Genetic variability of five ADRB2 polymorphisms among Mexican Amerindian ethnicities and the Mestizo population

Autoři: María Guadalupe Salas-Martínez aff001;  Yolanda Saldaña-Alvarez aff001;  Emilio J. Cordova aff001;  Diana Karen Mendiola-Soto aff001;  Miguel A. Cid-Soto aff001;  Angélica Luckie-Duque aff003;  Hermenegildo Vicenteño-Ayala aff004;  Francisco Barajas-Olmos aff001;  Cecilia Contreras-Cubas aff001;  Humberto García-Ortiz aff001;  Juan L. Jiménez-Ruíz aff001;  Federico Centeno-Cruz aff001;  Angélica Martínez-Hernández aff001;  Elvia C. Mendoza-Caamal aff005;  Elaheh Mirzaeicheshmeh aff001;  Lorena Orozco aff001
Působiště autorů: Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, Secretaría de Salud, Mexico City, Mexico aff001;  Genomic Sciences Program, Universidad Autónoma de la Ciudad de México, Mexico City, Mexico aff002;  Hospital Regional 1° de Octubre, ISSSTE, Mexico City, Mexico aff003;  Hospital Regional Adolfo López Mateos, ISSSTE, Mexico City, Mexico aff004;  Clinical Area, Instituto Nacional de Medicina Genómica, Secretaría de Salud, Mexico City, Mexico aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


The Mexican population is characterized by high and particular admixture, and the picture of variants associated with disease remains unclear. Here we investigated the distribution of single nucleotide polymorphisms (SNPs) in the Mexican population. We focused on two non-synonymous and three synonymous SNPs in the beta-2 adrenergic receptor gene (ADRB2), which plays key roles in energy balance regulation. These SNPs were genotyped in 2,011 Mexican Amerindians (MAs) belonging to 62 ethnic groups and in 1,980 geographically matched Mexican Mestizos (MEZs). The frequency distribution of all five ADRB2 variants significantly differed between MAs, MEZs, and other continental populations (CPs) from the 1000 Genomes database. Allele frequencies of the three synonymous SNPs rs1042717A, rs1042718A, and rs1042719C were significantly higher in Mexican individuals, particularly among MAs, compared to in the other analyzed populations (P<0.05). The non-synonymous ADRB2 Glu27 allele (rs1042714G), which is associated with several common conditions, showed the lowest frequency in MAs (0.03) compared to other populations worldwide. Among MEZs, this allele showed a frequency of 0.15, intermediate between that in MAs and in Iberians (0.43). Moreover, Glu27 was the only SNP exhibiting a geographic gradient within the MEZ population (from 0.22 to 0.11), reflecting admixed mestizo ancestry across the country. Population differentiation analysis demonstrated that Glu27 had the highest FST value in MAs compared with Europeans (CEU) (0.71), and the lowest between MAs and Japanese (JPT) (0.01), even lower than that observed between MAs and MEZs (0.08). This analysis demonstrated the genetic diversity among Amerindian ethnicities, with the most extreme FST value (0.34) found between the Nahuatls from Morelos and the Seris. This is the first study of ADRB2 genetic variants among MA ethnicities. Our findings add to our understanding of the genetic contribution to variability in disease susceptibility in admixed populations.

Klíčová slova:

Alleles – Genetics of disease – Geographic distribution – Haplotypes – Mexican people – Phylogeography – Population genetics – Variant genotypes


1. Johnson NA, Coram MA, Shriver MD, Romieu I, Barsh GS, London SJ, et al. Ancestral components of admixed genomes in a Mexican cohort. PLoS Genet. 2011;7(12): e1002410. doi: 10.1371/journal.pgen.1002410 22194699

2. Instituto Nacional de Estadística y Geografía (INEGI), 2010. México.

3. Contreras-Cubas C, Sánchez-Hernández BE, García-Ortiz H, Martínez-Hernández A, Barajas-Olmos F, Cid M, et al. Heterogenous Distribution of MTHFR Gene Variants among Mestizos and Diverse Amerindian Groups from Mexico. PLoS One. 2016;11(9): e0163248. doi: 10.1371/journal.pone.0163248 27649570

4. Moreno-Estrada A, Gignoux CR, Fernández-López JC, Zakharia F, Sikora M, Contreras AV, et al. Human genetics. The genetics of Mexico recapitulates Native American substructure and affects biomedical traits. Science. 2014;344(6189): 1280–1285.28. doi: 10.1126/science.1251688 24926019

5. 1000 Genomes Project Consortium, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422): 56–65. doi: 10.1038/nature11632 23128226

6. Myles S, Davison D, Barrett J, Stoneking M, Timpson N. Worldwide population differentiation at disease-associated SNPs. BMC Med Genomics. 2008;1:22. doi: 10.1186/1755-8794-1-22 18533027

7. Ortega VE, Meyers DA. Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine. J Allergy Clin Immunol. 2014;133(1): 16–26. doi: 10.1016/j.jaci.2013.10.040 24369795

