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LOXL1 gene polymorphisms are associated with exfoliation syndrome/exfoliation glaucoma risk: An updated meta-analysis

  • Xiaoyan Li,

    Roles Formal analysis, Methodology, Writing – original draft

    Affiliation Department of Endocrinology, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China

  • Jie He ,

    Roles Data curation, Resources, Validation

    13540246974@163.com

    Current address: Chengdu, Sichuan, China

    Affiliation Department of Pulmonary and Critical Care Medicine, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China

  • Jian Sun

    Roles Project administration, Supervision

    Affiliation Department of Pulmonary and Critical Care Medicine, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China

Abstract

Background

Single nucleotide polymorphisms (SNPs) in the gene encoding LOXL1 are risk factors for exfoliation syndrome and exfoliation glaucoma. This meta-analysis comprehensively investigated the association between LOXL1 gene polymorphisms (rs1048661, rs3825942, and rs2165241) and the risk of exfoliation syndrome/exfoliation glaucoma (XFS)/(XFG).

Methods

All eligible case-control studies, published before August 17, 2020, were searched on Medline (Ovid), PubMed, CNKI, EMBASE, and Wanfang databases.

Results

In total, 5022 cases and 8962 controls were included in this meta-analysis. Significant associations between LOXL1 gene polymorphisms and XFS/XFG risk was observed in the disease types-based subgroups. In addition, in the subgroup analysis of ethnicity, positive associations between LOXL1 gene polymorphisms (rs1048661, rs3825942, and rs2165241) and XFS/XFG risk were found in Caucasians. Furthermore, rs1048661 and rs3825942 polymorphisms were related to XFS/ XFG risk in Asians; however, no significant association was observed between the LOXL1 gene rs2165241 polymorphism and XFS/XFG risk in Asians. In addition, rs1048661 and rs3825942 correlated with XFS/XFG susceptibility in Africans.

Conclusions

Our results implicate LOXL1 gene polymorphisms as XFS/XFG risk factors, especially in Caucasians.

Introduction

Exfoliation syndrome (XFS) is an age-related, generalized disorder of the extracellular matrix characterized by progressive accumulation of abnormal fibrillar material in intra- and extra-ocular tissues [1, 2]. It is estimated to affect around 80 million people worldwide, and 10–20% of people aged >60 years are severely affected by XFS [3, 4]. This disorder is also associated with a progressive form of chronic open-angle glaucoma [2] and is the second most common cause of irreversible blindness globally.

Exfoliation glaucoma (XFG) is the most common form of secondary open-angle glaucoma and occurs in the context of XFS [4, 5]. Approximately 44% of XFS cases are estimated to progress to XFG [6]. XFG is characterized by deposition of exfoliation material in the anterior segment of the eyes, obstructing aqueous humor outflow, resulting in elevated intraocular pressure and secondary open-angle glaucoma [7]. Relative to primary open-angle glaucoma, XFS-associated secondary open-angle glaucoma is associated with a more severe prognosis, higher elevated intraocular pressure, and more severe optic nerve lesions at the time of diagnosis [8]. However, the mechanism of exfoliation material production is unclear.

XFS/XFG is a multifactorial disease involving a complex interaction between numerous risk factors, including genetic and environmental factors, myopia, cigarette smoking, and diabetes [9]. XFS/XFG prevalence varies widely across populations and geographical regions, ranging from <0.4% to >20% [10]. Thus, recent studies have increasingly focused on the relationship between gene polymorphisms and XFS/XFG susceptibility.

