DOI https://doi.org/10.23648/UMBJ.2018.30.14056

УДК 575

 

АССОЦИАЦИЯ ПОЛИМОРФИЗМА rs466639 ГЕНА RXRG С ВОЗРАСТОМ МЕНАРХЕ У ЖЕНЩИН ЦЕНТРАЛЬНОГО ЧЕРНОЗЕМЬЯ РОССИИ

 

И.В. Пономаренко, Е.А. Решетников, М.И. Чурносов

ФГАОУ ВО «Белгородский государственный национальный исследовательский университет», г. Белгород, Россия

e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

Цель исследования – изучить ассоциации однонуклеотидного полиморфизма (ОНП) rs466639 гена RXRG (retinoid X receptor gamma) с возрастом менархе у русских женщин Центрального Черноземья РФ и рассмотреть регуляторный потенциал этого полиморфизма.

Материалы и методы. Выборка для исследования включала 1613 женщин. Проведено генотипирование ОНП rs466639 гена RXRG.

Результаты. Установлена ассоциация аллеля Т ОНП rs466639 гена RXRG с ранним менархе у русских женщин Центрального Черноземья РФ в рамках рецессивной модели (р=5,58·10-9). Показано важное регуляторное значение данного полиморфизма и сильно сцепленных (r2≥0,8) с ним пяти ОНП, которые находятся в регионе гистонов, маркирующих энхансеры в головном мозге, жировой, мышечной ткани и влияют на аффинность регуляторных мотивов ДНК к более чем 25 транскрипционным факторам.

Выводы. Полиморфизм rs466639 гена RXRG ассоциирован с возрастом менархе у русских женщин Центрального Черноземья РФ и имеет значимый регуляторный потенциал.

Ключевые слова: возраст менархе, полиморфизм, регуляторный потенциал.

 

Литература

  1. Guo X., Ji C. Earlier menarche can be an indicator of more body fat: study of sexual development and waist circumference in Chinese girls. Biomedical and Environmental Sciences. 2011; 24 (5): 451–458.

  2. Leung A.W.H., Mak J., Cheung P.S.Y., Epstein R.J. Evidence for a programing effect of early menarche on the rise of breast cancer incidence in Hong Kong. Cancer Detection and Prevention. 2008;32156–161.

  3. Tanikawa C., Okada Y., Takahashi A., Oda K., Kamatani N., Kubo M., Nakamura Y., Matsuda K. Genome Wide Association Study of Age at Menarche in the Japanese Population. PLoS ONE. 2013; 8 (5): e63821. DOI: 10.1371/journal.pone.0063821.

  4. Dreyfus J.G., Lutsey P.L., Huxley R., Pankow J.S., Selvin E., Fernández-Rhodes L., Franceschini N., Demerath E.W.Age at menarche and risk of type 2 diabetes among African-American and white women in the Atherosclerosis Risk in Communities (ARIC) study. Diabetologia. 2012;552371–2380.

  5. Feng Y., Hong X., Wilker E., Li Z., Zhang W., Jin D., Liu X., Zang T., Xu X. Effects of age at menarche, reproductive years, and menopause on metabolic risk factors for cardiovascular diseases. Atherosclerosis. 2008; 196 (2): 590–597.

  6. Trikudanathan S., Pedley A., Massaro J.M., HoffmannAssociation of female reproductive factors with body composition: the framingham heart study. J. of Clinical Endocrinology and Metabolism. 2013; 98 (1): 236–244.

  7. Ho A.Y.Y., Kung A.W.C. Determinants of peak bone mineral density and bone area in young women. J. Bone Min Metab. 2005;23:470–475. DOI: 10.1007/s00774-005-0630-7.

  8. Rudra C.L., Williams M.A. BMI as a modifying factor in the relations between age at menarche, menstrual cycle characteristics, and risk of preeclampsia. Gynecol Endocrinol. 2005;21:200–205.

  9. Kaprio J., Rimpela A., Winter T., Viken R.J., Rimpela M., Rose R.J. Common genetic influences on BMI and age at menarche. Hum Biol. 1995;67:739–

  10. Chie W.C., Liu Y.H., Chi J. Predictive factors for early menarche in Taiwan. J. Formos Med. Assoc. 1997; 96: 446–450.

  11. Ong K.K., Elks C.E., Li S., Zhao J.H., Luan J., Andersen B., Bingham S.A., Brage S., Smith G.D., Ekelund U. Genetic variation in LIN28B is associated with the timing of puberty. Nat. Genet. 2009; 41: 729–733.

  12. He C., Kraft P., Chen C., Buring J.E., Paré G., Hankinson S.E., Chanock S.J., Ridker P.M., Hunter D.J., Chasman D.I. Genome-wide association studies identify novel loci associated with age at menarche and age at natural menopause. Nat. Genet. 2009;41:724–728.

