title: Effects of polymorphisms in vitamin E-, vitamin C-, and glutathione peroxidase-related genes on serum biomarkers and associations with glaucoma.
abstract: OBJECTIVE
  To study the association of selected polymorphism in genes related to vitamin E, vitamin C, and glutathione peroxidase with these biomarkers and primary open-angle glaucoma (POAG) risk.
  
  
  METHODS
  A case-control study matched for age, sex, and bodyweight was undertaken. Two hundred fifty POAG cases and 250 controls were recruited from a Mediterranean population. Plasma concentrations of vitamin C, vitamin E, and glutathione peroxidase (GPx) activity were measured. We analyzed the polymorphisms rs1279683 in the Na(+)-dependent L-ascorbic acid transporter 2 (SLC23A2) gene, rs6994076 in the tocopherol alpha transfer protein (TTPA) gene, rs737723 in the tocopherol-associated protein (SEC14L2/TAP) gene, and rs757228 in the glutathione peroxidase 4 (GPX4) gene. We also analyzed expression of the SLC23A2 gene in a subsample.
  
  
  RESULTS
  We found a novel association between the rs737723 polymorphism and POAG risk. Homozygous subjects for the C allele had a higher POAG risk than carriers of the ancestral G allele (adjusted odds ratio 1.73, 95% confidence interval 1.13-2.65, p=0.011). This association remained statistically significant after adjustment for multiple comparisons. We also confirmed the association between the rs1279683 polymorphism and a higher POAG risk in GG homozygous subjects and detected statistically significant differences in SLC23A2 gene expression between POAG cases and controls, even after adjustment for multiple testing. We observed a nominally significant (p<0.05) gene-gene interaction between the SEC14L2/TAP and SLC23A2 polymorphisms in determining POAG risk, increasing POAG risk in those subjects who had both risk genotypes at the same time (p<0.01). This increase was statistically significant even after adjustment for multiple comparisons. We did not detect any association with POAG risk for the rs6994076 or rs757228 polymorphisms. We also found that POAG patients had statistically significant (after correction for multiple testing) lower plasma vitamin E (p<0.001) and vitamin C (p<0.001) concentrations than control subjects. However, we detected a higher plasma GPx activity in POAG cases than in controls (p<0.001). The rs6994076 and rs1279683 polymorphisms were significantly (p<0.001) associated with plasma vitamin E and vitamin C, respectively. However, the rs757228 polymorphism in the GPX4 gene was not associated with plasma GPx activity.
  