The lysyl oxidase-like 1 (LOXL1) gene has been extensively studied [1114]. The LOXL family comprises five genes (LOXL, LOXL1, LOXL2, LOXL3 and LOXL4), which encode enzymes involved in fibrillin, elastin, and collagen cross-linking reactions (2). LOXL1, which catalyzes the oxidative deamination of tropoelastin lysine residues, is essential for elastogenesis [15]. A 2007 genome-wide association study of a Scandinavian population, found a significant association between XFS/XFG and the LOXL1 single nucleotide polymorphisms, rs1048661, rs3825942, and rs2165241, located on chromosome 15q24.1 [16]. Since then, numerous studies have affirmed that the LOX1 polymorphisms are associated with XFS/XFG in various populations, including Caucasians, Latin Americans, Africans and Asians. Dubey et al. [17] reported that LOXL1 G (rs1048661), G (rs3825942) and T (rs2165241) alleles are XFS/XFG risk factors in Asians, which were similar to the results found in the original study conducted by Thorleifsson et al (2007) in Caucasians (Scandinavian population), as well as in most studies carried out in Caucasians [13, 16]. However, in most studies in Asians, the alleles T and C of rs1048661 and rs2165241, respectively, are the risk alleles. Tanito et al. [18], Ozaki et al. [19], Fuse et al. [20] and Hayashi et al. [21] reported that the alleles T of rs1048661 as well as the alleles C of rs2165241 are associated with increased risk of XFS/XFG in the Japanese population. Park DY et al. [22] and Sagong et al. [11] also found a similar phenomenon in Koreans. Similar observations were made by Chen et al. in Chinese [23]. Moreover, De Juan-Marcos et al. [24] showed that the G allele of rs3825942 and the T allele of rs2165241 were XFS/XFG risk factors in a Spanish population. However, in contrast to what was observed in most Caucasian populations, no significant association between XFS/XFG and SNP rs1048661 was observed. In addition, Rautenbach et al. [25] and Williams et al. [26] indicated that the G allele of rs3825942 was protective in Black South Africans, and the G allele of rs1048661 was a risk allele for XFS/XFG. Therefore, the associations of LOXL1 gene polymorphisms (rs1048661, rs2165241, rs3825942) may differ across patients of different ethnicities.

Despite the existence of discrepancies between some studies related to the risk alleles of LOXL1 SNPs, it is widely accepted that LOXL1 gene is the most important genetic risk factor known so far for XFS/XFG. Additionally, a single study may be insufficient to explore the small effect of LOXL1 gene polymorphisms on XFS/XFG susceptibility, especially when the sample size is small. Given the associations between LOXL1 gene polymorphisms and XFS/XFG pathogenesis, we carried out an updated meta-analysis on the correlation between LOXL1 gene polymorphisms (rs1048661, rs2165241, rs3825942) and XFS/XFG risk. To our knowledge, this is the most comprehensive and accurate meta-analysis of LOXL1 gene polymorphisms in the context of XFS/XFG susceptibility.

Materials and methods

Search strategy and criteria

Medline (Ovid), PubMed, CNKI, EMBASE, and Wanfang database searches for articles published before August 17, 2020, were performed using the following terms: “Lysyl oxidase-like 1”, “LOXL1”, “Exfoliation syndrome”, “XFS”, “Exfoliation glaucoma”, “XFG”, and “Polymorphism”. Articles were included if: 1) they examined the relationship between XFS/XFG susceptibility and LOXL1 variations, 2) they were case-control studies, and 3) they had complete genotype frequency data. Articles were excluded if: 1) they lacked a control group, 2) the presented data was incomplete, 3) they were duplicate publications, and 4) controls failed to meet Hardy Weinberg Equilibrium (HWE) standards.

Quality score evaluation

The quality of the included studies was determined using the Newcastle-Ottawa Scale [27] which assesses quality based on selection, comparability, and exposure in the study. Quality scores ranged from 0 to 9. Studies scoring >6 were considered high quality. Furthermore, study quality was determined by consensus between authors.

Data extraction

Two independent investigators extracted tangible data from each study based on the inclusion criteria. In the case of divergent views, a third author examined the controversial articles. For each study, the first author, country, publication year, ethnicities, sample size, genotyping method, and genotype frequency in the case and control groups, were extracted.

Statistical analyses

All analyses were conducted using STATA 10.0 and RevMan 5.2. The Odds ratio (OR) and 95% confidence interval (CI) were used to estimate the association between the LOXL1 gene polymorphisms and XFS/XFG susceptibility. Heterogeneity among studies was evaluated using the χ2-based Q statistic and a p value ≤ 0.1 was considered statistically significant. When the p value was >0.1, the pooled OR of each study was calculated using a fixed-effects model. Otherwise, a random-effects model was used. The significance of the pooled OR was demonstrated using the Z-test and a p value ≤ 0.05 was considered statistically significant. The association between LOXL1 gene polymorphisms and XFS/XFG risk was evaluated in different genetic models. To assess the effects of ethnicity and disease type, we performed additional subgroup analyses based on ethnicity and disease type. Sensitivity analysis was carried out to assess the stability of the results. Hardy Weinberg equilibrium was evaluated using Pearson’s χ2 test, and p ≥0.05 was considered statistically significant.

