Mthfr:677тт genotype and hyperhomocysteinemia in children from areas affected by the Chоrnobyl nuclear power plant accident Текст научной статьи по специальности «Фундаментальная медицина»



ГЕНОТИП MTHFR:677TT I СТАН ППЕРГОМОЦИСТЕ1НЕММ У Д1ТЕЙ I3 РАЙОН1В, ЩО ПОСТРАЖДАЛИ ВНАСЛ1ДОК АВАР11 НА ЧОРНОБИЛЬСЬК1Й

АТОМН1Й ЕЛЕКТРОСТАНЦ11

Бандажевський Ю.1., Дубова Н.Ф.

MTHFR:G77TT GENOTYPE AND HYPERHOMOCYSTEINEMIA IN CHILDREN FROM AREAS AFFECTED BY THE CH0RN0BYL NUCLEAR POWER PLANT ACCIDENT

1BANDAZHEVSKYI Yu.I., 2DUBOVA N.F.

1 Ecology and Health Coordination and Analytical Centre, Ivankiv. 2National Medical Academy of Postgraduate Education named after P.L. Shupyk, Ministry of Health of Ukraine, Kyiv.

УДК 616-008.9:577.112.386]-008.61-001.28-053.206:575.191]-02:614.73:614.876.004.6(477)

utations in folate metabolism genes are one of the main causes of abnormal metabolism of methionine — an essential amino acid for the human body.

This may result in excessive formation of homocysteine, which is associated with malignant tumors, changes in rheo-logical properties of blood and congenital defects [1-9].

Studies carried out in 2015 within projects of the European Commission and the RhoneAlpes Region (France) showed that hyperhomocysteinemia was observed in the majority of examined adolescent children living in areas of Ukraine affected by the Chornobyl nuclear power plant accident [10-11].

The TT homozygous variant of MTHFR:C677T genetic polymorphism is associated with an almost complete loss of activity of methylenetetrahy-drofolate reductase, a key enzyme of folate metabolism

[12, 13]. The degree of manifestation of the genetic polymorphism is linked to the effect of an external factor.

In order to develop effective preventive measures, it is important to identify the phenotypic manifestation of this genetic defect in the form of increased formation of a sulphur-containing amino acid homocysteine in children living in areas contaminated with radioactive substances as a result of the Chornobyl nuclear power plant accident.

The aim of the study was to identify the phenotypic manifestation of the MTHFR:677TT genotype in groups of children from districts contaminated with radioactive agents due to the Chornobyl nuclear power plant accident and having different levels of socioeconomic development with the use of blood homocysteine values and hyperhomocysteinemia rate figures.

ГЕНОТИП MTHFR:677ТТ I СТАН ППЕРГОМОЦИСТЕ1НЕМ11УД1ТЕЙ13 РАЙОН1В, ЩО ПОСТРАЖДАЛИ ВНАСЛ1ДОК АВАРП НА ЧОРНОБИЛЬСЬКЙ АТОМН1Й ЕЛЕКТРОСТАНЦП 1 Бандажевський Ю.1., 2Дубова Н.Ф. 1 Координашйний аналтичний центр "Еколопя \здоров'я", м. 1ванюв, Укра/на, 2Нац'юнальна медична академ'(я пслядипломно/ освти iм. П.Л. Шупика, м. Ки/в

Гомозиготний вар'(ант ТТ генетичного полiмор-фiзму MTHFR:С677T асощюеться з майже повною втратою активност метшентетропдро-фолатредуктази — основного ферменту фолат-ного циклу. Стутнь прояву генетичного полiмор-фiзму пов'язана з впливом факторiв зовнiшнього середовища.

Мета роботи — визначити фенотипiчний прояв генотипу MTHFR:677TТ у групах дтей 'з район'(в, територ '(я яких забруднена рад'юактивними агентами внасл'щок аварп на Чорнобильськй атомнй електростанцп, як мають р'\зний рiвень сощаль-но-економiчного розвитку, використовуючи показники вмсту гомоцисте/ну у крови \ частоти поширеност стану ппергомоцисте/'немп. Методи дослдження. Iмунохiмiчний, матема-тико-статистичний.

