [327] for researches a case-control and family (genealogical) and sibsovyj the analysis; GMDR (Generalized Multifactor Dimentional - ity Reduction) [166, 270] which advantage is possibility of the analysis different in number vyborok; CPM (combinatorial partitioning method) [300]; RPM (restricted partition method) [172]; SAA (Set-Association Approach) [210], PIA (Polymorphism Interaction Analysis) [283]; GENN (Grammatical Evolution Neural Network) [297].

The majority of researches in the literature is devoted intergene vzaimodejyostvijam genes interlejkinov. An interaction Gene-sredovye, mainly, concern genes of the xenobiotics participating in a pathogenesis of an asthma.

So, according to Choi W.A., Kang M.J., Kim Y.J. And co-workers. (2012) at Korean children with BA the best models of interactions are defined trehlokusnaja model (IL13, IL13Ra1и CTLA4и BA with raised by the general IgE in blood) and pjatilokusnaja model (IL4R, IL13, IL13Ra1, CD14и CTLA4) [169].

At Chinese children with BA it is taped shestilokusnaja model of interactions IL-4 (C33T), IL-13 (R130Q), IL - 4Ra (I75V), IL - 4Ra (Q576R), STAT6 (C2892T) and CD14 (-C159T) (ОШ=4,43; 95%ДИ [1,3-15,0], r T), EPHX1 (H139R) and GCLM (-588C> T) (pmin=0,0042), at women of 3 locuses: IL5 (C-703T), EPHX1 (Y113H) and NQO1 (P187S) (pmin=0,0001). At the analysis metoyodom MDR at men with atopicheskoj BA it is established by the best chetyrehlokusnaja moyodel intergene interactions CAT (-21A> T) h GPX2 (G173V) h GSR (T/C) h IL5 (C-703T) (p=0,001); at women - trehlokusnaja model of interaction of genes EPHX1 (Y113H) h IL5 (C-703T) h GPX1 (P198L) (p=0,001). Were observed sushcheyostvennye differences in structure and character of interrelations between locuses razyolichnyh clinico-pathogenetic variants BA, and are shown gender razyolichija at use in the analysis of 2 programs Set-Association and MDR [99].

The important advantage of method MDR, in comparison with method SetAssociation, possibility of a statistical estimation validnosti or vosyoproizvodimosti tested models (Cross-validation consistency, CVC), calculation of an error of a prediction of model (Prediction error, PE), representations of graphically hierarchical structure and character of interactions between various genayomi, including between the genes which have been not presented in the best models is.

Method MDR allows to reduce dimension of number of counted parametres at a simultaneous estimation of interactions of a considerable quantity of SNP-markers puyotem designing of new variables on the basis of summation of combinations geyonotipov both raised, and the lowered risk of a course of a disease [99].

Thus, the analysis of intergene interactions can open new mechanisms of a pathogenesis of disease.

Interaction Gene-sredovye

Interaction Gene-sredovye can be the critical factor, modifiyotsirujushchim fenotipicheskoe implication of genes. It first of all will be compounded with the numerous epidemiological researches showing the appreciable contribution of factors of an environment in development BA. Biological meyohanizmy outwardly-sredovyh updatings of the genetic program at development
BA are not clear yet. Nevertheless the analysis a gene-sredovyh of mutual relations pokazyvayoet, that the same polymorphism can possess as protective effect, well a risk factor concerning development BA and related phenotypes under the influence of factors of an environment [105]. To external risk factors razviyotija BA carry influence of allergens, ORVI, character of a food, smoking, proyomyshlennye chemical substances, the social and economic status of a family (fig. 3) [79, 80, 188].

For modelling a gene-sredovyh of interactions use basically a method of logistical regress.

Fig. 3. The scheme a gene-sredovyh of interactions in development of a bronchial asthma (on

Gallagher J., Hudgens E., Williams A. et al., 2011) [188].