  13. Sulem P., Gudbjartsson D.F., Rafnar T., Holm H., Olafsdottir E.J., Olafsdottir G.H., Jonsson T., Alexandersen P., Feenstra B., Boyd H.A. Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche. Nat. Genet. 2009; 41: 734–738.

  14. Perry J.R.B., Stolk L., Franceschini N., Lunetta K.L., Zhai G., McArdle P.F., Smith A.V., Aspelund T., Bandinelli S., Boerwinkle E. Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat. Genet. 2009; 41: 648–650.

  15. Demerath E.W., Liu C.-T., Franceschini N., Chen G., Palmer J.R., Smith E.N., Chen C.T.L., Ambrosone C.B., Arnold A.M., Bandera E.V. Genome-wide association study of age at menarche in African-American women. Hum Mol. Genet. 2013; 22: 3329–3346. DOI:

  16. Elks C.E., Perry J.R.B., Sulem P., Chasman D.I., Franceschini N., He C., Lunetta K.L., Visser J.A., Byrne E.M., Cousminer D.L. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat. Genet. 2010; 42: 1077–1085.

  17. Perry J.R., Day F., Elks C.E. Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014; 514 (7520): 92–97. DOI: 10.1038/nature13545.

  18. Delahanty R.J., Beeghly-Fadiel A., Long J.R. Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women. Hum Reprod. 2013;28: 1135–1143. DOI: 10.1093/humrep/det011.

  19. Pyun J.A., Kim S., Cho N.H., Koh I., Lee J.Y., Shin C. Genome-wide association studies and epistasis analyses of candidate genes related to age at menarche and age at natural menopause in a Korean population. Menopause. 2014; 21: 522–529. DOI: 10.1097/GME.0b013e3182a433f7.

  20. He C., Kraft P., Buring J.E., Chen C., Hankison S.E., Pare G., Chanock S., Ridker P.M., Hunter D.J.A large-scale candidate-gene association study of age at menarche and age at natural menopause. Hum. Genet. 2010;128: 515–527.

  21. Yermachenko A., Dvornyk V. UGT2B4 previously implicated in the risk of breast cancer is associated with menarche timing in Ukrainian females. Gene. 2016; 590 (1): 85–89.

  22. Ward L.D., Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 2016; 44: 877–881.

  23. Ward L.D., Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Research. 2012; 40 (Database issue): 930–934. DOI: 10.1093/nar/gkr917.

  24. Plant T.M. Neuroendocrine control of the onset of puberty. Front Neuroendocrinol. 2015; 38: 73–88. DOI: 10.1016/j.yfrne.2015.04.002.

 

DOI https://doi.org/10.23648/UMBJ.2018.30.14056 

ASSOCIATION OF POLYMORPHISM (rs466639) IN GENE RXRG WITH AGE AT MENARСHE IN WOMEN OF CENTRAL BLACK EARTH REGION (RUSSIA)

 

I.V. Ponomarenko, E.A. Reshetnikov, M.I. Churnosov

Belgorod National Research University, Belgorod, Russia

e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

The objective of the trial is to study the association of single nucleotide polymorphism (SNP) rs466639 in gene RXRG (retinoid X receptor gamma) with the age at menarche in Russian women living in the Central Black Earth Region of the Russian Federation and the regulatory potential of this polymorphism.

Materials and Methods. The sample for the research study included 1613 women. The authors conducted genotyping of SNP (rs466639) in gene RXRG.

Results. The association of T SNP (rs466639) allele in gene RXRG with early menarche in Russian women living in the Central Black Earth Region of the Russian Federation was established under the recessive model (р=5,58·10-9). The authors showed the important regulatory value of this polymorphism and five strongly linked SNPs (r2≥0.8) located in the histone area that mark enhancers in the brain, adipose tissue, muscle tissue and affect the affinity of regulatory DNA motifs to more than 25 transcription factors.

Conclusion. The polymorphism (rs466639) in gene RXRG is associated with age at menarche in Russian women living in the Central Black Earth Region of the Russian Federation; it also has a significant regulatory potential.

Keywords: age at menarche, polymorphism, regulatory potential.

 

References

  1. Guo X., Ji C. Earlier menarche can be an indicator of more body fat: study of sexual development and waist circumference in Chinese girls. Biomedical and Environmental Sciences. 2011; 24 (5): 451–458.

  2. Leung A.W.H., Mak J., Cheung P.S.Y., Epstein R.J. Evidence for a programing effect of early menarche on the rise of breast cancer incidence in Hong Kong. Cancer Detection and Prevention. 2008; 32 (2): 156–161.

  3. Tanikawa C., Okada Y., Takahashi A., Oda K., Kamatani N., Kubo M., Nakamura Y., Matsuda K. Genome Wide Association Study of Age at Menarche in the Japanese Population. PLoS ONE. 2013; 8 (5): e63821. DOI: 10.1371/journal.pone.0063821.