Результати. У пiдгрупi д'ией-носпв генотипу MTHFR:677ТT \з район'(в, що постраждали в'щ аварп на Чорнобильськй атомнй електростанцп, вмст гомоцисте/ну у крови був достовiрно бль-шим порiвняно з п'щгрупами д'шей, як не е нолями даного генотипу.

Присутнсть алел '1 ризику Т полiморфiзму MTHFR:C677T у гомозиготному стан'1 зумовлюе у д'шей, як проживають на територн, забрудненй рад 'юактивними елементами внасл'щок аварп на Чорнобильськй атомнй електростанцп, пдви-щене утворення гомоцисте/ну, порiвняно з дть-ми, як не мають у склад\ свого генома генотип MTHFR:677ТT.

Фенотипiчний прояв генотипу MTHFR:677TТ у вигляд п'щвищеного утворення гомоцисте/ну в органiзмi (стан ппергомоцисте/'немп) бльш виражений у дтей Iз район'(в, що мають прш'1 соцiально-економiчнi умови псля аварп на Чорнобильськй атомнй електростанцп.

Ключов'1 слова: ппергомоцисте'шем'ш, генотип МТИРЙ:677ТТ, пол!морф!зм фолатного циклу, алель ризику Т, територп, забруднен! радюнуклщами, авар!я на Чорнобильськй атомнй електростанцп', д!ти.

© Бандажевський Ю.1., Дубова Н.Ф. СТАТТЯ, 2018.

MTHFR: 677TT GENOTYPE AND STATE OF HYPERHOMOCYSTEINEMIA IN THE CHILDREN OF REGIONS SUFFERED AS A RESULT OF THE ACCIDENT AT THE CHORNOBYL NUCLEAR POWER PLANT

1Bandazhevskyi Yu.I., 2Dubova N.F.

1 Coordinative Analytical Center "Ecology and Health", Ivankiv, Ukraine, 2National P.L. Shupyk Medical Academy of Postgraduate Education, Kyiv, Ukraine

TT homozygous variant of MTHFR: C677T genetic polymorphism is associated with almost full loss of methylene tetrahydrofolatreductasa, the main enzyme of folate cycle. A degree of the manifestation of genetic polymorphism is connected with the external impact.

Objective. We determined the phenotypical manifestation of MTHFR: C677T genotype in the groups of the children from the regions, contaminated with the radioactive agents as a result of the accident of the Chornobyl nuclear power plant and having a different level of social-and-economic development, using the parameters of the content of homocystein in blood and frequencies of the occurrence of the state of hyperhomocysteinemia. Methods: immunochemical, mathematical-and-statistical.

Results. In the subgroup of the children-carriers of MTHFR:677TT genotype, suffered from the accident at the Chornobyl nuclear power plant, a content of homocystein in blood was authentically^ larger in comparison with the subgroups of the children that were not the carrier of given genotype. The presence of risk allele of MTHFR:677TT Tpolymorphism predetermines the elevated homocystein formation in the children residing at the territory, contaminated with radioactive elements as a result of the accident at the Chornobyl nuclear power plant, in comparison with the children not having MTHFR:677TTgenotype in the content of their genome. Phenotypic manifestation of MTHFR:677TT genome as elevated formation of homocystein in the organism (state of hyperhomocysteinemia) is more expressed in the children from the regions that are in worse social-and-economic conditions after the accident at the Chornobyl nuclear power plant.

Keywords; hyperhomocysteinemia, MTHFR:677Tj genotype, polymorphisms of folate cycle, T risk allele, areas contaminated with radionuclides, accident at the Chornobyl nuclear power plant, children.

Material and methods. 179

children from Ivankiv district and 84 children from Polesie district, Kiev region, Ukraine, whose average age was (14.7 ± 0.1) years (95% CI 14.6-14.9 years), living permanently since birth in rural localities affected by the CNPP accident (with a 137Cs soil contamination density of <2 Cu/km2 [14]) were studied.