8. Wechsler ME, Castro M, Lehman E, Chinchilli VM, Sutherland ER, Denlinger L, et al. NHLBI Asthma Clinical Research Network. Impact of race on asthma treatment failures in the asthma clinical research network. Am J Respir Crit Care Med. 2011;184(11): 1247–1253. doi: 10.1164/rccm.201103-0514OC 21885625

9. Di Rienzo A, Hudson RR. An evolutionary framework for common diseases: the ancestral-susceptibility model. Trends Genet. 2005;21(11): 596–601. doi: 10.1016/j.tig.2005.08.007 16153740

10. Liang SQ, Chen XL, Deng JM, Wei X, Gong C, Chen ZR, et al. Beta-2 adrenergic receptor (ADRB2) gene polymorphisms and the risk of asthma: a meta-analysis ofcase-control studies. PLoS One. 2014;9(8): e104488. doi: 10.1371/journal.pone.0104488 25111792

11. Litonjua AA, Gong L, Duan QL, Shin J, Moore MJ, Weiss ST, et al. Very important pharmacogene summary ADRB2. Pharmacogenet Genomics. 2010;20(1): 64–69. doi: 10.1097/FPC.0b013e328333dae6 19927042

12. Anwar MS, Iskandar MZ, Parry HM, Doney AS, Palmer CN, Lang CC. The future of pharmacogenetics in the treatment of heart failure. Pharmacogenomics. 2015;16(16): 1817–1827. doi: 10.2217/pgs.15.120 26555119

13. Masuo K. Roles of beta2- and beta3-adrenoceptor polymorphisms in hypertension and metabolic syndrome. Int J Hypertens. 2010; 832821.

14. Zhang H, Wu J, Yu L. Association of Gln27Glu and Arg16Gly polymorphisms in Beta2-adrenergic receptor gene with obesity susceptibility: a meta-analysis. PloS One. 2014;9(6): e100489. doi: 10.1371/journal.pone.0100489 24960039

15. Xia K, Ding R, Zhang Z, Li W, Shang X, Yang X, et al. The association of eight potentially functional polymorphisms in five adrenergic receptor-encoding genes with myocardial infarction risk in Han Chinese. Gene. 2017;624: 43–49. doi: 10.1016/j.gene.2017.04.045 28456594

16. Young JH, Chang YP, Kim JD, Chretien JP, Klag MJ, Levine MA, et al. Differential susceptibility to hypertension is due to selection during the out-of-Africa expansion. PLoS Genet. 2005;1(6): e82. doi: 10.1371/journal.pgen.0010082 16429165

17. Cagliani R, Fumagalli M, Pozzoli U, Riva S, Comi GP, Torri F, et al. Diverse evolutionary histories for beta-adrenoreceptor genes in humans. Am J Hum Genet. 2009;85(1): 64–75. doi: 10.1016/j.ajhg.2009.06.005 19576569

18. Takenaka A, Nakamura S, Mitsunaga F, Inoue-Murayama M, Udono T, Suryobroto B. Human-specific SNP in obesity genes, adrenergic receptor beta2 (ADRB2), Beta3 (ADRB3), and PPAR γ2 (PPARG), during primate evolution. PLoS One. 2012;7(8): e43461. doi: 10.1371/journal.pone.0043461 22937051

19. Larocca N, Moreno D, Garmendia JV, Velasquez O, Martin-Rojo J, Talamo C, et al. Beta 2 adrenergic receptor polymorphisms, at codons 16 and 27, and bronchodilator responses in adult Venezuelan asthmatic patients. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2013;57(4): 374–378.

20. Valencia DM, Naranjo CA, Parra MV, Caro MA, Valencia AV, Jaramillo CJ, et al. Association and interaction of AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R and PTGS2 genes on the risk of hypertension in Antioquian population. Biomedica, 2013;33(4): 598–614. doi: 10.7705/biomedica.v33i4.1489 24652215

21. Zhao L, Yang F, Xu K, Cao H, Zheng GY, Zhang Y, et al. Common genetic variants of the β2-adrenergic receptor affect its translational efficiency and are associated with human longevity. Aging Cell. 2012;11(6): 1094–1101. doi: 10.1111/acel.12011 23020224

22. Saadi AV, Gupta H, Angural A, Dhanya SK, Mony S, Oberoi D, et al. Single nucleotide polymorphisms of ADRB2 gene and their association with susceptibility for Plasmodium falciparum malaria and asthma in an Indian population. Infect Genet Evol. 2013; 20: 140–147. doi: 10.1016/j.meegid.2013.08.026 24012958

23. Martínez-Aguilar NE, Del Río-Navarro BE, Navarro-Olivos E, García-Ortíz H, Orozco L, Jiménez-Morales S. SPINK5 and ADRB2 haplotypes are risk factors for asthma in Mexican pediatric patients. J Asthma. 2015; 52(3): 232–239. doi: 10.3109/02770903.2014.966913 25233048

