EVALUATION OF GENETIC MECHANISMS IMPLEMENTATION OF THE EFFECTS OF STARVATION IN EARLY CHILDHOOD

Objective. To define relation rs9939609 FTO gene polymorphism, rs1225537 TCF7L2 gene polymorphism, relative telomere length with cardiovascular diseases and metabolic disorders in survivors of Siege of Leningrad who lived in the besieged city in the early childhood. Material and methods. During period from December 2009 to May 2012 305 survivors of Leningrad Siege (64-81 years) and two control group: first group (n = 47, 67-82 years) and second group (n = 440, 25-64 years) were examined. All participants were interviewed regarding risk factors, cardiovascular diseases and therapy. Blood pressure (BP) measurement, anthropometry, echocardiography, electrocardiography were performed according to standard guidelines. Fasting serum lipids and plasma glucose were measured. Relative telomere length was measured by quantitative PCR and the ratio of telomere repeat copy number to single gene copy number (T/S) was calculated for each DNA sample. Rs1225537 TCF7L2 gene polymorphism and rs9939609 FTO gene polymorphism was determined by real-time PCR with allele-specific primers. Results. Survivors had lower anthropometric parameters and higher HDL level. There were no significant differences in the prevalence of cardiovascular diseases and target organ damage between groups, even prevalence of atrial fibrillation was slightly higher in the control group. However, survivors have shorter telomere length T/S ratio 0,44 [0,25; 0,64] versus controls 0,91 [0,47; 1,13] (p < 0,0001) both in males and females with clear association with the period of famine in early life. Analysis of prevalence of FTO and TCF7L2 genotype and allele frequencies did not reveal their significant differences in the control group versus the group Siege of Leningrad survivors. In the Siege of Leningrad survivors group TT genotype of rs9939609 FTO gene polymorphism was significantly more frequent in the group with low birth weight (less than 2500 g) versus the group with normal birth weight, χ² = 6,2, p = 0,04. Relation of TT genotype and weight at the age of 65-80 years was not recorded. Conclusions. Early life famine among those who survived to the age over 70 years is associated with telomere shortening in both genders but not with cardiovascular diseases and target organ damage. The influence of other genes associated with the risk of obesity and type 2 diabetes, also leveled after seven decades after the Siege of Leningrad.

блокада Ленинграда, длина теломер, полиморфизм генов FTO и TCF7L2, заболевания сердечно-сосудистой системы, генетические маркеры, Leningrad Siege, telomere length, FTO and TCF7L2 genes polymorphism, cardiovascular diseases, genetic markers

1. Lucas A., Baker B.A., Desai M. et al. Nutrition in pregnant or lactating rats programs lipid metabolism in the offspring // Br. J. Nutr. - 1996. - Vol. 76, № 4. - P. 605-612.

2. Stanner S.A., Bulmer K., Andres C. et al. Does malnutrition in utero determine diabetes and coronary heart disease in adulthood? Results from the Leningrad siege study, a cross sectional study // BMJ. - 1997. - Vol. 315. - P. 1342-1348.

3. Stanner S.A., Yudkin J.S. Fetal programming and the Leningrad Siege study // Twin Res. - 2001. - Vol. 4, № 5. - P. 287-292.

4. Doblhammer G., van den Berg G.J., Lumey L.H. A reanalysis of the long-term-effects on life-expectancy of the Great Finnish Famine of 1866-68 // Popul. Stud. (Camb). - 2013. - Vol. 67, № 3. - P. 309-322.

5. De Rooij S.R., Roseboom T.J. The developmental origins of ageing: study protocol for the Dutch famine birth cohort study on ageing // BMJ Open. - 2013. - Vol. 3, № 6. - e003167.

6. Kannisto V., Christensen K., Vaupel J.W. No increased mortality in later life for cohorts born during famine // Am. J. Epidemiol. - 1997. - Vol. 145, № 11. - P. 987-94.

7. Franzek E.J., Sprangers N., Janssens A.C. et al. Prenatal exposure to the 1944-45 Dutch ‘hunger winter’ and addiction later in life // Addiction. - 2008. - Vol. 103, № 3. - P. 433-438.

8. Koupil I., Plavinskaja S., Parfenova N. et al. Cancer mortality in women and men who survived the siege of Leningrad (1941-1944) // Int. J. Cancer. - 2009. - Vol. 124, № 6. - P. 1416-1421.

9. Sparén P., Vågerö D. Shestov D.B. et al. Long term mortality after severe starvation during the siege of Leningrad: prospective cohort study // BMJ. - 2004. / [Электронный ресурс]. doi:10.1136.

10. Stanner S.A., Bulmer K., Andrès C. et al. The intrauterine origins of cardiovascular disease and obstructive lung disease in adult life // J. R. Coll. Physicians Lond. - 1991. - Vol. 25. - P. 129-133.

11. Stein A.D., Kahn H.S., Rundle A. et al. Anthropometric measures in middle age after exposure to famine during gestation: evidence from the Dutch famine // Amer. J. Clin. Nutr. - 2007. - Vol. 85. - P. 869-876.

12. Stöger R. The thrifty epigenotype: an acquired and heritable predisposition for obesity and diabetes? // Bioessays. - 2008. - Vol. 30, № 2. - P. 156-166.