All the children had blood drawn from the ulnar vein on an empty stomach in the morning to determine homocysteine levels and carry out genetic analysis of folate metabolism. All the children at the time of blood draw attended school.

The blood samples were analysed in a laboratory certified under quality standards within the project of the European Commission in Ukraine «Health and ecological programmes around the Chornobyl Exclusion Zone: Development, training

and coordination of health-related projects» with the financial support of the Rh^ne-Alpes Regional Council (France) and agreed with the parents in 2015.

Blood homocysteine levels were determined using an immunochemical method with chemiluminescent detection (CLIA). An analyser and a test system: Architect 1000 (ABBOT Diagnostics, USA).

In the children, blood homo-cysteine levels of over 10 pmol/L were defined as hyperhomocys-teinemia.

The allelic variants C677T and A1298C of the MTHFR gene (methylenetetrahydrofolate reductase), A2756G of the MTR gene (B12-dependent methionine synthase) and A66G of the MTRR gene (methionine syn-thase reductase) were determined during genetic analysis of folate metabolism.

A real-time PCR method was

used. An analyser and a test system: the DT-96 detecting thermocycler, DNA-Technology (Russia).

An assessment of degree of phenotypic manifestation of the MTHFR:677TT genotype was carried out by comparing the percentage of hyperhomocys-teinemia cases and blood homocysteine levels in genetic subgroups having and not having the MTHFR:677TT genotype in the children from two districts with different socioeconomic levels.

The comparison groups included the children with the same genotype of one of the four genetic polymorphisms of folate metabolism.

The statistical processing of the obtained results was performed using the IBM SPSS Statistics 22 software (USA). The arithmetic mean (M) ± standard error of mean (m), confidence

Table 1

Percentage of hyperhomocysteinemia cases in groups of children from Ivankiv

and Polesie districts

Genotype Ivankiv district Polesie district

Number of cases Hyperhomo-cysteinemia Number of cases Hyperhomo-cysteinemia

Absolute number % Absolute number %

Homozygous TT 15 12 80.0 11 11 100.0

Other variants 164 119 73.01 73 56 76.72

Note: 1 — statistical differences, Ivankiv district (* — t = 0.68; p = 0.497577); 2 — statistical differences, Polesie district (** — t = 4.6; p = 0.000017).

interval for the average value (95% CI), median (Me), interquartile range (IR), minimum and maximum parameter values and percentiles were calculated for the variables analysed. The

distribution hypothesis was tested (a Kolmogorov-Smirnov test). All the parameters under study did not conform to the normal distribution law, thus, a non-parametric U Mann-Whitney test was used to compare values. The statistical significance of variables was assessed by determining a significance level for p with the help of the statistical software programme. The Student's t-test was used to compare relative values. The critical level of significance for the null hypothesis (p) was set at 0.05.

Results and discussion. The

MTHFR:677TT genotype was present in 8.4% of cases (15 out

Table 2

Percentage of hyperhomocysteinemia cases in groups of children from Polesie district

Ol z Polymorphisms, genotypes Number of Number of hyperhomocysteinemia cases

p u or u children in groups Absolute number Percentage among children in a group, % Statistical differences with a group № 9

1 MTR:2756 AA 48 38 79.17 t = 3.55; p = 0.000889

2 MTR:2756 AG 23 16 69.57 t = 3.17; p = 0.004132

3 MTR:2756 GG 2 2 100 -

4 MTHFR:1298A A 36 30 83.33 t = 2.68; p = 0.010707

5 MTHFR:1298A C 25 19 76.00 t = 2.81; p = 0.009098

6 MTHFR:1298C C 12 7 58.33 t = 2.93; p = 0.010381

7 MTHFR:677 CC 44 31 70.45 t = 4.30; p = 0.000112

8 MTHFR:677 CT 29 25 86.21 t = 2.15; p = 0.038581

9 MTHFR:677 TT 11 11 100

10 MTRR:66AA 15 11 73.33 t = 2.34; p = 0.030642

11 MTRR:66AG 33 25 75.76 t = 3.25; p = 0.002662

12 MTRR:66GG 25 20 80.00 t = 2.50; p = 0.018551

Note: * — statistically significant differences between values of all groups and that of a group № 9 (MTHFR:677TT genotype).

