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>Journals >Gaceta Médica de México >Year 2017, Issue 2

Ramírez-Bello J, Jiménez-Morales M
Functional implications of single nucleotide polymorphisms (SNPs) in protein-coding and non-coding RNA genes in multifactorial diseases
Gac Med Mex 2017; 153 (2)

Language: Español
References: 104
Page: 238-250
PDF: 208.82 Kb.

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Single nucleotide polymorphisms (SNPs) represent the most common type of variation in the human genome. The SNPs located in protein-coding and non-coding RNA genes are classified as neutral and functional. The neutral have no effect, while the functional affect different biological processes and continually confer risk for multifactorial diseases. Functional SNPs found in the promoters of protein-coding and non-coding RNA genes (microRNAs: miRNAs) termed regulatory SNP (rSNPs) and miRNAs rSNPs (miR-rSNPs), respectively, affect the gene expression. Functional SNPs located on the structure of the precursor mRNAs (exons and introns), mature mRNA (5´ untranslated region [UTR], coding sequence, and 3´ UTR), and primary, precursor, and mature miRNAs are termed structural RNA SNPs (srSNPs) and miR-srSNPs, respectively. The srSNPs affect the splicing (and alternative splicing), srSNPs affect the splicing (and alternative splicing), the translation, stability, amino acid sequence, structure, and function of proteins and interaction between mRNA/miRNAs. Finally, the miR-srSNPs affect the struc ture, processing and interaction between miRNAs/mRNAs. Functional characterization of potentially harmful risk alleles of the SNPs located in protein-coding and non-coding RNA genes have contributed to an understanding of their functions in the complex diseases. The objective of this review is update the reader on the functional role of the SNPs located in protein-coding and non-coding RNA genes and their relationship with multifactorial diseases.

Key words: Single nucleotide polymorphism, Protein-coding gene, Non-coding RNA.


  1. Sachidanandam R, Weissman D, Schmidt SC, et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature. 2001;409:928-33.

  2. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science. 2001;291:1304-51.

  3. Ramírez Bello J, Vargas Alarcón G, Tovilla-Zárate C, Fragoso JM. Single nucleotide polymorphisms (SNPs): functional implications of regulatory SNP (rSNP) and structural RNA (srSNPs) in complex diseases. Gac Med Mex. 2013;149:220-8.

  4. BØnnelykke K, Sparks R, Waage J, Milner JD. Genetics of allergy and allergic sensitization: common variants, rare mutations. Curr Opin Immunol. 2015;36:115-26.

  5. Zeng P, Zhao Y, Qian C, et al. Statistical analysis for genome-wide association study. J Biomed Res. 2015;29:285-97.

  6. Kato N. Insights into the genetic basis of type 2 diabetes. J Diabetes Investig. 2013;4:233-44.

  7. Mekinian A, Tamouza R, Pavy S, et al. Functional study of TNF-α promoter polymorphisms: literature review and meta-analysis. Eur Cytokine Netw. 2011;22:88-102.

  8. Fiorillo E, Orrú V, Stanford SM, et al. Autoimmune-associated PTPN22 R620W variantion reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue. J Biol Chem. 2010;285:26506-18.

  9. Gianchecchi E, Palombi M, Fierabracci A. The putative role of the C1858T polymorphism of protein tyrosine phosphatase PTPN22 gene in autoimmunity. Autoimmun Rev. 2013;12:717-25.

  10. Mishra, PJ, Mishra, PJ, Banerjee D, Bertino JR. MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: introducing microRNA pharmacogenomics. Cell Cycle. 2008;7:853-8.

  11. Sadee W, Wang D, Papp AC, et al. Pharmacogenomics of the RNA world: structural RNA polymorphisms in the drug therapy. Clin Pharmacol Ther. 2011;89:355-65.

  12. Obsteter J, Dovc P, Kunej T. Genetic variability of microRNA regulome in human. Mol Genet Genomic Med. 2015;3:30-39.

  13. Remensky V, Bork P, Sunyaev S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 2002;30:3894-900.

  14. Chen R, Davydow EV, Sirota M, Butte AJ. Non-synonymous and synonymous coding SNPs show similar likelihood and effect size of human disease association. PLoS One. 2010;5:e13574.

  15. Haraksingh RR, Snyder MP. Impact of variation in the human genome on gene regulation. J Mol Biol. 2013;425:3970-7.

  16. Hull J, Campino S, Rowlands K, et al. Identification of common genetic variation that modulates alternative splicing. PLoS Genet. 2007;3:e99.