13. Scuteri A., Sanna S., Chen W.M. et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits // Plos. Genet. - 2007. - Vol. 3, № 7. - e.15.

14. Jin T., Liu L. The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus // Molecular Endocrinology. - 2008. - Vol. 22, № 11. - P. 23832392.

15. Frayling T.M., Timpson N.J., Weedon M.N. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity // Science. - 2007. - № 316. - P. 889-894.

16. Wang J., Zhang J., Li L. et al. Association of rs122537 in the TCF7L2 gene with type 2 diabetes mellitus: a metaanalysis // Brazilian Journal of Medical and Biological Research. - 2013. - Vol. 46, № 4. - P. 382-393.

17. Giardini M.A., Segatto M., da Silva M.S. et al. Telomere and telomerase biology // Prog. Mol. Biol. Transl. Sci. - 2014. - Vol. 125. - P. 1-40.

18. Ротарь О.П., Могучая Е.В., Костарева А.А., Конради А.О. Теломеры: реальная связь с сердечнососудистыми заболеваниями или чрезмерные надежды? // Российские Медицинские вести. - 2010. - Т. XVII, № 3. - С. 4-13.

19. Vera E., Bernardes de Jesus B., Foronda M. et al. Telomerase reverse transcriptase synergizes with calorie restriction to increase health span and extend mouse longevity // PLoS One. - 2013. - Vol. 8, № 1. - e53760.

20. Эпидемиология сердечно-сосудистых заболеваний в различных регионах России (ЭССЕ-РФ). Обоснование и дизайн исследования. Научно-организационный комитет проекта ЭССЕ-РФ // Профилактическая медицина. - 2013. - № 6. - С. 25-34.

21. Cawthon R.M. Telomere measurement by quantitative PCR // Nucleic Acids Res. - 2002. - Vol. 30, № 10. - e47.

22. Забуга О.Г., Ахаладзе Н.Г, Вайсерман А.М. Метаболическое программирование: теоретические концепции и экспериментальные доказательства // Успехи геронтол. - 2013. - Т. 26, № 2. - С. 212-223.

23. Pavlov D. Leningrad 1941: the Blockade. - Chicago: University of Chicago Press. - 1965. - 186 p.

24. Бойцов С.А., Карпенко М.А., Кучмин М.А. и др. Особенности клинических проявлений артериальной гипертонии у жителей блокадного Ленинграда (ретроспективный анализ архивных материалов) // Тер. арх. - 2000. - № 4. - C. 54-58.

25. Хорошинина Л.П. Особенности соматических заболевании у людей среднего и пожилого возраста, переживших в детстве блокаду Ленинграда // Успехи геронтологии. - 2004. - № 14. - С. 55-65.

26. Neel J.V. Diabetes mellitus: a «thrifty» genotype rendered detrimental by “progress”? // Amer. J. Hum. Genet. - 1962. - Vol. 14. - P. 353-362.

27. Hales C.N., Barker D.J. Type 2 (non-insulindependent) diabetes mellitus: the thrifty phenotype hypothesis // Diabetologia. - 1992. - Vol. 35. - P. 595-601.

28. Алиментарная дистрофия в блокированном Ленинграде / под ред. проф. М.В. Черноруцкого. - Л.: Медгиз, Ленингр. отд., 1947. - 367 с.

29. Antonov A.N. Children born during the Siege of Leningrad in 1942 // J. Pediatr. - 1947. - Vol. 30, № 3. - P. 250-259.

30. Lee M., Martin H., Firpo M.A., Demerath E.W. Inverse association between adiposity and telomere length: the Fels Longitudinal Study // Am. J. Hum. Biol. - 2011. - Vol. 23. - P. 100-106.

31. Nordjjäll K., Eliasson M., Stegmayr B. et al. Telomere length is associated with obesity parameters but with a gender difference // Obesity (Silver Spring). - 2008. - Vol. 16, № 12. - P. 2682-2689.

32. Demerath E.W., Cameron N., Gillman M.W. et al. Telomeres and telomerase in the fetal origins of cardiovascular disease: a review // Hum. Biol. - 2004. - Vol. 76, № 1. - P. 127-146.

33. Mainous A.G. 3rd, Codd V., Diaz V.A. et al. Leukocyte telomere length and coronary artery calcification // Atherosclerosis. - 2010. - Vol. 210, № 1. - P. 262-267.

34. Haycock P.C., Heydon E.E., Kaptoge S. et al. Leucocyte telomere length and risk of cardiovascular disease : systematic review and meta-analysis // BMJ. - 2014. - Vol. 349. - g4227.

35. Samuel J.-L., Schab M.C. et al. Genomics and cardiac metabolism // Cardiovascular Research. - 2008. - № 79. - Р. 218-227.

36. Saunders C.L. Meta-analysis of genome-wide linkage studies in BMI and obesity // Obesity. - 2007. - № 15. - P. 2263-2275.

37. Kaakinen M., Läärä E., Pouta A. et al. Life-course analysis of a fat mass and obesity-associated (FTO) gene variant and body mass index in the Northern Finland Birth Cohort 1966 using structural equation modeling // Am. J. Epidemiol. - 2010. - Vol. 172, № 6. - P. 653-665.