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Clinical and Experimental Ophthalmology 2015; 43: 26–30 doi: 10.1111/ceo.12367
Original Article Genetic polymorphism related to exfoliative glaucoma is also associated with primary open-angle glaucoma risk Vicente Zanon-Moreno PhD,1,2,3 Laura Zanon-Moreno BS,1 Carolina Ortega-Azorin PhD,1,2 Eva M Asensio-Marquez BS,1,2 Jose Javier Garcia-Medina MD PhD,4,5 Pedro Sanz MD PhD,6 Maria D Pinazo-Duran MD PhD,3 Jose M Ordovás PhD7,8,9 and Dolores Corella PhD1,2 1
Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 3Ophthalmology Research Unit ‘Santiago Grisolia’, and 6Department of Ophthalmology, Doctor Peset University Hospital, Valencia, 2Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), 8Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional de Investigaciones Cardiovasculares (CNIC), and 9Instituto Madrileño de Estudios Avanzados (IMDEA), Madrid, 4Department of Ophthalmology, Reina Sofia Hospital, and 5Department of Ophthalmology, University of Murcia, Murcia, Spain; and 7Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA
ABSTRACT Background: To investigate the possible association of the rs2165241 polymorphism (C > T) in LOXL1 gene with the risk of primary open-angle glaucoma in a Mediterranean population. Methods: The analysis of genetic polymorphisms was performed by standard TaqMan allelic discrimination technique, using a 7900HT Sequence Detection System (Applied Biosystems). Results: In a recessive genetic model, the T allele of the rs2165241 polymorphism was significantly associated with the risk of primary open-angle glaucoma (TT vs. CC: odds ratios = 2.19, 95% confidence interval = [1.33–3.62]). After multivariate logistic regression model adjusted by age and weight, the magnitude of the association decreased but remained statistically significant (TT vs. CC: odds ratios = 2.07, 95% confidence interval = [1.20–3.57]). Conclusion: This polymorphism seems to be associated with high risk for primary open-angle glaucoma in a Mediterranean population.
Key words: genetics, LOXL1 polymorphism, Mediterranean population, primary open-angle glaucoma.
INTRODUCTION The glaucomas are a group of neurodegenerative diseases of the optic nerve characterized by a progressive and irreversible loss of nerve fibres, which results in a loss of visual field and, in many cases, bilateral blindness. It is estimated that there are 60 million people with glaucoma worldwide and 8.4 million people blinded by glaucoma, and these numbers will rise to 80 million and 11.2 million respectively in 2020.1,2 Exfoliative glaucoma (ExG) is a type of glaucoma caused by exfoliative syndrome. In this syndrome, abnormal proteins are deposited in different parts of the eye, including lens, iris and cornea and even the trabecular meshwork, and also affect some extraocular tissues such as heart, lung, kidney, bladder and meninges. Therefore, aqueous humour drainage is blocked, resulting in an increase of intraocular pressure (IOP) and, ultimately, glaucoma onset. Thus, it is not a primary glaucoma, but a secondary glaucoma. However, the most common form of glaucoma is the primary open-angle
■ Correspondence: Dr Vicente Zanon-Moreno, Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, Avda. Blasco Ibáñez, 15, 46010 Valencia, Spain. Email: [email protected] Received 15 November 2013; accepted 22 May 2014. Competing/conflicts of interest: No stated conflict of interest. Funding sources: No stated funding sources. © 2014 Royal Australian and New Zealand College of Ophthalmologists
LOXL1 gene and risk of open-angle glaucoma glaucoma (POAG), representing 60–80% of all cases in the world.3,4 Both ExG and POAG have a large iridocorneal angle, which means that they are both open-angle glaucomas, but ExG usually occurs after 70 years old, being therefore later than the POAG. POAG is an optic neuropathy characterized by changes in the papilla and visual field deterioration. It is mechanically characterized by a high IOP, morphologically by an alteration in the optic nerve head and functionally by a progressive loss of visual field and vision. It is important to take into account the socio-economic impact of the productivity decrease of glaucomatous people because of their visual impairment. The cause of POAG is still unknown, but there are several risk factors identified in relation to this optic neuropathy, such as IOP, age, family history of POAG, race, severe myopia, central corneal thickness, diabetes mellitus or arterial hypertension.5–7 Therefore, it is a complex and multifactorial disease with many molecular mechanisms underlying the glaucomatous pathogenesis. The genetic heterogeneity is the hallmark of all forms of glaucoma. Many chromosomic