  17. Baer C, Claus R, Plass C. Genome-wide epigenetic regulation of miRNAs in cancer. 2013;73:473-7.

  18. Guo Y, Jamison DC. The distribution of SNPs in human gene regulatory regions. BMC Genomics. 2005;6:140.

  19. Kim BC, Kim WY, Park D, Chung WH, Shin KS, Bhak J. SNP@Promoter: a database of human SNPs (single nucleotide polymorphisms) within the putative promoter regions. BMC Bioinformatics. 2008;(9 Suppl):S2.

  20. Kochi Y, Yamada R, Szuki A, et al. A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet. 2005;37:478-85.

  21. Fragoso JM, Vargas Alarcón G, Jiménez Morales S, Reyes Hernández OD, Ramírez Bello J. Tumor necrosis factor alpha (TNF-α) in autoimmune diseases (AIDs): molecular and biology and genetics. Gac Med Mex. 2014;150:334-44.

  22. Swanberg M, Lidman O, Padyukov L, et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat Genet. 2005;37:486-94.

  23. Moshynska O, Moshynskyy I, Misra V, Saxena A. G125A single-nucleotide polymorphism in the human BAX promoter affects gene expression. Oncogene. 2005;24:2042-9.

  24. Frey UH, Hauner H, Jöckel KH, Manthey I, Brockmeyer N, Siffert W. A novel promoter polymorphism in the human gene GNAS affects binding of transcription factor upstream stimulatory factor 1, Galphas protein expression and body weight regulation. Pharmacogenet Genomics. 2008;18:141-51.

  25. Lovewell TR, McDonagh AJ, Messenger AG, Azzouz M, Tazi-Ahnini R. The AIRE -230Y polymorphism affects AIRE transcriptional activity: potential influence on AIRE function in the thymus. PLoS One. 2015;10:e0127476.

  26. Cui L, Gao Y, Xie Y, et al. An ADAM10 promoter polymorphism is a functional variant in severe sepsis patients and confers susceptibility to the development of sepsis. Crit Care. 2015;19:73.

  27. Luo X, Yang W, Ye DQ, et al. A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus. PLoS One. 2011;7:e1002128.

  28. Zhang S, Qian J, Cao Q, et al. A potentially functional polymorphism in the promoter region of miR-34b/c is associated with renal cell cancer risk in a Chinese population. Mutagenesis. 2014;29:149-54.

  29. Xu M, Qiang F, Gao Y, et al. Evaluation of a novel functional single-nucleotide polymorphism (rs35010275G>C) in MIR196A2 promoter region as a risk factor of gastric cancer in a Chinese population. Medicine (Balt.). 2014;93:e173.

  30. Li P, Yan H, Zhang H, et al. A functional polymorphism in MIR196A2 is associated with risk and progression of nasopharyngeal carcinoma in the Chinese population. Genet Test Mol Biomarkers. 2014;18:149-55.

  31. Cui L, Li Y, Ma G, et al. A functional polymorphism in the promoter region of microRNA-146a is associated with the risk of Alzheimer disease and the rate of cognitive decline in patients. PLoS One. 2014;9:ee89019.

  32. Wilkie GS, Dickson KS, Gray NK. Regulation of mRNA translation by 5´-and 3´-UTR-binding factors. Trends Biochem Sci. 2003;28:182-8.

  33. Mignone F, Gissi C, Liuni S, Pesole G. Untranslated regions of mRNAs. Genome Biol. 2002;3:REVIEWS0004.

  34. Van der Velden AW, Thomas AA. The role of the 5´ untranslated region of in mRNA in translation regulation during development. Int J Biochem Cell Biol. 1999;31:87-106.

  35. Mori H, Okazawa H, Iwamoto K, Maeda E, Hashiramoto M, Kasuda M. A polymorphism in the 5´ untranslated region and a Met229 > Leu variant in exon 5 of the human UCP1 gene are associated with susceptibility to type II diabetes mellitus. Diabetologia. 2001;44:373-6.

  36. Cruickshank MN, Karimi M, Mason RL, et al. Translational effects of a lupus- associated polymorphism in the 5´ untranslated region (UTR) of human complement receptor 2 (CR2/CD21). Mol Immunol. 2012;52:165-72.

  37. Somers J, Wilson LA, Kilday JP, et al. A common polymorphism in the 5´ UTR of ERCC5 creates an upstream ORF that confers resistance to platinum-based chemotherapy. Genes Dev. 2015;29:1891-6.

