Obesity is one of the global health problems resulting in significant economic and social damage in both developed and developing countries. Overweight and obesity are key risk factors of diabetes and cardiovascular and oncological diseases that cause high morbidity and mortality. In the present paper, the method of multiplex genotyping of polymorphic variants of genes associated with obesity and variability of body mass index (BMI) was developed on the basis of multilocus PCR and MALDI-TOF mass spectrometry of DNA molecules. The frequencies of 51 single-nucleotide polymorphisms of obesity candidate genes in a population sample of Russians in Kemerovo were characterized. The results obtained were compared with the data for populations from the 1000 Genomes project. The association of markers rs12446632 of the LOC105371116 locus and rs16851483 of the RASA2 gene with BMI variability in the Russian population of Kemerovo was shown.
This is a preview of subscription content,to check access.
Access this article
Dedov, I.I., Mel’nichenko G.A., and Romantsova, T.I., Pathogenetic aspects of obesity, Ozhirenie Metabol., 2004, no. 1, pp. 3–9.
Dedov, I.I., Mel’nichenko G.A., Shestakova, M.V., et al., Russian national clinical recommendations for morbid obesity treatment in adults: 3rd revision (morbid obesity treatment in adults), Ozhirenie Metabol., 2018, vol. 15, no. 1, pp. 53–70. https://doi.org/10.14341/OMET2018153-70
Romieu, I., Dossus, L., Barquera, S., et al., Energy balance and obesity: what are the main drivers?, Cancer Causes Control, 2017, vol. 28, no. 3, pp. 247–258. https://doi.org/10.1007/s10552-017-0869-z
Huvenne, H., Dubern, B., Clément, K., and Poitou, C., Rare genetic forms of obesity: clinical approach and current treatments in 2016, Obes. Facts, 2016, vol. 9, no. 3, pp. 158–173. https://doi.org/10.1159/000445061
GWAS Catalog. https://www.ebi.ac.uk/gwas/. Accessed December, 2018.
Rohde, K., Keller, M., la Cour Poulsen, L., et al., Genetics and epigenetics in obesity, Metabolism, 2019, vol. 92, pp. 37–50. https://doi.org/10.1016/j.metabol.2018.10.007
Srivastava, A., Srivastava, N., and Mittal, B., Genetics of obesity, Indian J. Clin. Biochem., 2016, vol. 31, no. 4, pp. 361–371. https://doi.org/10.1007/s12291-015-0541-x
Day, F.R. and Loos, R.J., Developments in obesity genetics in the era of genome-wide association studies, J. Nutrigenet. Nutrigenomics, 2011, vol. 4, no. 4, pp. 222–238. https://doi.org/10.1159/000332158
Gabriel, S., Ziaugra, L., and Tabbaa, D., SNP genotyping using the Sequenom MassARRAY iPLEX platform, Curr. Protoc. Hum. Genet., 2009, vol. 60, pp. 2.12.1–2.12.18. https://doi.org/10.1002/0471142905.hg0212s60
Stepanov, V.A. and Trifonova, E.A., Multiplex SNP genotyping by MALDI-TOF mass spectrometry: Frequencies of 56 immune response gene SNPs in human populations, Mol. Biol. (Moscow), 2013, vol. 47, no. 6, pp. 852—862. https://doi.org/10.1134/S0026893313060149
AgenaCx customer portal. https://www.agenacx.com. Accessed January, 2019.
Weir, B.S., Genetic Data Analysis: Method for Discrete Population Genetic Data, Sunderland: Sinauer Associates, 1990.
Glantz, S.A., Primer of Biostatistics, New York: McGraw-Hill, 1997, 4th ed.
Triska, P., Chekanov, N., Stepanov, V., et al., Between lake Baikal and the Baltic sea: genomic history of the gateway to Europe, BMC Genet., 2017, vol. 18, suppl. 1. https://doi.org/10.1186/s12863-017-0578-3
Stepanov, V.A., Evolution of genetic diversity and human diseases, Russ. J. Genet., 2016, vol. 52, no. 7, pp. 746—756. https://doi.org/10.1134/S1022795416070103
Stepanov, V.A., Etnogenomika naseleniya Severnoi Evrazii (Ethnogenomics of the Northern Eurasia Population), Tomsk: Pechatnaya Manufaktura, 2002.