According to research of trends ISAAC the augmentation rasprostrayonennosti asthmas last decades in the countries with high sotsialnoyoekonomicheskim level which cannot be explained change geneticheyoskoj to a component for such short time interval with evolutionary tochyoki visions is shown; in Europe and the North America specify in a key role I surround - a Russian cabbage soup of medium. It is noticed, that children and adults on cattle-breeding farms had lower prevalence of an asthma, a pollinosis and the raised levels speyotsificheskih IgE to local allergens, than city dwellers [183, 325, 326, 377]. Influence of high levels of microbic agents Is known, that, such as endotoxin in a countryside (on a farm) reduces risk of development atopicheskoj an asthma, a pollinosis and atopicheskoj sensibilizations at children of school age [151]. Genetic variability of genes of congenital immunity can moduliyorovat the answer to microbic agents and thus influence on predraspolozhenyonost to an asthma and an atopy.

During communication studying between SNP gene CD14, a Toll-like receptor 2 (TLR2) and TLR4генов, an atopy and a debut of an asthma at young Danish farmers, kotoyorye were born and have grown on a farm, it has been shown, that CD14 (-260T) an allele oblayodal protective effect to atopy development (ОШ=0,39; 95%ДИ [0,2-0,7]), toyogda as allele CD14 (-651T) associated with the raised risk of development atoyopii (ОШ=2,53; 95%ДИ [1,3-4,8]). It is not taped interactions of genes CD14х TLR2х TLR4и of development of an asthma [349].

Toll-like receptors (TLR) represent evoljutsionno konseryovativnye families of receptors of congenital immunity of a microbic molecule and play a role ligandov. Austrian and German children of farmers with allelem T gene TLR2 (-16934), in comparison with children having genotype AA, were ill BA (3 % against 13 % less often; p=0,012), had symptoms of a current asthma (3 % against 16 %; p=0,004), atopicheskoj sensibilizations (14 % against 27 %; p=0,023), and also tekuyoshchie pollinosis symptoms (3 % against 14 %; p=0,01). Communication between TLR2 (-16934) and an asthma among children of farmers did not depend on an atopy. Researchers have shown, that genetic change in gene TLR2является a major factor, opredeljajuyoshchim predisposition to an asthma and an allergy at children of farmers [179].

It is spent prospektivnoe research within 12 months at children pasyosivnyh smokers in house conditions. Environment influence (influence of tobacco, household allergens, firm particles in air) on poyolimorfizm genes NOS1и NOS3 (G894T) and level oksida nitrogen (FeNO) is estimated. Not ustayo
novleno associations NoS1i NoS3polimorfizmov, and also ecological vozyodejstvy with level FeNO. Interaction NOS3и of concentration niyokotina with levels FeNO (р=0,01) is defined. Among children with homozygous genotype GG nicotine did not influence level FeNO, however among persons with allelem T gene NOS3, at rising of nicotine level FeNO decreased [350].

Typical example the gene-sredovogo of the interaction underlying multifactorial disease, is influence of passive smoking. In group of children sick BA, having contact to a tobacco smoke, mutant geyonotip 139RR gene EPHX1, was assotsiirovan more than with 9-fold augmentation of risk of development of an asthma (ОШ=9,09; 95%ДИ [1,1-72,8], p=0,03). Besides, in the same group the association of a heterozygotic genotype 105IV gene GSTP1с by the raised risk of development BA (ОШ=2,10 is taped; 95%ДИ [1,1-4,0], p=0,02) [47].

According to Wu H., I., Sienra-Monge J.J. And co-workers. (2007) at meksikanyoskih children the association minor allelja And TNFA (-308G> A) with risk of development of disease (ОР=1,54 is defined; 95%ДИ [1,0-2,3]), including at non-smoking bolyonyh with allelem And and heterozygotic genotype GA TNFA (-308G> A) otnositelyonyj the risk of development BA has made ОР=2,1; 95%ДИ [1,2-3,6], at subject pasyosivnomu to smoking it is not established associations with risk of development of disease [394].

At smoking patients BA from Belgium and China it is not taped associations of gene TNFA (-308G> A) with development BA [271, 276].