  38. Ridderstråle M, Carsson E, Klannemark M, et al. FOXC2 mRNA expression and a 5´ untranslated region polymorphism of the gene are associated with insulin resistance. Diabetes. 2002;51:3554-60.

  39. Holt RJ, Vandiedonck C, Willis-Owen SA, et al. A functional AT/G polymorphism in the 5´-untranslated region of SETDB2 in the IgE locus on human chromosome 13q14. Genes Immun. 2015;16:488-94.

  40. Duan J, Sanders AR, Molen JE, et al. Polymorphisms in the 5´-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression. Mol Psychiatry. 2003;8:901-10.

  41. Grzybowska EA. Human intronless genes: functional groups, associated diseases, evolution, and mRNA processing in absence of splicing. Biochem Biophys Res Commun. 2012;424:1-6.

  42. Yenerall P, Zhou L. Identifying the mechanisms of intron gain: progress and trends. Biol Direct. 2012;7:29.

  43. Rogozin IB, Carmel L, Csuros M, Koonin EV. Origin and evolution of spliceosomal introns. Biol Direct. 2012;7:11.

  44. UI Hussain M. Micro-RNAs (miRNAs): genomic organization, biogenesis and mode of action. Cell Tissue Res. 2012;349:405-13.

  45. Mattick JS, Gagen MJ. The evolution of controlled multitasked gene networks: the role of introns and other noncoding RNAs in the development of complex organisms. Mol Biol Evol. 2001;18:1611-30.

  46. Jin Y, Yang Y, Zhang P. New insights into RNA secondary structure in the alternative splicing of pre-mRNAs. RNA Biol. 2011;8:450-457.

  47. Zhang L, Li X, Zhao R. Structural analysis of the pre-mRNA splicing machinery. Protein Sci. 2013;22:677-92.

  48. Papp AC, Pinsonneault JK, Wang D, et al. Cholesteryl ester transfer protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex-dependent cardiovascular risk. PLoS One. 2012;7):e31930.

  49. Chen CH, Lee CS, Lee MT, et al. Variant GADL1 and response to lithium therapy in bipolar I disorder. N Engl J Med. 2014;370:119-28.

  50. Baldessarini RJ, Tondo L. Does lithium treatment still work? Evidence of stable responses over three decades. Arch Gen Psychiatry. 2000;57:187-90.

  51. Rybakowski JK. Lithium in neuropsychiatry: a 2010 update. World J Biol Psychiatry. 2011;12:340-8.

  52. Zhang Y, Bertolino A Fazio L, et al. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci USA. 2007;104:20552-7.

  53. Hirose Y, Chiba K, Karasugi T, et al. A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation. Am J Hum Genet. 2008;82:1122-9.

  54. Wang D, Poi MJ, Sun X, Gaedigk A, Leeder JS, Sadee W. Common CYP2D6 polymorphisms affecting alternative splicing and transcription: long-range haplotypes with two regulatory variants modulate CYP2D6 activity. Hum Mol Genet. 2014;23:268-78.

  55. Soemedi R, Vega H, Belmont JM, Ramachandran S, Fairbrother WG. Genetic variation and RNA binding proteins: tools and techniques to detect functional polymorphisms. Adv Exp Med Biol. 2014;825:227-66.

  56. Morrison FS, Locke JM, Wood AR, et al. The splice site variant rs11078928 may be associated with a genotype-dependent alteration in expression of GSDMB transcripts. BMC Genomics. 2013;14:627.

  57. Hecker M, Fitzner B, Blaschke J, Blaschke P, Zettl UK. Susceptibility variants in the CD58 gene locus point to a role of microRNA-548ac in the pathogenesis of multiple sclerosis. Mutat Res Rev Mutat Res. 2015;763:161-7.

  58. de Souza JE, Ramalho RF, Galante PA, Meyer D, de Souza SJ. Alternative splicing and genetic diversity: silencers are more frequently modified by SNVs associated with alternative exon/intron borders. Nucleic Acid Res. 2011;39:4942-8.

  59. Motta-Mena LB, Smith SA, Mallory MJ, Jackson J, Wang J, Lynch KW. A disease-associated polymorphism alters splicing of the human CD45 phosphatase gene by disrupting combinatorial repression by heterogeneous nuclear ribonucleoproteins (hnRNPs). J Biol Chem. 2011;286:20043-53.