The Human Gene Database GeneCards. https://www.genecards.org/. Accessed December, 2018.
Arafeh, R., Qutob, N., Emmanuel, R., et al., Recurrent inactivating RASA2 mutations in melanoma, Nat. Genet., 2015, vol. 47, no. 12, pp. 1408–1410. https://doi.org/10.1038/ng.3427
Tidyman, W.E. and Rauen, K.A., Expansion of the RASopathies, Curr. Genet. Med. Rep., 2016, vol. 4, no. 3, pp. 57–64.
HaploReg v4.1. https://pubs.broadinstitute.org/mammals/haploreg/haploreg.php. Accessed December, 2018.
Atanes, P., Ruz-Maldonado, I., Hawkes, R., et al., Identifying signalling pathways regulated by GPRC5B in β-Cells by CRISPR-Cas9-mediated genome editing, Cell Physiol. Biochem., 2018, vol. 45, no. 2, pp. 656–666. https://doi.org/10.1159/000487159
Kim, Y.J., Greimel, P., and Hirabayashi, Y., GPRC5B-mediated sphingomyelin synthase 2 phosphorylation plays a critical role in insulin resistance, Science, 2018, vol. 8, pp. 250–266. https://doi.org/10.1016/j.isci.2018.10.001
Kim, Y.J., Sano, T., Nabetani, T., et al., GPRC5B activates obesity-associated inflammatory signaling in adipocytes, Sci. Signal., 2012, vol. 5, no. 251. https://doi.org/10.1126/scisignal.2003149
Willer, C.J., Speliotes, E.K., Loos, R.J., et al., Six new loci associated with body mass index highlight a neuronal influence on body weight regulation, Nat. Genet., 2009, vol. 41, no. 1, pp. 25–34. https://doi.org/10.1038/ng.287
Speliotes, E.K., Willer, C.J., Berndt, S.I., et al., Association analyses of 249 796 individuals reveal 18 new loci associated with body mass index, Nat. Genet., 2010, vol. 42, no. 11, pp. 937–948. https://doi.org/10.1038/ng.686
Berndt, S.I., Gustafsson, S., Mägi, R., et al., Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture, Nat. Genet., 2013, vol. 45, no. 5, pp. 501–512. https://doi.org/10.1038/ng.2606
Locke, A.E., Kahali, B., Berndt, S.I., et al., Genetic studies of body mass index yield new insights for obesity biology, Nature, 2015, vol. 518, no. 7538, pp. 197–206. https://doi.org/10.1038/nature14177
Felix, J.F., Bradfield, J.P., Monnereau, C., et al., Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index, Hum. Mol. Genet., 2016, vol. 25, no. 2, pp. 389–403. https://doi.org/10.1093/hmg/ddv472
Justice, A.E., Winkler, T.W., Feitosa, M.F., et al., Genome-wide meta-analysis of 241 258 adults accounting for smoking behaviour identifies novel loci for obesity traits, Nat. Commun., 2017, vol. 8. https://doi.org/10.1038/ncomms14977
Akiyama, M., Okada, Y., Kanai, M., et al., Genome-wide association study identifies 112 new loci for body mass index in the Japanese population, Nat. Genet., 2017, vol. 49, no. 10, pp. 1458–1467. https://doi.org/10.1038/ng.3951
Graff, M., Scott, R.A., Justice, A.E., et al., Genome-wide physical activity interactions in adiposity—a meta-analysis of 200 452 adults, PLoS Genet., 2017, vol. 13, no. 4. e1006528. https://doi.org/10.1371/journal.pgen.1006528
Ng, M.C.Y., Graff, M., Lu, Y., et al., Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium, PLoS Genet., 2017, vol. 13, no. 4. e1006719. https://doi.org/10.1371/journal.pgen.1006719
Hinney, A., Nguyen, T.T., Scherag, A., et al., Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants, PLoS One, 2007, vol. 2, no. 12. e1361. https://doi.org/10.1371/journal.pone.0001361
Loos, R.J., Lindgren, C.M., Li, S., et al., Common variants near MC4R are associated with fat mass, weight and risk of obesity, Nat. Genet., 2008, vol. 40, no. 6, pp. 768–775. https://doi.org/10.1038/ng.140
Graff, M., Ngwa, J.S., Workalemahu, T., et al., Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course, Hum. Mol. Genet., 2013, vol. 22, no. 17, pp. 3597–3607. https://doi.org/10.1093/hmg/ddt205