24. Vargas-Alarcón G, Fragoso JM, Cruz-Robles D, Vargas A, Martinez A, Lao-Villadóniga JI, et al. Association of adrenergic receptor gene polymorphisms with different fibromyalgia syndrome domains. Arthritis Rheum. 2009;60(7): 2169–2173. doi: 10.1002/art.24655 19565482

25. Messina Baas O, Pacheco Cuellar G, Toral-López J, Lara Huerta SF, Gonzalez-Huerta LM, Urueta-Cuellar H, et al. ADRB1 and ADBR2 gene polymorphisms and the ocular hypotensive response to topical betaxolol in healthy Mexican subjects. Curr Eye Res. 2014;39(11): 1076–1080. doi: 10.3109/02713683.2014.900807 24749907

26. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3): 559±575. doi: 10.1086/519795 17701901

27. Rousset F. genepop'007: a complete re-implementation of the genepop software for Windows and Linux. Mol Ecol Resour. 2008;8(1): 103–106. doi: 10.1111/j.1471-8286.2007.01931.x 21585727

28. Comisión Nacional para el Conocimiento y Uso de la Biodiversidad (CONABIO), cartographer División política estatal 1:250000.2005. Available from:

29. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria (2013). URL:

30. Ordoñez G, Romero S, Orozco L, Pineda B, Jiménez-Morales S, Nieto A, et al. Genomewide admixture study in Mexican Mestizos with multiple sclerosis. Clin Neurol Neurosurg. 2015;130: 55–60. doi: 10.1016/j.clineuro.2014.11.026 25577161

31. Nakajima T, Wooding S, Sakagami T, Emi M, Tokunaga K, Tamiya G, et al. Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world. Am J Hum Genet. 2004;74(5): 898–916. doi: 10.1086/420793 15077204

32. Thompson EE, Kuttab-Boulos H, Witonsky D, Yang L, Roe BA, Di Rienzo A. CYP3A variation and the evolution of salt-sensitivity variants. Am J Hum Genet. 2004;75(6): 1059–1069. doi: 10.1086/426406 15492926

33. Pickrell JK, Reich D. Toward a new history and geography of human genes informed by ancient DNA. Trends Genet. 2014;30(9): 377–389. doi: 10.1016/j.tig.2014.07.007 25168683

34. Klimentidis YC, Abrams M, Wang J, Fernandez JR, Allison DB. Natural selection at genomic regions associated with obesity and type-2 diabetes: East Asians and sub-Saharan Africans exhibit high levels of differentiation at type-2 diabetes regions. Hum Genet. 2011;129(4): 407–418. doi: 10.1007/s00439-010-0935-z 21188420

35. Mansley MK, Ivy JR, Bailey MA. ISN Forefronts Symposium 2015: The Evolution of Hypertension-Old Genes, New Concepts. Kidney Int Rep. 2016;1(3):197–203. doi: 10.1016/j.ekir.2016.08.003 27722209

36. Wang DW, Liu M, Wang P, Zhan X, Liu YQ, Zhao LS. ADRB2 polymorphisms predict the risk of myocardial infarction and coronary artery disease. Genet Mol Biol. 2015; 38(4): 433–443. doi: 10.1590/S1415-475738420140234 26692153

37. Tomar A, Malhotra S, Sarkar S. Polymorphism profiling of nine high altitude relevant candidate gene loci in acclimatized sojourners and adapted natives. BMC Genet. 2015;16: 112. doi: 10.1186/s12863-015-0268-y 26373931

38. Kulminski AM, Culminskaya I, Ukraintseva SV, Arbeev KG, Land KC, Yashin AI. Beta2-adrenergic receptor gene polymorphisms as systemic determinants of healthy aging in an evolutionary context. Mech Ageing Dev. 2010;131(5): 338–345. doi: 10.1016/j.mad.2010.04.001 20399803

39. Kidd JR, Friedlaender F, Pakstis AJ, Furtado M, Fang R, Wang X, et al. Single nucleotide polymorphisms and haplotypes in Native Americanpopulations. Am J Phys Anthropol. 2011;146(4): 495–502. doi: 10.1002/ajpa.21560 21913176

40. Raghavan M, Skoglund P, Graf KE, Metspalu M, Albrechtsen A, Moltke I, et al. Upper Palaeolithic Siberian genome reveals dual ancestry of Native Americans. Nature. 2014;505(7481): 87–91. doi: 10.1038/nature12736 24256729

41. International HapMap 3 Consortium, Altshuler DM, Gibbs RA, Peltonen L, Altshuler DM, Gibbs RA, Peltonen L, et al. Integrating common and rare genetic variation in diverse human populations. Nature. 2010;467(7311): 52–58. doi: 10.1038/nature09298 20811451

42. Gorlov IP, Gorlova OY, Amos CI. Allelic Spectra of Risk SNPs Are Different for Environment/Lifestyle Dependent versus Independent Diseases. PLoS Genet. 2015;11(7): e1005371. doi: 10.1371/journal.pgen.1005371 26201053

Článek vyšel v časopise


2019 Číslo 12
Nejčtenější tento týden