  60. Tazi J, Bakkour N, Stamm S. Alternative splicing and disease. Biochim Biophys Acta. 2009;1792:15-26.

  61. Rittore C, Sánchez E, Soler S, et al. Identification of a new exon 2-skipped TNFR1 transcript: regulation by three functional polymorphisms of the TNFR1-associated periodic syndrome (TRAPS) gene. Ann Rheum Dis. 2014;73:290-7.

  62. Bruun GH, Doktor TK, Andresen BS. A synonymous polymorphic variation in ACADM exon 11 affects splicing efficiency and may affect fatty acid oxidation. Mol Genet Metab. 2013;110:122-8.

  63. Burkhardt R, Kenny EE, Lowe JK, et al. Common SNPs in HMGCR in Micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon 13. Arterioscler Thromb Vasc Biol. 2008;28:2078-84.

  64. Kurmangaliyev YZ, Sutormin RA, Naumenko SA, Bazykin GA, Gelfand MS. Functional implications of splicing polymorphisms in the human genome. Hum Mol Genet. 2013;22:3449-5.

  65. Shabalina SA, Spiridonov NA, Kashina A. Sound of silence: synonymous nucleotides as a key to biological regulation and complexity. Nucleic Acids Res. 2013;41:2073-94.

  66. Tuller T, Zur H. Multiple roles of the coding sequence 5´ end in gene expression regulation. Nucleic Acids Res. 2015;43:13-28.

  67. Zhao Z, Fu YX, Hewett-Emmett D, Boerwinkle E. Investigating single nucleotide polymorphism (SNP) density in the human genome and its implication for molecular evolution. Gene. 2003;312:207-13.

  68. Hunt R, Sauna ZE, Ambudkar SV, Gottesman MM, Kimchi-Sarfaty C. Silent (synonymous) SNPs: should we care about them? Methods Mol Biol. 2009;578:23-39.

  69. Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM. Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer. Cancer Res. 2007;67:9609-12.

  70. Waldman YY, Tuller T, Keinan A, Ruppin E. Selection for translation efficiency on synonymous polymorphisms in recent human evolution. Genome Biol Evol. 2011;3:749-61.

  71. Yates CM, Sternberg MJ. Proteins and domains vary in their tolerance of non-synonymous single nucleotide polymorphisms (nsSNPs). J Mol Biol. 2013;425:1274-86.

  72. Stitziel NO, Tseng YY, Pervouchine D, Goddeau D, Kasif S, Liang J. Structural location of disease-associated single-nucleotide polymorphisms. J Mol Biol. 2003;327:1021-30.

  73. Kimchi-Sarfaty C, Oh JM, Kim IW, et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315:525-8.

  74. Komar AA. Silent SNPs: impact on gene function and phenotype. Pharmacogenomics. 2007;8:1075-80.

  75. Capon F, Allen MH, Ameen M, et al. A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Hum Mol Genet. 2004;13:2361-8.

  76. Ueki M, Kimura-Kataoka K, Takeshita H, et al. Evaluation of all non-synonymous single nucleotide polymorphisms (SNPs) in the genes encoding human deoxiribonuclease I and I-like 3 as a functional SNP potentially implicated in autoimmunity. FEBS. 2014;281:376-90.

  77. Sheridan J, Mack DR, Amre DK, et al. A non-synonymous coding variant (L616F) in the TLR5 gene is potentially associated with Crohn’s disease and influences responses to bacterial flagellin. PLoS One. 2013;8:e61326.

  78. Burn GL, Svensson L, Sanchez-Blanco C, Saini M, Cope AP. Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? FEBS Lett. 2011;585:3689-98.

  79. Elshazli R, Settin A. Association of PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with rheumatoid arthritis: a meta-analysis update. Immunobiology. 2015;220:1012-24.

  80. Xuan C, Lun LM, Zhao JX, et al. PTPN22 gene polymorphism (C1858T) is associated with susceptibility to type 1 diabetes: a meta-analysis of 19,495 cases and 25,341 controls. Ann Hum Genet. 2013;77:191-203.

  81. Yates CM, Sternberg MJ. The effects of non-synonimous single nucleotide polymorphisms (nsSNPs) on protein-protein interactions. J Mol Biol. 2013;425:3949-63.

  82. Michalova E, Vojtesek B, Hrstka R. Impaired pre-mRNA processing and altered architecture of 3´ untranslated regions contribute to the development of human disorders. Int J Mol Sci. 2013;14:15681-94.