loci have been linked to these diseases, but only a few have been well characterized.8 Outstanding among the most commonly studied genes in relation to the risk of POAG are the MYOC, CDKN2B-AS1 and TMCO1 genes9–11 and some of the associated genes with the ExG are TLR4, CNTNAP2 and LOXL1, the latter being the most important in relation to this type of glaucoma.12–14 The LOXL1 gene encodes an enzyme involved in the synthesis and homeostasis of collagen and elastic fibres and also in the biogenesis of the connective tissue. This gene can inhibit the Ras/Erk signalling pathway in bladder cancer, acting as a tumour suppressor gene.15 The rs2165241 polymorphism of this gene has been classically associated with ExG and normal tension glaucoma.16 However, it is not the only single nucleotide polymorphism (SNP) associated to these pathologies.13,17–20 There are also studies that have investigated the relationship between the rs2165241 polymorphism in the LOXL1 gene and POAG,21–23 but only one of them has found a marginally significant association with POAG risk.24 This SNP was a study in different populations: American,25 African-American,23 NorthEuropean,24,26 Indian,27 Japanese,28–30 Chinese,31 Arabian.22 Despite the lack of positive results on the influence of the LOXL1 gene in POAG development and progression, and taking into account the functions of this gene, the alteration of collagen and elastin fibres might cause alterations in the trabecular meshwork, which could be related to the mechanisms that raise IOP in POAG.32,33 Hence, considering that this gene might play an important role on the etiopathogenesis of POAG, we
27 aimed to investigate the possible association of the rs2165241 polymorphism in the LOXL1 gene with the risk of POAG in a Mediterranean population.
METHODS We carried out a case-control study involving 329 subjects with POAG and 329 healthy controls, matched by sex, all of them selected from Province of Valencia (Valencia, Spain) and with the same ethnic characteristics. All the study procedures were performed in accordance with the Declaration of Helsinki on human experimentation34 and with current legislation on this type of study in the European Community. Subjects were informed about the specifics of the study and researchers of our group informed and explained all the details of the plan to them. Informed consent was signed by the study participants. The subjects of the cases group were patients diagnosed with POAG. This diagnosis was made by ophthalmologists of Dr. Peset University Hospital, as the result of three eye tests: • • •
Measurement of IOP (>21 mmHg) Visual field exam (
Clinical and Experimental Ophthalmology 2015; 43: 26–30 doi: 10.1111/ceo.12367
Original Article Genetic polymorphism related to exfoliative glaucoma is also associated with primary open-angle glaucoma risk Vicente Zanon-Moreno PhD,1,2,3 Laura Zanon-Moreno BS,1 Carolina Ortega-Azorin PhD,1,2 Eva M Asensio-Marquez BS,1,2 Jose Javier Garcia-Medina MD PhD,4,5 Pedro Sanz MD PhD,6 Maria D Pinazo-Duran MD PhD,3 Jose M Ordovás PhD7,8,9 and Dolores Corella PhD1,2 1
Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 3Ophthalmology Research Unit ‘Santiago Grisolia’, and 6Department of Ophthalmology, Doctor Peset University Hospital, Valencia, 2Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), 8Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional de Investigaciones Cardiovasculares (CNIC), and 9Instituto Madrileño de Estudios Avanzados (IMDEA), Madrid, 4Department of Ophthalmology, Reina Sofia Hospital, and 5Department of Ophthalmology, University of Murcia, Murcia, Spain; and 7Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA
ABSTRACT Background: To investigate the possible association of the rs2165241 polymorphism (C > T) in LOXL1 gene with the risk of primary open-angle glaucoma in a Mediterranean population. Methods: The analysis of genetic polymorphisms was performed by standard TaqMan allelic discrimination technique, using a 7900HT Sequence Detection System (Applied Biosystems). Results: In a recessive genetic model, the T allele of the rs2165241 polymorphism was significantly associated with the risk of primary open-angle glaucoma (TT vs. CC: odds ratios = 2.19, 95% confidence interval = [1.33–3.62]). After multivariate logistic regression model adjusted by age and weight, the magnitude of the association decreased but remained statistically significant (TT vs. CC: odds ratios = 2.07, 95% confidence interval = [1.20–3.57]). Conclusion: This polymorphism seems to be associated with high risk for primary open-angle glaucoma in a Mediterranean population.
Key words: genetics, LOXL1 polymorphism, Mediterranean population, primary open-angle glaucoma.