  
  CONCLUSIONS
  We have described a novel association between the rs737723 polymorphism (SEC14L2/TAP) and higher POAG risk and confirmed the association between rs1279683 (SLC23A2) and POAG. Our results also suggested a gene-gene interaction between both polymorphisms that increases POAG risk.
authors: Department of Preventive Medicine & Public Health, School of Medicine, University of Valencia, Valencia, Spain. Vicente.Zanon-Moreno@uv.es
authors: Vicente
authors: V
authors: Zanon-Moreno
authors: Eva M
authors: EM
authors: Asensio-Marquez
authors: Lucia
authors: L
authors: Ciancotti-Oliver
authors: Jose J
authors: JJ
authors: Garcia-Medina
authors: Pedro
authors: P
authors: Sanz
authors: Carolina
authors: C
authors: Ortega-Azorin
authors: Maria D
authors: MD
authors: Pinazo-Duran
authors: Jose M
authors: JM
authors: Ordovás
authors: Dolores
authors: D
authors: Corella
mesh_terms: D000368:Aged; D001205:Ascorbic Acid / Q000097:blood* / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D056726:Genetic Association Studies; D005902:Glaucoma, Open-Angle / Q000097:blood* / Q000235:genetics*; D005979:Glutathione Peroxidase / Q000097:blood* / Q000235:genetics*; D006801:Humans; D008074:Lipoproteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D060347:Sodium-Coupled Vitamin C Transporters / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014810:Vitamin E / Q000097:blood* / Q000235:genetics*
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D008074:Lipoproteins; C432422:SEC14L2 protein, human; C555163:SLC23A2 protein, human; D060347:Sodium-Coupled Vitamin C Transporters; D015534:Trans-Activators; C017763:alpha-tocopherol transfer protein; D014810:Vitamin E; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D001205:Ascorbic Acid
references: N Engl J Med. 2009 Mar 12;360(11):1113-24
references: 19279343
references: Lipids. 2012 Dec;47(12):1193-207
references: 23086553
references: Nature. 1999 May 6;399(6731):70-5
references: 10331392
references: Mol Vis. 2011 Feb 08;17:430-5
references: 21321670
references: Vet J. 2009 Dec;182(3):463-8
references: 18829353
references: Cancer Res. 2009 Feb 15;69(4):1429-38
references: 19190344
references: PLoS One. 2012;7(4):e35623
references: 22558179
references: Exp Eye Res. 2001 Aug;73(2):159-65
references: 11446766
references: Arch Ophthalmol. 2011 Jun;129(6):773-80
references: 21670344
references: Curr Eye Res. 2010 Sep;35(9):842-9
references: 20795867
references: Nutr Metab (Lond). 2012 Jun 15;9(1):59
references: 22703731
references: Am J Epidemiol. 2009 Apr 15;169(8):946-53
references: 19218294
references: Vitam Horm. 2007;76:45-65
references: 17628171
references: Clin Exp Ophthalmol. 2006 Jul;34(5):472-84
references: 16872346
references: J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Apr 1;877(10):853-6
references: 19250886
references: Free Radic Biol Med. 2003 Jun 1;34(11):1458-72
references: 12757856
references: J Biol Chem. 2012 Mar 2;287(10):7675-82
references: 22207760
references: Eye (Lond). 2012 Mar;26(3):355-69
references: 22173078
references: Am J Clin Nutr. 2002 Oct;76(4):703-16
references: 12324281
references: J Glaucoma. 2008 Jun-Jul;17(4):263-8
references: 18552610
references: J Glaucoma. 2009 Aug;18(6):423-8
references: 19680048
references: Mutat Res. 2009 Jul 10;667(1-2):98-117
references: 19046976
references: Mol Aspects Med. 2007 Oct-Dec;28(5-6):400-22
references: 17624418
references: Biol Chem. 2006 Oct-Nov;387(10-11):1329-35
references: 17081103
references: Nat Genet. 2011 Jun;43(6):574-8
references: 21532571
references: Br J Nutr. 2004 Jun;91(6):809-29
references: 15182385
references: Mol Vis. 2010 Jul 09;16:1260-71
references: 20664701
references: J Chromatogr. 1991 Dec 6;572(1-2):103-16
references: 1818046
references: Vitam Horm. 2007;76:23-43
references: 17628170
references: Eur J Epidemiol. 2012 May;27(5):385-93
references: 22461101
references: Int J Ophthalmol. 2012;5(2):231-7
references: 22762057
references: Free Radic Biol Med. 2010 Sep 1;49(5):821-9
references: 20541602
references: Prog Mol Biol Transl Sci. 2012;108:179-200
references: 22656378
references: Nat Genet. 2010 Oct;42(10):906-9
references: 20835238
references: PLoS Genet. 2012;8(5):e1002611
references: 22570627
references: Am J Ophthalmol. 2012 Oct;154(4):635-44
references: 22818906
references: Mol Vis. 2011;17:2544-51
references: 22025889
references: Exp Mol Pathol. 2011 Apr;90(2):231-7
references: 21241689
references: J Fr Ophtalmol. 2005 Mar;28(3):312-6
references: 15883498
references: Antioxid Redox Signal. 2009 Apr;11(4):715-24
references: 18823256
references: Br J Pharmacol. 2011 Dec;164(7):1793-801
references: 21418192
references: Prog Mol Biol Transl Sci. 2012;108:427-46
references: 22656386
references: PLoS Genet. 2006 Sep 22;2(9):e148
references: 17044736
references: Prog Mol Subcell Biol. 2010;50:1-20
references: 19841878
references: Invest Ophthalmol Vis Sci. 2010 Feb;51(2):971-9
references: 19815736
references: Eur J Ophthalmol. 2007 Jul-Aug;17(4):528-33
references: 17671926
references: Ophthalmology. 2011 Dec;118(12):2389-97
references: 21872936
references: Hum Mol Genet. 2011 Jun 15;20(12):2464-71
references: 21427129
references: Mol Nutr Food Res. 2010 May;54(5):583-7
references: 20458704
references: Mol Vis. 2012;18:1083-92
references: 22605921
references: Am J Epidemiol. 2003 Aug 15;158(4):337-46
references: 12915499
references: Am J Ophthalmol. 2008 Jun;145(6):1081-9
references: 18355790
references: Mol Vis. 2011;17:2997-3004
references: 22171153
references: Hum Mol Genet. 2011 Feb 15;20(4):649-58
references: 21098505