Publication bias

Publication bias was determined using asymmetry Begger’s plots and Egger’s tests [28, 29] and was carried out using STATA 10.0.

Results

Study characteristics

Our initial literature search returned 197 articles. Upon browsing the titles and abstracts, 111 articles were excluded, leaving 86 articles that underwent full-text review. Of the 86 articles, 41 articles were excluded because 32 articles involved other LOXL1 gene polymorphisms (rs4461027, rs4886761, and rsl6958477), and six articles were excluded because they were not case-control studies, and three articles were excluded for meta-analyses. Then the remaining 45 full-text articles were assessed for eligibility, although five articles [10, 3033] had been analyzed in a previous meta-analysis [34], we excluded them because three articles [10, 30, 31] did not achieve HWE in the control group, and two articles [32, 33] reported the relationship between LOXL1 polymorphisms and primary open-angle glaucoma. This process yielded 40 case-control articles [9, 1114, 1626, 3558] that were eligible for our study (Table 1). Of these, 38 articles [9, 1114, 1626, 3556] studied rs1048661, 22 articles [11, 1720, 2224, 35, 3842, 4547, 49, 52, 5557] involved rs2165241, and 38 articles [9, 1114, 1626, 3537, 3955, 57, 58] involved rs3825942 (Fig 1).

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Table 1. Characteristics of case-control studies included in meta-analysis on LOXL1 gene polymorphism (rs1048661, rs2165241, rs3825942).

https://doi.org/10.1371/journal.pone.0250772.t001

Quantitative synthesis of data

rs1048661 LOXL1 gene polymorphism.

Thirty-eight articles that examined the relationship between the LOXL1 gene polymorphism, rs1048661, and XFS/XFG risk were included in this meta-analysis. Some studies recruited XFS and XFG patients as research subjects, but these subjects did not distinguish XFS patients from XFG patients when DNA samples were sequenced. Thus, in the subgroup analysis based on the type of disease, we only extracted data from studies in which disease types (XFS or XFG) are clearly illustrated. In the subgroup analysis based on ethnicity, we combined all types of studies (XFS, XFG, XFS/XFG) to conduct the meta-analysis. Because the reason that analysis of SNPs by ethnicity is more comprehensive, we choose its merger result as the overall result. Although negative associations were found in the total sample (G vs. T, OR:1.13,95%CI: 0.85–1.52, p:0.40), allelic contrast analysis revealed positive associations in the XFS (G vs. T, OR: 1.50,95%CI: 1.16–1.93, p<0.001) and XFG (G vs. T, OR: 1.97,95%CI: 1.45–2.66, p<0.001) subgroups. (Fig 2, Table 2). The rs1048661 G allele was significantly correlated with higher XFG and XFS risk relative to the T allele. In the subgroup analysis of ethnicity, the meta-analysis indicated a significant association between the LOXL1 polymorphism (rs1048661) and XFS/XFG risk in Africans (G vs. T, OR: 23.42, 95%CI: 4.48–122.47, p < 0.001) (Fig 3, Table 2). Notably, allelic contrast analysis showed that XFS/XFG susceptibility markedly increased in Caucasians (G vs. T, OR:1.99, 95%CI: 1.70–2.33, p <0.001) and significantly decreased in Asians (G vs. T, OR: 0.52, 95%CI: 0.29–0.94, p:0.03) (Fig 3, Table 2). In Asians, the association between rs1048661 alleles and risk was opposite to that in Caucasians and Africans. A summary of the results from other comparative genetic models is shown in Table 2.