Table 3

Statistical characteristics of blood homocysteine levels in children from Ivankiv and Polesie districts (^mol/L)

Genotype Number of cases Ivankiv district Number of cases Polesie district

Me IR Me IR

Homozygous TT 15 16.6 12.1-26.7 11 15.0 13.2-22.1

Other variants 164 11.6 9.7-13.21 73 11.7 10.1-13.82

Note: Me — median, IR — interquartile range;

1 - statistical differences: Ivankiv district, TT variant: average

rank - 127.8; variant without TT - 86.5; U Mann-Whitney test - 662.5;

p=0.003; 2 — statistical differences: Polesie district,

TT variant: average rank - 39.0; variant without TT - 65.7;

U Mann-Whitney test - 146.5; p=0.001.

of 179 cases) in the group of children from Ivankiv district and in 13.1% of cases (11 out of 84 cases) in the group of children from Polesie district.

The proportion of hyperhomo-cysteinemia cases was statistically higher in the group of children from Polesie district in the subgroup of carriers of the MTHFR:677TT genotype than in the subgroup of subjects from the same district who do not have this genotype. No such association was noticed in the group of children from Ivankiv district (table 1).

A similar situation was observed when comparing the proportion of hyperhomocysteine-mia in the subgroups with the MTHFR:677TT genotype and other folate metabolism genotypes. Unlike the group of children from Ivankiv district, the proportion of hyperhomocys-teinemia was statistically lower in most subgroups of children from Polesie district compared to that with the MTHFR:677TT genotype (table 2).

Blood homocysteine levels were statistically significantly higher in the group of children who are carriers of the MTHFR:677TT genotype than in the general group of children as well as in other genetic subgroups who do not have this genotype (tables 3-6), except for the subgroup of children with the MTR:2756GG genotype from Polesie district, where no statistically significant differences were detected (tables 4, 6).

The studies conducted showed that under conditions of permanent living in the areas contaminated with radioactive substances as a result of the Chornobyl nuclear power plant accident, the children - carriers of the MTHFR:677TT genotype have higher levels of homocys-teine in the blood compared to the children who are not carriers of this genotype.

All cases of carriership of the MTHFR:677TT genotype in the children from Polesie district were accompanied by hyperho-mocysteinemia, while it did not occur in the children from Ivankiv district.

A statistically significant difference in the proportion of hyperhomocysteinemia cases was found between the subgroup of

children from Polesie district who are carriers of the MTHFR:677TT genotype and the subgroups of children who are not carriers of this genotype.

Thus, the presence of the T risk allele of the MTHFR:C677T polymorphism in a homozygous state predetermines increased homocysteine formation in the children living in the areas contaminated with radioactive elements as a result of the Chornobyl nuclear power plant accident in comparison with the children who do not have the MTHFR:677TT genotype as part of their genome.

Taking into account the results of comparison of figures of the percentage of hyperhomocys-teinemia in genetic subgroups, it can be concluded that the phe-notypic manifestation of the MTHFR:677TT genotype in the group of children from Polesie district was more effective than in the group of children from Ivankiv district. Perhaps this is due to the fact that inhabitants of Polesie district live in worse socioeconomic conditions after the Chornobyl nuclear power plant accident than those in Ivankiv district [15] and do not have the opportunity to receive vital nutrients, including folic acid, in an adequate amount.

At the same time, they are forced to consume locally produced foodstuffs, forest gifts, wild animal meat and fish from local water bodies containing radioactive elements.

Conclusions

1. Blood homocysteine levels in the children - carriers of the MTHFR:677TT genotype from the districts affected by the Chornobyl nuclear power plant accident are significantly higher than in the children who are not carriers of this genotype.

2. Carriership of the T risk allele of the MTHFR:C677T polymorphism in a homozygous state is an internal risk factor for abnormal folate metabolism and hyperhomocysteinemia in the children living in the areas contaminated with radioactive elements as a result of the Chornobyl nuclear power plant accident.

