PURPOSE: Matrix metalloproteinases (MMPs) are postulated to be involved in the development of retinal angiogenesis through the regulation of extracellular matrix. The objective of the present study was to test for a possible association of five single nucleotide polymorphisms (SNPs) in the MMP-2 gene and two polymorphisms in the MMP-9 gene with proliferative diabetic retinopathy (PDR) and to determine their plasma levels. METHODS: The study comprised 490 Caucasian participants, who were divided into three groups: diabetics with PDR, diabetics without PDR, and nondiabetics. Genotypes were detected by polymerase chain reactions followed by restriction analyses with specific endonucleases and their frequencies determined. Plasma levels of MMP-2 and MMP-9 proteins were analyzed by ELISA. RESULTS: Neither MMP-2 SNPs nor MMP-9 SNPs revealed significant association with PDR in single-locus comparisons; similarly, MMP-2 haplotype frequencies did not differ notably between groups, although the C-allele of the -1306C/T polymorphism and the C-allele containing haplotype (CGCG) in MMP-2 exhibited marginally significant association with PDR in males (p<0.05, p(corr)=NS). Both MMP-2 and MMP-9 plasma levels showed statistically significant differences among the studied groups (p<0.001 and p=0.001, respectively) with highest levels in the PDR group. MMP-2 plasma levels were markedly higher in carriers of either the -1306CC and -1306CT genotypes and (p=0.009) or CGCG haplotype (p=0.043). CONCLUSIONS: These findings indicate that genotype- and haplotype-specific effects on MMP-2 expression corresponding with its plasma levels may contribute to the susceptibility to PDR.

Department of Pathophysiology Faculty of Medicine Masaryk University Brno Czech Republic

Zobrazit více v PubMed

Kohner EM. Diabetic retinopathy. BMJ. 1993;307:1195–9. PubMed PMC

Abu El-Asrar AM, Van den Steen PE, Al-Amro SA, Missotten L, Opdenakker G, Geboes K.Expression of angiogenic and fibrogenic factors in proliferative vitreoretinal disorders. Int Ophthalmol 20072711–22.Epub 2007 Mar 21 PubMed

Forrester JV, Shafiee A, Schroder S, Knott R, McIntosh L. The role of growth factors in proliferative diabetic retinopathy. Eye. 1993;7:276–87. PubMed

Cruickshanks KJ, Vadheim CM, Moss SE, Roth MP, Riley WJ, Maclaren NK, Langfield D, Sparkes RS, Klein R, Rotter JI. Genetic marker associations with proliferative retinopathy in persons diagnosed with diabetes before 30 yr of age. Diabetes. 1992;41:879–85. PubMed

Hiscott P, Waller HA, Grierson I, Butler MG, Scott DL. The extracellular matrix of reparative tissue in the vitreous: fibronectin production in proliferative diabetic retinopathy membranes. Eye. 1993;7:288–92. PubMed

Khokha R, Denhart DT. Matrix metalloproteinases and tissue inhibitor of metalloproteinases: a review of their role in tumorigenesis and tissue invasion. Invasion Metastasis. 1989;9:391–405. PubMed

Taylor CM, Thompson JM, Weiss JB. Matrix integrity and the control of angiogenesis. Int J Radiat Biol. 1991;60:61–4. PubMed

Furness PN. Basement membrane synthesis and degradation. J Pathol. 1997;183:1–3. PubMed

Golubnitschaja O, Jaksche A, Moenkemann H, Yeghiazaryan K, Karl SE, Trog D, Schild HH, Löffler KU.Molecular imaging system for possible prediction of active retinopathy in patients with Diabetes mellitus. Amino Acids 200528229–37.Epub 2005 Feb 23 PubMed

Grant MB, Caballero S, Tarnuzzer RW, Bass KE, Ljubimov AV, Spoerri PE, Galardy RE. Matrix metalloproteinase expression in human retinal microvascular cells. Diabetes. 1998;47:1311–7. PubMed

Qi JH, Ebrahem Q, Yeow K, Edwards DR, Fox PL, Anand-Apte B.Expression of Sorsby's fundus dystrophy mutations in human retinal pigment epithelial cells reduces matrix metalloproteinase inhibition and may promote angiogenesis. J Biol Chem 200227713394–400.Epub 2002 Jan 30 PubMed

Salzmann J, Limb GA, Khaw PT, Gregor ZJ, Webster L, Chignell AH, Charteris DG. Matrix metalloproteinases and their natural inhibitors in fibrovascular membranes of proliferative diabetic retinopathy. Br J Ophthalmol. 2000;84:1091–6. PubMed PMC

