Association of LOXL1 Gene Polymorphisms with Exfoliation Glaucoma Patients
Background: Pseudoexfoliation syndrome (XFS) is pathogenetically related to exfoliative glaucoma (XFG), which is the most common type of secondary glaucoma. We aimed to investigate the relationship between LOXL1 SNPs (rs1048661, rs3825942) and XFS and/or XFG in a cohort of Iranian subjects.
Methods: This cross-sectional study investigated possible association between LOXL1 gene polymorphisms and exfoliative glaucoma in Northeastern part of Iran between May 2014 and May 2015. Sixty unrelated XFS/XFG patients, as well as 40 control subjects, were studied by direct sequencing. In fifteen senile cataract patients without glaucoma and fifteen patients with coexisting XFG and cataract, capsulorhexis specimen of the anterior lens capsule was used to evaluate LOXL1 gene transcripts by Real-Time PCR technique. We analyzed the results for allele frequencies and haplotype association and investigated the relative gene expression.
Results: Significant associations between the rs382594 SNP and XFG and between rs1048661 SNP and XFG were observed (P<0.05 for both). The frequency of the G allele in the exonic SNP (rs1048661) appeared to be higher in XFS or XFG patients compared to control subjects (P= 0.0497). Moreover, in the rs3825942 SNP, the G allele was more frequent in XFS/XFG patients compared to control subjects (P=0.0016). The highest cumulative frequency was for the GG haplotype. GG haplotype was associated with increased risk of XFG compared to the rs1048661 G/T and rs3825942 G/A haplotypes. LOXL1 mRNA expression was not statistically significantly different between XFS/XFG and control subjects.
Conclusion: We reported the LOXL1 gene polymorphism in an Iranian XFS/XFG cohort. Similar to many other ethnic groups and geographic regions, our results confirmed an association between LOXL1 gene variants and XFG in Iran.
2. Iancu R, Corbu C (2014). Intraocular pres-sure after phacoemulsification in patients with uncontrolled primary open-angle glaucoma. J Med Life, 7 (1):11-6.
3. Rao KN, Ritch R, Dorairaj SK et al ¬(2008). Exfoliation syndrome and exfoliation glaucoma-associated LOXL1 variations are not involved in pigment dispersion syndrome and pigmentary glaucoma. Mol Vis, 14:1254-1262.
4. Ritch R (2004). Pigment dispersion syndrome. In: Grehn F, Stamper R, editors. Glaucoma–update 2003. Berlin: Springer-Verlag. p. 177–92.
5. Weinreb RN, Aung T, Medeiros FA (2014). The pathophysiology and treatment of glaucoma: a review. JAMA, 311(18):1901-11.
6. Wu M, Zhu XY, Ye J (2015). Associations of polymorphisms of LOXL1 gene with primary open-angle glaucoma: a meta-analysis based on 5,293 subjects. Mol Vis, 21:165-72.
7. Huang W, Wang W, Zhou M et al (2013). Association of glutathione S-transferase polymorphisms (GSTM1 and GSTT1) with primary open-angle glaucoma: an evidence-based meta-analysis. Gene, 526 (2): 80-6.
8. Shen L, Melles RB, Metlapally R et al (2016). The Association of Refractive Error with Glaucoma in a Multiethnic Population. Ophthalmology, 123 (1): 92-101.
9. Thorleifsson G, Magnusson KP, Sulem P et al (2007). Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science, 317(5843): 1397-400.
10. Schlötzer-Schrehardt U, Hammer CM, Krysta AW et al (2012). LOXL1 deficien-cy in the lamina cribrosa as candidate susceptibility factor for a pseudoexfolia-tion-specific risk of glaucoma. Ophthalmol-ogy, 119 (9):1832-43.
11. Whigham BT, Allingham RR (2011). Review: The role of LOXL1 in exfoliation syn-drome/ glaucoma. Saudi J Ophthalmol, 25(4): 347-52.
12. Tanito M, Minami M, Akahori et al (2008). LOXL1 variants in elderly Japanese pa-tients with exfoliation syndrome/ glau-coma, primary open-angle glaucoma, normal tension glaucoma, and cataract. Mol Vis, 14:1898-905.
13. Fuse N, Miyazawa A, Nakazawa T et al (2008). Evaluation of polymorphisms in eyes with exfoliation glaucoma in Japa-nese. Mol Vis, 14:1338-43.
14. Mori K, Imai K, Matsuda A et al (2008). LOXL1 genetic polymorphisms are as-sociated with exfoliation glaucoma in the Japanese population. Mol Vis, 14:1037-40.
15. Hall TA (1999). BioEdit: a user-friendly bio-logical sequence alignment editor and analysis program for Windows 95/98/NT. NUCL ACID S, 41: 95-98
16. Solé X, Guinó E, Valls J et al (2006). SNPStats: a web tool for the analysis of association studies. Bioinformatics, 15: 1928–1929.
17. Pfaffle MW (2001). A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res, 29(9):e45.
18. Lumme P, Laatikainen L (1993). Exfoliation syndrome and cataract extraction. Am J Ophthalmol, 116 (1): 51–5.
19. Drolsum L, Haaskjold E, Davanger M (1993). Pseudoexfoliation syndrome and extracapsular cataract extraction. Acta Ophthalmol (Copenh), 71(6): 765–70.
20. Garway-HeathD, Ruben S, Viswanathan A et al (1998). Vertical cup/disc ratio in rela-tion to optic disc size: its value in the as-sessment of the glaucoma suspect. Br J Ophthalmol, 82(10): 1118–1124.
21. Gardiner SK, Fortune B, Wang L et al (2012). Intraocular pressure magnitude and variability as predictors of rates of structural change in non-human primate experimental glaucoma. Exp Eye Res, 103:1- 8.
22. Awadalla MS, Fingert JH, Rooofs BE et al (2015). Copy number variations of TBK1 in Australian patients with primary open-angle glaucoma. Am J Ophthalmol, 159 (1):124-130.
23. Lucero HA, Kagan HM (2006). Lysyl oxi-dase: an oxidative enzyme and effector of cell function. Cell Mol Life Sci, 63(19-20):2304-16.
24. Liu X, Zhao Y, Gao J et al (2004). Elastic fi-ber homeostasis requires lysyl oxidase-like 1 protein. Nat Genet, 36(2):178-82.
25. Umihira J, Nagata S, Nohara M et al (1994). Localization of elastin in the normal and glaucomatous human trabecular mesh-work. Invest Ophthalmol Vis Sci, 35(2): 486-94.
26. Ramprasad VL, George R, Soumittra N et al (2008). Association of non-synonymous single nucleotide polymorphisms in the LOXL1 gene with pseudoexfoliation syndrome in India. Mol Vis, 14:318- 22.
27. Lee KY, Ho SL, Thalamuthu A et al (2009). Association of LOXL1 polymorphisms with pseudoexfoliation in the Chinese. Mol Vis, 15:1120-1126.
28. Sagong M, Gu BY, Cha SC (2011). Associa-tion of lysyl oxidase-like 1 gene polymor-phisms with exfoliation syndrome in Ko-reans. Mol Vis,17:2808-17.
29. Rautenbach RM, Bardien S, Harvey J et al (2011). An investigation into LOXL1 var-iants in black South African individuals with exfoliation syndrome. Arch Ophthal-mol, 129(2):206-10.
30. Urban Z, Agapova O, Hucthagowder V et al (2007). Population differences in elastin maturation in optic nerve head tissue and astrocytes. Invest Ophthalmol Vis Sci, 48(7): 3209–3215.