3. The phenotypic manifestation of the MTHFR:677TT genotype in the form of increased homocysteine (hyperhomocys-teinemia) formation is more pro-

Table 4

Statistical characteristics of homocysteine levels within genetic groups in children from Ivankiv and Polesie districts

(Hmol/L)

Polymorphism, genotype Ivankiv district Polesie district

Me IR Me IR

MTR:A2756G

AA 11.7 9.7 -13.7 12.4 10.8-15.0

AG 11.4 10.1 -13.3 10.6 9.8-12.3

GG 9.5 8.5 - 11.6 13.0 12.97-12.99

MTHFR:A1298C

AA 11.2 9.6 - 12.7 11.8 10.6-13.4

AC 11.9 10.4 - 13.3 12.0 10.1-14.4

CC 9.1 7.9 - 12.6 10.8 9.4-16.9

MTHFR:C677T

CC 11.3 9.4 - 12.9 11.4 9.7-14.1

CT 11.6 9.9 - 13.3 12.0 10.6-13.4

TT 16.6 12.1 - 26.7 15.0 13.2-22.1

MTRR:A66G

AA 10.7 8.9 - 11.8 11.2 9.3-12.6

AG 11.3 9.5 - 12.9 12.0 10.0-13.4

GG 12.1 10.6 - 13.8 12.8 10.2-16.8

Note: Me — median, IR — interquartile range.

Table 5

Results of quantitative comparison (Ivankiv district) of populations (nonparametric analysis)

Polymorphism, genotype Number of cases Average rank

MTR:A2756G AA 96 52.8

MTHFR:C677T TT 15 76.6

MTR:A2756G AG 57 33.0

MTHFR:C677T TT 15 50.0

MTR:A2756G GG 11 8.4

MTHFR:C677T TT 15 17.3

MTHFR:A1298C AA 75 42.1

MTHFR:C677T TT 15 62.5

MTHFR:A1298C AC 80 44.6

MTHFR:C677T TT 15 66.2

MTHFR:A1298C CC 9 8.2

MTHFR:C677T TT 15 15.1

MTHFR:C677T CC 81 44.7

MTHFR:C677T TT 15 69.1

MTHFR:C677T CT 83 46.4

MTHFR:C677T TT 15 66.8

MTRR:A66G AA 24 16.0

MTHFR:C677T TT 15 26.3

MTRR:A66G AG 84 46.2

MTHFR:C677T TT 15 71.1

MTRR:A66G GG 56 34.1

MTHFR:C677T TT 15 48.1

Hc, pmol/L

U Mann-Whitney test, statistical significance, p

411.0, p=0.008

225.5, p=0.005

26.0, p=0.003

307.0, p=0.006

326.5, p=0.005

29.0, p=0.022

299.0, p=0.002

85.0, p=0.011

102.5, p=0.006

313.5, p=0.008

264.0, p=0.028

nounced in the children from the areas being in worse socioeconomic conditions after the Chornobyl nuclear power plant accident.

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Table 6

Results of quantitative comparison (Polesie district) of populations (nonparametric analysis)