  83. Sandberg R, Neilson JR, Sarma A, Sharp PA, Burge CB. Proliferating cells express mRNAs with shortened 3´ untranslated regions and fewer microRNA target sites. Science. 2008;320:1643-7.

  84. Mayr C, Bartel DP. Widespread shortening of 3´UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell. 2009;138:673-84.

  85. Miura P, Shenker S, Andreu-Agullo C, Westholm JO, Lai EC. Widespread and extensive lengthening of 3´ UTRs in the mammalian brain. Genome Res. 2013;23:812-25.

  86. Wabg L, Yi R. 3´UTRs take a long shot in the brain. Bioessays. 2014;36: 39-45.

  87. Matoulkova E, Michalova E, Vojtesek B, Hrstka R. The role of the 3´ untranslated region in post-transcriptional regulation of protein expression in mammalian cells. RNA Biol. 2012;9:563-76.

  88. Liu ME, Liao YC, Lin RT, et al. A functional polymorphism of PON1 interferes with microRNA binding to increase the risk of ischemic stroke and carotid atherosclerosis. Atherosclerosis. 2013;228:161-7.

  89. Seneviratne C, Huang W, Ait-Daoud N, Li MD, Johnson BA. Characterization of a functional polymorphism in the 3´ UTR of SLC6A4 and its association with drinking intensity. Alcohol Clin Exp Res. 2009;33:332-9.

  90. Pugal I, Lainez B, Fernández-Real JM, et al. A polymorphism in the 3´ untranslated region of the gene for tumor necrosis factor receptor 2 modulates reporter gene expression. Endocrinology. 2005;146:2210-20.

  91. Akdeli N, Riemann K, Westphal J, Hess J, Siffert W, Bachmann HS. A 3´ UTR polymorphism modulates mRNAm of the oncogene and drug target Polo-like kinase 1. Mol Cancer. 2014;13:87.

  92. Miller CL, Haas U, Diaz R, et al. Coronary heart disease-associated variation in TCF21 disrupts a miR-224 binding site and miRNA-mediated regulation. PLoS Genet. 2014;10:e1004263.

  93. Richardon K, Louie-Gao Q, Arnett DK, et al. The PLIN4 variant rs8887 modulates obesity related phenotypes in humans through creation of a novel miR-522 seed site. PLoS One. 2011;6:317944.

  94. Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet. 2006;15:R17-29.

  95. Hüttenhofer A, Schattner P, Polacek N. Non-coding RNAs: hope and hype? Trends Genet. 2005;21:289-97.

  96. Kagevama Y, Kondo T, Hashimoto Y. Coding vs non-coding: translatability of short ORFs found in putative non-coding transcripts. Biochimie. 2011;93:1981-6.

  97. Mattick JS, Makunin IV. Small regulatory RNAs in mammals. Hum Mol Genet. 2005;14:R121-32.

  98. Rodríguez A, Griffths Jones S, Ashurst JL, Bradley A. Identification of mammalian microRNA host genes and transcription units. Genome Res. 2004;14:1902-10.

  99. Cai X, Hagedorn CH, Cullen BR. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA. 2004;10:1957-66.

  100. Shao Y, Li J, Cai Y, et al. The functional polymorphisms of miR-146a are associated with susceptibility to severe sepsis in the Chinese population. Mediators Inflamm. 2014;2014:916202.

  101. Wang N, Li Y, Zhu LI, et al. A functional polymorphism rs11614913 in microRNA-192a2 is associated with an increased risk of colorectal cancer although not with tumor stage and grade. Biomed Rep. 2013;1:737-42.

  102. Lv H, Pei J, Liu H, Wang H, Liu J. A polymorphism site in the pre-miR- 34a coding region reduces miR-34a expression and promotes osteosarcoma cell proliferation and migration. Mol Med Rep. 2014;10:2912-6.

  103. Dai ZJ, Shao YP, Wang XJ, et al. Five common functional polymorphisms in microRNAs (rs2910164, rs2292832, rs11614913, rs3746444, rs895819) and the susceptibility to breast cancer: evidence from 8361 cancer cases and 8504 controls. Curr Pharm Des. 2015;21:1455-63.

  104. Slaby O, Bienertova-Vasku J, Svoboda M, Vyzula R. Genetic polymorphisms and microRNAs: new direction in molecular epidemiology of solid cancer. J Cell Mol Med. 2012;16:8-21.

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