INTRODUCTION The glaucomas are a group of neurodegenerative diseases of the optic nerve characterized by a progressive and irreversible loss of nerve fibres, which results in a loss of visual field and, in many cases, bilateral blindness. It is estimated that there are 60 million people with glaucoma worldwide and 8.4 million people blinded by glaucoma, and these numbers will rise to 80 million and 11.2 million respectively in 2020.1,2 Exfoliative glaucoma (ExG) is a type of glaucoma caused by exfoliative syndrome. In this syndrome, abnormal proteins are deposited in different parts of the eye, including lens, iris and cornea and even the trabecular meshwork, and also affect some extraocular tissues such as heart, lung, kidney, bladder and meninges. Therefore, aqueous humour drainage is blocked, resulting in an increase of intraocular pressure (IOP) and, ultimately, glaucoma onset. Thus, it is not a primary glaucoma, but a secondary glaucoma. However, the most common form of glaucoma is the primary open-angle
■ Correspondence: Dr Vicente Zanon-Moreno, Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, Avda. Blasco Ibáñez, 15, 46010 Valencia, Spain. Email: [email protected] Received 15 November 2013; accepted 22 May 2014. Competing/conflicts of interest: No stated conflict of interest. Funding sources: No stated funding sources. © 2014 Royal Australian and New Zealand College of Ophthalmologists
LOXL1 gene and risk of open-angle glaucoma glaucoma (POAG), representing 60–80% of all cases in the world.3,4 Both ExG and POAG have a large iridocorneal angle, which means that they are both open-angle glaucomas, but ExG usually occurs after 70 years old, being therefore later than the POAG. POAG is an optic neuropathy characterized by changes in the papilla and visual field deterioration. It is mechanically characterized by a high IOP, morphologically by an alteration in the optic nerve head and functionally by a progressive loss of visual field and vision. It is important to take into account the socio-economic impact of the productivity decrease of glaucomatous people because of their visual impairment. The cause of POAG is still unknown, but there are several risk factors identified in relation to this optic neuropathy, such as IOP, age, family history of POAG, race, severe myopia, central corneal thickness, diabetes mellitus or arterial hypertension.5–7 Therefore, it is a complex and multifactorial disease with many molecular mechanisms underlying the glaucomatous pathogenesis. The genetic heterogeneity is the hallmark of all forms of glaucoma. Many chromosomic loci have been linked to these diseases, but only a few have been well characterized.8 Outstanding among the most commonly studied genes in relation to the risk of POAG are the MYOC, CDKN2B-AS1 and TMCO1 genes9–11 and some of the associated genes with the ExG are TLR4, CNTNAP2 and LOXL1, the latter being the most important in relation to this type of glaucoma.12–14 The LOXL1 gene encodes an enzyme involved in the synthesis and homeostasis of collagen and elastic fibres and also in the biogenesis of the connective tissue. This gene can inhibit the Ras/Erk signalling pathway in bladder cancer, acting as a tumour suppressor gene.15 The rs2165241 polymorphism of this gene has been classically associated with ExG and normal tension glaucoma.16 However, it is not the only single nucleotide polymorphism (SNP) associated to these pathologies.13,17–20 There are also studies that have investigated the relationship between the rs2165241 polymorphism in the LOXL1 gene and POAG,21–23 but only one of them has found a marginally significant association with POAG risk.24 This SNP was a study in different populations: American,25 African-American,23 NorthEuropean,24,26 Indian,27 Japanese,28–30 Chinese,31 Arabian.22 Despite the lack of positive results on the influence of the LOXL1 gene in POAG development and progression, and taking into account the functions of this gene, the alteration of collagen and elastin fibres might cause alterations in the trabecular meshwork, which could be related to the mechanisms that raise IOP in POAG.32,33 Hence, considering that this gene might play an important role on the etiopathogenesis of POAG, we
27 aimed to investigate the possible association of the rs2165241 polymorphism in the LOXL1 gene with the risk of POAG in a Mediterranean population.
METHODS We carried out a case-control study involving 329 subjects with POAG and 329 healthy controls, matched by sex, all of them selected from Province of Valencia (Valencia, Spain) and with the same ethnic characteristics. All the study procedures were performed in accordance with the Declaration of Helsinki on human experimentation34 and with current legislation on this type of study in the European Community. Subjects were informed about the specifics of the study and researchers of our group informed and explained all the details of the plan to them. Informed consent was signed by the study participants. The subjects of the cases group were patients diagnosed with POAG. This diagnosis was made by ophthalmologists of Dr. Peset University Hospital, as the result of three eye tests: • • •
Measurement of IOP (>21 mmHg) Visual field exam (