Ljahovich V.V. and co-workers. (2002) have shown association GSTM1*0/0 with forwardness BA at passive smokers ОШ=9,0 [1,1-409,9 [64]. At children, pasyosivnyh smokers, from genotypes GSTM1*0/0 the association with razyovitiem BA (ОШ=5,5 also is taped; 95%ДИ [1,6-18,6]), symptoms of an asthma during a life (ОШ=2,8; 95%ДИ [1,3-6,0]), current whistling rhonchuses (ОШ=4,7; 95%ДИ [1,8-12,6]) and a dyspnea (ОШ=8,9, 95%ДИ [2,1-38,4]). At children from California (n=2950) genotype GSTM1*0/0 was assotsiirovan with pre-natal influence of tobacco and the early beginning of an asthma (ОШ=1,6; 95%ДИ [1,0-2,5]); flowing simptoyomami asthmas (ОШ=1,7; 95%ДИ [1,1-2,8]), a persistent asthma (ОШ=1,6;
95%ДИ [1,1-2,4]), a dyspnea at an exercise stress (ОШ=2,1; 95%ДИ [1,3-3,3]), a goose breathing demanding a prescription of medicines (ОШ=2,2; 95%ДИ [1,43,4]) and an emergency treatment for the past of 12 months (ОШ=3,7; 95%ДИ [1,9-7,3]) [195]. During too time it is not received associations GSTM1*0/0 at Taiwan shkolniyokov passive smokers with a goose breathing [263]. It is taped vzaimoyosvjaz GSTM1 *0/0 with risk of occurrence BA at adults (ОШ=1,56; 95%ДИ [1,31,9]) and at non-smoking (ОШ=1,95; 95%ДИ [1,2-3,1]). At the same time by data metayoanaliza Saadat M., Ansari-Lari M. (2007) associations GSTM1 *0/0 with smoking are not established [335].

Long smoking leads to suppression в2-АР and to their depression plotnoyosti on a surface of lymphocytes, to formation reduction tsamf and to disturbance of the answer to catecholamins. At the smoking termination in 8 weeks the density adyorenoretseptorov is restored and reaches level at non-smoking [251].

Daily smoking at homozygotes (Arg-16) assotsiirovano with raised risk BA at the Chinese patients (ОШ=57,81; 95%ДИ [2,1-29,5]). Associations (Gln27Glu) gene ADRB2с by smoking it is not established [383].

In kogortnom research at children of passive smokers of homozygotes Arg16Arg subject to a tobacco smoking fetally, in 3 times more often otmechayolos a goose breathing; night symptoms and current rhonchuses. Associations genoyotipov Glu27Gln and Gly16Arg gene ADRB2с by passive smoking it is not found [379].

Among children subject to influence of a tobacco smoke, with allelem Arg16 and homozygotes Arg16/Arg16 indicators ОФВ1 (2,19 against 2,38) and FZHEL (2,43 against 2,64) were more low, than at Gly16 homozygotes. Persons with allelem Gln27 and gomoyozigoty Gln27/Gln27 also had lower ОФВ1 in relation to gomozigoyotam Glu2/Glu27 (2,24 against 2,39). Children not exhibited to tobacco with Arg16 or Gln27 showed lower level NO in comparison with Gly16 goyomozigotami (15,4 ppm in comparison 30,9 ppm) and Glu27 homozygotes (18,0 ppm in comparison with 49,7 ppm) [409].

The interrelation of passive smoking at patients BA c rs2305480 gene GSDMB [148, 185], including fetally and at early age [375] is shown.

Thus, despite the numerous genetic researches spent in various ethnic groups, data wear rather protivoreyochivyj character. It was a substantiation for role studying in formation BA, communication with clinico-laboratory indicators, polymorphic variants of geyonov-candidates BA (FCER2 (T2206C), TNFA (-308G> A), GSTM1 del, NOS2А (CCTTT) n, NOS3 (VNTR), ADRB2 (Arg16Gly) and ADRB2 (Gln27Glu), rs7216389 and rs2305480 GSDMB) and genes-candidates of nicotinic dependence (THOI (STR), rs16969968 CHRNA5), their intergene and a gene-sredovyh of interactions in various ethnic groups.

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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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