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Table 1 Selected examples of in vitro characterised human functional intronic polymorphisms located more than ~30 bp from the nearest splice site

From: Functional intronic polymorphisms: Buried treasure awaiting discovery within our genes

Gene Disease/phenotype Chromosomal location Polymorphism, intronic location and dbSNP number Consequences for gene expression or mRNA splicing Reference
AGTR2 Predisposition to congenital anomalies of the kidney and urinary tract Xq22-q23 IVS1, AS, A > G, -29
SNP occurs within branchpoint motif and alters splicing efficiency Nishimura et al. (1999)a
BANK1 Susceptibility to systemic lupus erythematosus 4q23 IVS1, AS, T > C, -43
SNP occurs within branchpoint motif and risk allele alters expression of alternative transcripts Kozyrev et al. (2008)b
CD244 Susceptibility to rheumatoid arthritis 1q23.1 IVS3, AS, T > C, -164
Risk allele associated with increased transcriptional activity Suzuki et al. (2008)c
CD244 Susceptibility to rheumatoid arthritis 1q23.1 IVS5, DS, G > A, +526 (rs3766379) Risk allele associated with increased transcriptional activity Suzuki et al. (2008)c
COL1A1 Reduced bone density/osteoporosis 17q21.33 IVS1, AS, G > T, -440
SNP occurs within Sp1-binding site; risk allele alters Sp1 binding and transcriptional activity Mann et al. (2001)d
CXCR3 Variation in immune cell response to chemokine-cytokine signals Xq13 IVS1, DS, G > A, +234
Risk allele associated with reduced CXCR3 gene expression Choi et al. (2008)e
CYP2D6 Intermediate metaboliser (reduced expression of CYP2D6) 22q13.1 IVS6, DS, G > A, +39
Increased level (7.3-fold) of non-functional splice variant transcript lacking exon 6 and reduced level (2.9-fold) of functional transcript Toscano et al.
DRD2 Reduced DRD2 expression 11q22-q23 IVS1, DS, A > G, +3850
Risk allele associated with increased binding of transcriptional repressor (Freud-1) leading to reduced DRD2 expression Rogaeva
et al. (2007)g
DRD2 Reduced DRD2 expression 11q23 IVS6, AS, C > A, -83
(rs 1076560)
Risk allele alters expression of alternative transcripts Zhang et al.
F2 Elevated prothrombin level/thrombosis 11p11-q12 IVS13, AS, A > G, -59 Risk allele influences splicing efficiency von Ahsen & Oellerich (2004)i
FGFR2 Susceptibility to breast cancer 10q26 IVS2, DS, T > C,+ 12912
Risk allele alters binding affinity for transcription factors Oct-1/Runx2, leading to increased FGFR2 expression Meyer et al.
FOXP3 Susceptibility to psoriasis Xp11.23 IVS1, DS, A > C, +2882
Risk allele causes loss of binding of E47 and c-Myb, leading to reduced FOXP3 transcription Shen et al.
GFPT1 Reduced GFPT1 expression 2p13 IVS1, DS, T > C, +36
SNP occurs within GC box and risk allele decreases transcriptional activity Kunika et al.
GSK3B Risk of Parkinson's disease 3q13.3 IVS5, AS, T > C, -157
Risk allele associated with increased level of GSK3B transcripts lacking exons 9 and 11 Kwok et al.
IRF4 Risk of childhood acute lymphoblastic leukaemia in males 6p25-p23 IVS4, DS, C > T, +386
Risk allele increases IRF4 promoter activity/expression Do et al.
LTA Susceptibility to myocardial infarction 6p21.3 IVS1, AS, G > A, -198
Risk allele associated with increased transcriptional activity Ozaki et al.
NLRP3 Susceptibility to food-induced anaphylaxis 1q44 IVS7, AS, C > T, -202
Risk allele increases enhancer activity by 20% Hitomi et al.
SCG3 Association with obesity 15q21 IVS1, DS, G > A, +190
Risk allele alters transcriptional activity Tanabe et al.
TH Risk of essential tension 11p15.5 IVS12, DS, T > C, +127
Risk allele associated with increased transcriptional activity Wang et al.
USF1 Association with familial combined hyperlipidaemia 1q22-q23 IVS7, AS, G > A, -100
SNP alleles exhibit differential binding to nuclear proteins.
USF1-regulated genes are differentially regulated, depending on the identity of the rs2073658 allele
Naukkarinen et al. (2005)s
Naukkarinen et al. (2009)t
  1. Abbreviations: AS, acceptor splice site; DRD2, dopamine D2 receptor; DS, donor splice site; IVS, intron (number) Nucleotide numbering relative to specified splice site.
  2. rs numbers are provided courtesy of dbSNP For the sake of simplicity, only SNPs have been included in Table 1 (thus, for example, functional intronic microsatellite polymorphisms would require a separate treatment).
  3. References to table
  4. a. Nishimura, H., Yerkes, E., Hohenfellner, K., Miyazaki, Y. et al. (1999), 'Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men', Mol. Cell Vol. 3, pp. 1-10.