Ferrand PE, Parry S, Sammel M, Macones GA, Kuivaniemi H, Romero R, Strauss JF. A polymorphism in the matrix metalloproteinase-9 promoter is associated with increased risk of preterm premature rupture of membranes in African Americans. Mol Hum Reprod. 2002;8:494–501. PubMed

Price SJ, Greaves DR, Watkins H.Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: role of Sp1 in allele-specific transcriptional regulation. J Biol Chem 20012767549–58.Epub 2000 Dec 12 PubMed

Vasku A, Goldbergova M, Izakovicova Holla L, Siskova L, Groch L, Beranek M, Tschoplova S, Znojil V, Vacha J. A haplotype constituted of four MMP-2 promoter polymorphisms (−1575G/A, −1306C/T, −790T/G and −735C/T) is associated with coronary triple-vessel disease. Matrix Biol. 2004;22:585–91. PubMed

Zhang B, Henney A, Eriksson P, Hamsten A, Watkins H, Ye S. Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2–13.1. Hum Genet. 1999;105:418–23. PubMed

Zhang B, Herrmann SM, Eriksson P, de Maat M, Evans A, Arveiler D, Luc G, Cambien F, Hamsten A, Watkins H, Henney AM. Functional polymorphism in the regulatory region of gelatinase B gene in relation severity of coronary atherosclerosis. Circulation. 1999;99:1788–94. PubMed

Early Treatment Diabetic Retinopathy Study Research Group Grading diabetic retinopathy from stereoscopic color fundus photographs-an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology. 1991;98:786–806. PubMed

Stephens M, Smith NJ, Donnelly P.A new statistical method for haplotype reconstruction from population data. Comment in: Am J Hum Genet. 2001 Oct;69(4):906–14. Am J Hum Genet 200168978–89.Epub 2001 Mar 9 PubMed PMC

Kon CH, Occleston NL, Charteris D, Daniels J, Aylward GW, Khaw PT. A prospective study of matrix metalloproteinases in proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 1998;39:1524–9. PubMed

Lamblin N, Bauters C, Hermant X, Lablanche JM, Helbecque A, Amouyel P. Polymorphisms in the promoter regions of MMP-2, MMP-3, MMP-9 and MMP-12 genes as determinants of aneurysmal coronary artery disease. J Am Coll Cardiol. 2002;40:43–8. PubMed

Koh KK, Ahn JY, Kang MH, Kim DS, Jin DK, Sohn MS, Park GS, Choi IS, Shin EK. Effects of hormone replacement therapy on plaque stability, inflammation, and fibrinolysis in hypertensive or overweight postmenopausal women. Am J Cardiol. 2001;88:1423–6. PubMed

Vegeto E, Bonincontro C, Pollio G, Sala A, Viappiani S, Nardi F, Brusadelli A, Viviani B, Ciana P, Maggi A. Estrogen prevents the lipopolysaccharide-induced inflammatory response in microglia. J Neurosci. 2001;21:1809–18. PubMed PMC

Beranek M, Kankova K, Benes P, Izakovicova-Holla L, Znojil V, Hajek D, Vlkova E, Vacha J. Polymorphism R25P in the gene encoding transforming growth factor-beta (TGF-beta1) is a newly identified risk factor for proliferative diabetic retinopathy. Am J Med Genet. 2002;109:278–83. PubMed

Brown D, Hamdi H, Bahri S, Kenney MC. Characterization of an endogenous metalloproteinase in human vitreous. Curr Eye Res. 1994;13:639–47. PubMed

Das A, McGuire PG, Eriqat C, Ober RR, DeJuan E, Jr, Williams GA, McLamore A, Biswas J, Johnson DW. Human diabetic neovascular membranes contain high levels of urokinase and metalloproteinase enzymes. Invest Ophthalmol Vis Sci. 1999;40:809–13. PubMed

De La Paz MA, Itoh Y, Toth CA, Nagase H. Matrix metalloproteinases and their inhibitors in human vitreous. Invest Ophthalmol Vis Sci. 1998;39:1256–60. PubMed

Jin M, Kashiwagi K, Iizuka Y, Tanaka Y, Imai M, Tsukahara S. Matrix metalloproteinases in human diabetic and nondiabetic vitreous. Retina. 2001;21:28–33. PubMed

Kosano H, Okano T, Katsura Y, Noritake M, Kado S, Matsuoka T, Nishigori H. ProMMP-9 (92 kDa gelatinase) in vitreous fluid of patients with proliferative diabetic retinopathy. Life Sci. 1999;64:2307–15. PubMed

Harendza S, Lovett DH, Panzer U, Lukacs Z, Kuhnl P, Stahl RA. Linked common polymorphisms in the gelatinase a promoter are associated with diminished transcriptional response to estrogen and genetic fitness. J Biol Chem. 2003;278:20490–9. PubMed