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Fig 2. Meta-analysis for the association between exfoliation syndrome/exfoliation glaucoma risks and LOXL1 gene polymorphism rs1048661 (G vs. T): Subgroup analysis by disease types (squares depict individual studies and diamonds depict summary effect size estimates (Odds Ratio, OR)).

https://doi.org/10.1371/journal.pone.0250772.g002

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Fig 3. Meta-analysis for the association between exfoliation syndrome/exfoliation glaucoma risks and LOXL1 gene polymorphism rs1048661 (G vs. T): Subgroup analysis by ethnicity (squares depict individual studies and diamonds depict summary effect size estimates (Odds Ratio, OR)).

https://doi.org/10.1371/journal.pone.0250772.g003

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Table 2. Summary of different comparative results on LOXL1 gene polymorphism (rs1048661, rs2165241, rs3825942).

https://doi.org/10.1371/journal.pone.0250772.t002

rs2165241 LOXL1 gene polymorphism.

Twenty-two case-control articles on the relationship between the LOXL1 gene polymorphism, rs2165241, and XFS/XFG risk were included in the meta-analysis. Overall analyses revealed a significant association between XFS/XFG susceptibility and the rs2165241 (T vs. C, OR: 1.61, 95%CI: 1.18–2.19, p:0.002) polymorphism (Table 2). The results revealed that genetic polymorphism of LOXL1(rs2165241) was associated with susceptibility to XFS (T vs. C, OR: 2.14, 95%CI: 1.33–3.45, p:0.002) and XFG (T vs. C, OR: 2.00, 95%CI: 1.21–3.31, p:0.007) (Fig 4, Table 2), in the allelic contrast.

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Fig 4. Meta-analysis for the association between exfoliation syndrome/exfoliation glaucoma risks and LOXL1 gene polymorphism rs2165241 (T vs. C): Subgroup analysis by disease types (squares depict individual studies and diamonds depict summary effect size estimates (Odds Ratio, OR)).

https://doi.org/10.1371/journal.pone.0250772.g004

Subgroup analysis by ethnicity identified an increased risk in Caucasians (T vs. C, OR: 2.76, 95%CI: 1.99–3.84, p <0.001) (Fig 5, Table 2). However, there was no significant association between the LOXL1 gene rs2165241 polymorphism and XFS/XFG risk in Asians (T vs. C, OR: 0.65, 95%CI: 0.36–1.17, p:0.15) (Fig 5, Table 2). A summary of the results from other comparative genetic models is also shown in Table 2.

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Fig 5. Meta-analysis for the association between exfoliation syndrome/exfoliation glaucoma risks and LOXL1 gene polymorphism rs2165241 (G vs. A): Subgroup analysis by ethnicity (squares depict individual studies and diamonds depict summary effect size estimates (Odds Ratio, OR)).

https://doi.org/10.1371/journal.pone.0250772.g005

rs3825942 LOXL1 gene polymorphism.

For the LOXL1 gene polymorphism, rs3825942, 38 articles were included in our meta-analysis. Overall analyses revealed a positive LOXL1 rs3825942 (G vs. A, OR: 5.33, 95%CI: 3.49–8.16, p <0.001) association with XFS/XFG susceptibility (Table 2). In the subgroup analysis by disease type, the LOXL1 rs3825942 gene polymorphism revealed a significant association with XFS (G vs. A, OR: 4.16, 95%CI: 1.86–9.30, p <0.001) and XFG (G vs. A, OR: 4.72, 95%CI: 2.10–10.60, P<0.001) (Fig 6, Table 2) susceptibility in a genetic model, G vs. A. In subgroup analysis by ethnicity, increased risks were identified among Caucasians (G vs. A, OR: 6.48, 95%CI: 3.67–11.44, P<0.001) and Asians (G vs. A, OR: 5.89, 95%CI: 3.79–9.16, p <0.001) (Fig 7, Table 2), suggesting that variant G allele carriers are at higher risk of XFS/XFG relative to A allele carriers. In contrast, the G allele indicates protection from XFS/XFG in Africans (G vs. A, OR: 0.10, 95%CI: 0.06–0.16, p <0.001). A summary of the results from other comparative genetic models is shown in Table 2.