Wheeler, E., Huang, N., Bochukova, E.G., et al., Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity, Nat. Genet., 2013, vol. 45, no. 5, pp. 513–517. https://doi.org/10.1038/ng.2607
Wen, W., Zheng, W., Okada, Y., et al., Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index, Hum. Mol. Genet., 2014, vol. 23, no. 20, pp. 5492–5504. https://doi.org/10.1093/hmg/ddu248
Meyre, D., Delplanque, J., Chevre, J.C., et al., Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations, Nat. Genet., 2009, vol. 41, no. 2, pp. 157–159. https://doi.org/10.1038/ng.301
Scherag, A., Dina, C., Hinney, A., et al., Two new loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and German study groups, PLoS Genet., 2010, vol. 6, no. 4. e1000916. https://doi.org/10.1371/journal.pgen.1000916
Dorajoo, R., Blakemore, A.I., Sim, X., et al., Replication of 13 obesity loci among Singaporean Chinese, Malay and Asian-Indian populations, Int. J. Obes. (London), 2012, vol. 36, no. 1, pp. 159–163. https://doi.org/10.1038/ijo.2011.86
Warrington, N.M., Howe, L.D., Paternoster, L., et al., A genome-wide association study of body mass index across early life and childhood, Int. J. Epidemiol., 2015, vol. 44, no. 2, pp. 700–712. https://doi.org/10.1093/ije/dyv077
Okada, Y., Kubo, M., Ohmiya, H., et al., Common variants at CDKAL1 and KLF9 are associated with body mass index in east Asian populations, Nat. Genet., 2012, vol. 44, no. 3, pp. 302–306. https://doi.org/10.1038/ng.1086
Thorleifsson, G., Walters, G.B., Gudbjartsson, D.F., et al., Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity, Nat. Genet., 2009, vol. 41, no. 1, pp. 18–24. https://doi.org/10.1038/ng.274
Comuzzie, A.G., Cole, S.A., Laston, S.L., et al., Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population, PLoS One, 2012, vol. 7, no. 12. e51954. https://doi.org/10.1371/journal.pone.0051954
Cotsapas, C., Speliotes, E.K., Hatoum, I.J., et al., Common body mass index-associated variants confer risk of extreme obesity, Hum. Mol. Genet., 2009, vol. 18, no. 18, pp. 3502–3507. https://doi.org/10.1093/hmg/ddp292
Wen, W., Cho, Y.S., Zheng, W., et al., Meta-analysis identifies common variants associated with body mass index in east Asians, Nat. Genet., 2012, vol. 44, no. 3, pp. 307–311. https://doi.org/10.1038/ng.1087
Pei, Y.F., Zhang, L., Liu, Y., et al., Meta-analysis of genome-wide association data identifies novel susceptibility loci for obesity, Hum. Mol. Genet., 2014, vol. 23, no. 3, pp. 820–830. https://doi.org/10.1093/hmg/ddt464
Wan, E.S., Cho, M.H., Boutaoui, N., et al., Genome-wide association analysis of body mass in chronic obstructive pulmonary disease, Am. J. Respir. Cell Mol. Biol., 2011, vol. 45, no. 2, pp. 304–310. https://doi.org/10.1165/rcmb.2010-0294OC
Namjou, B., Keddache, M., Marsolo, K., et al., EMR-linked GWAS study: investigation of variation landscape of loci for body mass index in children, Front Genet., 2013, vol. 4. https://doi.org/10.3389/fgene.2013.00268
This work was financially supported by the Russian Foundation for Basic Research (project no. 18-04-00758).
Conflicts of interest. The authors declare that they have no conflict of interest.
Statement of compliance with standards of research involving humans as subjects. All procedures performed in the study involving human participants are in accordance with the ethical standards of the institutional and/or national research ethics committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from each participant involved in the study.
Translated by D. Novikova
About this article
Cite this article
Trifonova, E.A., Popovich, A.A., Vagaitseva, K.V. et al. The Multiplex Genotyping Method for Single-Nucleotide Polymorphisms of Genes Associated with Obesity and Body Mass Index. Russ J Genet 55, 1282–1293 (2019). https://doi.org/10.1134/S1022795419100144