Polymorphism, genotype Number of cases Average rank

MTR:A2756G АА 48 26.9

MTHFR:C677T TT 11 43.4

MTR:A2756G AG 23 13.3

MTHFR:C677T TT 11 26.6

MTR:A2756G GG 2 3.5

MTHFR:C677T TT 11 7.6

MTHFR:A1298C AA 36 20.3

MTHFR:C677T TT 11 36.1

MTHFR:A1298C AC 25 15.2

MTHFR:C677T TT 11 26.1

MTHFR:A1298C CC 12 8.8

MTHFR:C677T TT 11 15.6

MTHFR:C677T CC 44 24.5

MTHFR:C677T TT 11 41.9

MTHFR:C677T CT 29 17.0

MTHFR:C677T TT 11 29.8

MTRR:A66G AA 15 9.2

MTHFR:C677T TT 11 19.4

MTRR:A66G AG 33 18.7

MTHFR:C677T TT 11 34.0

MTRR:A66G GG 25 15.9

MTHFR:C677T TT 11 24.3

Hc, Mmol/L

U Mann-Whitney test, statistical significance, р

116.5, p=0.004

26.0, p=0.00001

4.0, p=0.231

65.0, p=0.001

54.5, p=0.004

27.0, p=0.016

89.0, p=0.001

57.5, p=0.002

18.0, p=0.001

55.0, p=0.001

73.5, p=0.028

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ALLELIC POLYMORPHISM OF THE GENES OF DNA REPARATION AND LIKELIHOOD OF BRONCHOPULMONARY PATHOLOGY DEVELOPMENT IN MINERS AND WORKERS OF ASBESTOS CEMENT PLANTS IN UKRAINE

Andrushchenko T.A.

АЛЛЕЛЬНЫЙ ПОЛИМОРФИЗМ ГЕНОВ РЕПАРАЦИИ ДНК И ВЕРОЯТНОСТЬ РАЗВИТИЯ БРОНХОЛЕГОЧНОЙ ПАТОЛОГИИ У ШАХТЕРОВ И РАБОТНИКОВ АСБЕСТОЦЕМЕНТНЫХ ЗАВОДОВ УКРАИНЫ

аболевания органов дыхания от воздействия промышленных аэрозолей занимают центральное место в структуре профессиональной патологии и продолжают оставаться приоритетной проблемой медицины труда [1].

Важным направлением молекулярной биологии и медицины на современном этапе развития является разработка молекулярных основ профилактической медицины, фундаментом которой есть генетический полиморфизм. Известно несколько десятков генных полиморфизмов, вовлеченных в разные виды системы репарации [2]. Установлено, что нарушения в системе контроля над процессами репарации ДНК и апопто-за вызваны не только генетическими и эпигенетическими нарушениями, но и вариабельностью функционирования генов, обусловленной генетическим полиморфизмом [6].

АНДРУЩЕНКО Т.А.

ГУ "Институт медицины труда им. Ю.И. Кундиева Национальной академии медицинских наук Украины", г. Киев, Украина

УДК [575.113: 577.21 : [622+666.961. 006.3] - 057 (477)

Ключевые слова: молекулярно-генетические маркеры, XRCC1, XRCC3, бронхолегочная патология.

АЛЕЛЬНИЙ ПОЛ1МОРФ13М ГЕН1В РЕПАРАЦП' ДНК ТА В1РОПДНЮТЬ РОЗВИТКУ БРОНХОЛЕГЕНЕВО/ ПАТОЛОГИ У ШАХТАР1ВIПРАЦ1ВНИК1В АЗБЕСТОЦЕМЕНТНИХ 3АВОД1В УКРА1НИ Андрущенко Т.А.

ДУ "1нститут медицини пращ Iм. Ю.1. Кунаева НАМН Укра/ни", м. Ки/в

У статт'1 представлено результати досл^ення полiморфiзму гешв репарацп ДНК у шахтарiв / пращвниюв азбестоцементних завод'в з професiйно зумовленою бронхолегеневою патолопею. Мета роботи — вивчити розподл частот генотитв генiв XRCC1 (гэ25487) IXRCC3 (гэ861539) у прашвниюв азбестоцементних заво^в та шахтар'в для виявлення маркерiв ризику розвитку бронхолегенево/ патологи.

Матер!али та методи. Обстежено пращвниюв азбестоцементних заво^в I шахтар'в. Методом полiмеразноi ланцюгово/ реакцп у реальному час визначали генотипи гешв репарацп ДНК. Результати досл'щження. Встановлено, що генотип XRCC1*AA асоцйований з ризиком розвитку бронхолегенево/ патологи у популяцп прашвниюв азбестоцементних заво^в / шахтарiв Укра/ни. Встановлено протективну роль генотипу XRCC1*GA щодо ризику розвитку захворювань бронхолегенево/ системи у прашв-ник'в азбестоцементних заво^в Укра/ни.

Ключов/ слова: молекулярно-генетичн маркери, ХЯСС1, ХЯСС3, бронхолегенева патолопя.

© Андрущенко Т.А. СТАТТЯ, 2018.