  4. Dreyfus J.G., Lutsey P.L., Huxley R., Pankow J.S., Selvin E., Fernández-Rhodes L., Franceschini N., Demerath E.W. Age at menarche and risk of type 2 diabetes among African-American and white women in the Atherosclerosis Risk in Communities (ARIC) study. Diabetologia. 2012; 55 (9): 2371–2380.

  5. Feng Y., Hong X., Wilker E., Li Z., Zhang W., Jin D., Liu X., Zang T., Xu X. Effects of age at menarche, reproductive years, and menopause on metabolic risk factors for cardiovascular diseases. Atherosclerosis. 2008; 196 (2): 590–597.

  6. Trikudanathan S., Pedley A., Massaro J.M., HoffmannAssociation of female reproductive factors with body composition: the framingham heart study. J. of Clinical Endocrinology and Metabolism. 2013; 98 (1): 236–244.

  7. Ho A.Y.Y., Kung A.W.C. Determinants of peak bone mineral density and bone area in young women. J. Bone Min Metab. 2005; 23: 470–475. DOI: 10.1007/s00774-005-0630-7.

  8. Rudra C.L., Williams M.A. BMI as a modifying factor in the relations between age at menarche, menstrual cycle characteristics, and risk of preeclampsia. Gynecol Endocrinol. 2005; 21: 200–205.

  9. Kaprio J., Rimpela A., Winter T., Viken R.J., Rimpela M., Rose R.J. Common genetic influences on BMI and age at menarche. Hum Biol. 1995; 67: 739–

  10. Chie W.C., Liu Y.H., Chi J. Predictive factors for early menarche in Taiwan. J. Formos Med. Assoc. 1997; 96: 446–450.

  11. Ong K.K., Elks C.E., Li S., Zhao J.H., Luan J., Andersen B., Bingham S.A., Brage S., Smith G.D., Ekelund U. Genetic variation in LIN28B is associated with the timing of puberty. Nat. Genet. 2009; 41: 729–733.

  12. He C., Kraft P., Chen C., Buring J.E., Paré G., Hankinson S.E., Chanock S.J., Ridker P.M., Hunter D.J., Chasman D.I. Genome-wide association studies identify novel loci associated with age at menarche and age at natural menopause. Nat. Genet. 2009; 41: 724–728.

  13. Sulem P., Gudbjartsson D.F., Rafnar T., Holm H., Olafsdottir E.J., Olafsdottir G.H., Jonsson T., Alexandersen P., Feenstra B., Boyd H.A. Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche. Nat. Genet. 2009; 41: 734–738.

  14. Perry J.R.B., Stolk L., Franceschini N., Lunetta K.L., Zhai G., McArdle P.F., Smith A.V., Aspelund T., Bandinelli S., Boerwinkle E. Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat. Genet. 2009; 41: 648–650.

  15. Demerath E.W., Liu C.-T., Franceschini N., Chen G., Palmer J.R., Smith E.N., Chen C.T.L., Ambrosone C.B., Arnold A.M., Bandera E.V. Genome-wide association study of age at menarche in African-American women. Hum Mol. Genet. 2013; 22: 3329–3346. DOI: 10.1093/hmg/ddt181.

  16. Elks C.E., Perry J.R.B., Sulem P., Chasman D.I., Franceschini N., He C., Lunetta K.L., Visser J.A., Byrne E.M., Cousminer D.L. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. Nat. Genet. 2010; 42: 1077–1085.

  17. Perry J.R., Day F., Elks C.E. Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014; 514 (7520): 92– 97. DOI: 10.1038/nature13545.
  18. Delahanty R.J., Beeghly-Fadiel A., Long J.R. Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women. Hum Reprod. 2013; 28: 1135–1143. DOI: 10.1093/humrep/det011.

  19. Pyun J.A., Kim S., Cho N.H., Koh I., Lee J.Y., Shin C. Genome-wide association studies and epistasis analyses of candidate genes related to age at menarche and age at natural menopause in a Korean population. Menopause. 2014; 21: 522–529. DOI: 10.1097/GME.0b013e3182a433f7.

  20. He C., Kraft P., Buring J.E., Chen C., Hankison S.E., Pare G., Chanock S., Ridker P.M., Hunter D.J.A large-scale candidate-gene association study of age at menarche and age at natural menopause. Hum. Genet. 2010; 128: 515–527.

  21. Yermachenko A., Dvornyk V. UGT2B4 previously implicated in the risk of breast cancer is associated with menarche timing in Ukrainian females. Gene. 2016; 590 (1): 85–89.

  22. Ward L.D., Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 2016; 44: 877–881.

  23. Ward L.D., Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Research. 2012; 40 (Database issue): 930–934. DOI: 10.1093/nar/gkr917.

  24. Plant T.M. Neuroendocrine control of the onset of puberty. Front Neuroendocrinol. 2015; 38: 73–88. DOI: 10.1016/j.yfrne.2015.04.002.