  5. b. Kozyrev, S.V., Abelson, A.K., Wojcik, J., Zaghlool, A. et al. (2008), 'Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus', Nat. Genet. Vol. 40, pp. 211-216.
  6. c. Suzuki, A., Yamada, R., Kochi, Y., Sawada, T. et al. (2008), 'Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population', Nat. Genet. Vol. 40, pp. 1224-1229.
  7. d. Mann, V., Hobson, E.E., Li, B., Stewart, T.L et al. (2001), 'A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality', J. Clin. Invest. Vol. 107, pp. 899-907.
  8. e. Choi, J.W., Park, C.S., Hwang, M., Nam, H.Y. et al. (2008), 'A common intronic variant of CXCR3 is functionally associated with gene expression levels and the polymorphic immune cell responses to stimuli', J. Allergy Clin. Immunol. Vol. 122, pp. 1119-1126.
  9. f. Toscano, C., Klein, K., Blievernicht, J., Schaeffeler, E. et al. (2006), 'Impaired expression of CYP2D6 in intermediate metabolizers carrying the *41 allele caused by the intronic SNP 2988G > A: Evidence for modulation of splicing events', Pharmacogenet. Genomics Vol. 16, pp. 755-766.
  10. g. Rogaeva, A., Ou, X.M., Jafar-Nejad, H., Lemonde, S. et al. (2007), 'Differential repression by freud-1/CC2D1A at a polymorphic site in the dopamine-D2 receptor gene'. J. Biol. Chem. Vol. 282, pp. 20897-20905.
  11. h. Zhang, Y., Bertolino, A., Fazio, L., Blasi, G. et al. (2007), 'Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory', Proc. Natl. Acad. Sci. USA Vol. 104, pp. 20552-20557.
  12. i. von Ahsen, N. and Oellerich, M. (2004), 'The intronic prothrombin 19911A > G polymorphism influences splicing efficiency and modulates effects of the 20210G > A polymorphism on mRNA amount and expression in a stable reporter gene assay system', Blood Vol. 103, pp. 586-593.
  13. j. Meyer, K.B., Maia, A.T., O'Reilly, M., Teschendorff, A.E. et al. (2008), 'Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer', PLoS Biol. Vol. 6, p. e108.
  14. k. Shen, Z., Chen, L., Hao, F., Wang, G. et al. (2010), 'Intron-1 rs3761548 is related to the defective transcription of Foxp3 in psoriasis through abrogating E47/c-Myb binding', J. Cell. Mol. Med. Vol. 14, pp. 226-241.
  15. l. Kunika, K., Tanahashi, T., Kudo, E., Mizusawa, N. et al. (2006), 'Effect of þ36T > C in intron 1 on the glutamine: fructose-6-phosphate amido-transferase 1 gene and its contribution to type 2 diabetes in different populations', J. Hum. Genet. Vol. 51, pp. 1100-1109.
  16. m. Kwok, J.B., Hallupp, M., Loy, C.T., Chan, D.K. et al. (2005), 'GSK3B polymorphisms alter transcription and splicing in Parkinson's disease', Ann. Neurol. Vol. 58, pp. 829-839.
  17. n. Do, T.N., Ucisik-Akkaya, E., Davis, C.F., Morrison, B.A. et al. (2010), 'An intronic polymorphism of IRF4 gene influences gene transcription in vitro and shows a risk association with childhood acute lymphoblastic leukemia in males', Biochim. Biophys. Acta Vol. 1802, pp. 292-300.
  18. o. Ozaki, K., Ohnishi, Y., Iida, A., Sekine, A. et al. (2002), 'Functional SNPs in the lymphotoxin-a gene that are associated with susceptibility to myocardial infarction', Nat. Genet. Vol. 32, pp. 650-654.
  19. p. Hitomi, Y., Ebisawa, M., Tomikawa, M., Imai, T. et al. (2009), 'Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma', J. Allergy Clin. Immunol. Vol. 124, pp. 779-785.
  20. q. Tanabe, A., Yanagiya, T., Iida, A., Saito, S. et al. (2007), 'Functional single-nucleotide polymorphisms in the secretogranin III (SCG3) gene that form secretory granules with appetite-related neuropeptides are associated with obesity', J. Clin. Endocrinol. Metab. Vol. 92, pp. 1145-1154.
  21. r. Wang, L., Li, B., Lu, X., Zhao, Q. et al. (2008), 'A functional intronic variant in the tyrosine hydroxylase (TH) gene confers risk of essential hypertension in the Northern Chinese Han population', Clin. Sci. Vol. 115, pp. 151-158.
  22. s. Naukkarinen, J., Gentile, M., Soro-Paavonen, A., Saarela, J. et al. (2005), 'USF1 and dyslipidemias: Converging evidence for a functional intronic variant', Hum. Mol. Genet. Vol. 14, pp. 2595-2605.
  23. t. Naukkarinen, J., Nilsson, E., Koistinen, H.A., Söderlund, S. et al. (2009), 'Functional variant disrupts insulin induction of USF1: Mechanism for USF1-associated dyslipidemias', Circ. Cardiovasc. Genet. Vol. 2, pp. 522-529.