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Fig 6. Meta-analysis for the association between exfoliation syndrome/exfoliation glaucoma risks and LOXL1 gene polymorphism rs3825942 (G vs. A): Subgroup analysis by disease types (squares depict individual studies and diamonds depict summary effect size estimates (Odds Ratio, OR)).

https://doi.org/10.1371/journal.pone.0250772.g006

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Fig 7. Meta-analysis for the association between exfoliation syndrome/exfoliation glaucoma risks and LOXL1 gene polymorphism rs3825942 (G vs. A): Subgroup analysis by ethnicity (squares depict individual studies and diamonds depict summary effect size estimates (Odds Ratio, OR)).

https://doi.org/10.1371/journal.pone.0250772.g007

Publication bias and sensitivity analyses

Funnel plot pictures were symmetrical inverted funnels. Egger’s test was used to provide statistical evidence of the funnel plot (rs1048661: t = 1.62, p = 0.114; rs3825942: t = 1.26, p = 0.215; rs2165241: t = -2.10, p = 0.148) (Fig 8). To determine the potential source of heterogeneity, we performed a sensitivity analysis by sequentially excluding studies from the meta-analysis and assessing the effect of each article on the pooled results. This analysis did not reveal any significant alterations to the pooled ORs, indicating the stability of the three polymorphisms studied.

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Fig 8.

(A) Begg’s funnel plot of publication bias for LOXL1 gene polymorphism rs1048661; (B) Begg’s funnel plot of publication bias for LOXL1 gene polymorphism rs2165241; (C) Begg’s funnel plot for of publication bias for LOXL1 gene polymorphism rs3825942.

https://doi.org/10.1371/journal.pone.0250772.g008

Discussion

XFS is associated with a high morbidity and blindness rate [5]. This systemic disease of the extracellular matrix, may cause pathological material accumulation in blood vessels, skin, heart, lung, liver, and cerebral meninges [59]. XFG, which results from XFS, is the most common identifiable cause of secondary open-angle glaucoma and is associated with cataracts [6062]. Additionally, XFG increases the risk of potentially sight-threatening conditions and serious complications from cataract surgery [59]. Numerous studies indicate that XFS/XFG risk factors include inflammation, immune dysfunction, oxidative stress, unhealthy lifestyle, and various environmental factors [63]. Owing to clustering of XFS/XFG in families, concordance in monozygotic twins, and prevalence variability by ethnicity, genetic factors are regarded as XFS/XFG risk factors [6468]. It is widely accepted that the LOXL1 gene is the most important genetic risk factor known so far for XFS/XFG. Besides, a single study might lack sufficient power to detect the potential small LOXL1 gene polymorphism effects associated with XFS/XFG, especially when the sample size is not adequate. Thus, a meta-analysis may effectively identify the association between genetic risk factors and XFS/XFG as such quantitative analyses integrate results from numerous studies on the topic of study, potentially drawing more objective and reliable conclusions. Here, we conducted a pooled analysis to evaluate the association between LOXL1 gene polymorphisms and XFS/XFG susceptibility.

Three recent meta-analyses [34, 69, 70] investigated the association between the LOXL1 gene polymorphisms and XFS/XFG risk. However, all of them covered papers published until to 2015, with the latest data unrepresented. Tang C et al. [69] and Chen H et al. [70] both indicated that the allele G of rs1048661, the allele T of rs2165241 and the allele G of rs3825942 were associated with an increased risk for XFS/XFG among Caucasians, and that only the allele G of rs1048661 and the allele T of rs2165241 had a potential protective effect on XFS/XFG in Asians. Nevertheless, our study showed that there was no significant association between the LOXL1 gene rs2165241 polymorphism and XFS/XFG risk in Asians, and that rs3825942 (“G” allele) carriers are at higher risk of XFS/XFG relative to A allele carriers in Asians. On this point, our conclusion seems partially inconsistent with the previous two meta-analyses. Moreover, their study did not involve XFS/XFG in Africans, which is important and worthy of attention. Wang L et al. [34] reported that rs1048661(“G” alleles) had a weak association with XFG/XGS; rs3825942 (“G” alleles) had a strong association with XFS/XFG; and rs2165241 (“T” alleles) had a significant risk with XFS/XFG in Caucasians. Our meta-analysis has corroborated their findings. However, three articles [10, 30, 31] included in Wang’s meta-analysis [34], did not achieve HWE in the control group, while two articles [32, 33] examined the relationship between LOXL1 gene polymorphisms and primary open-angle glaucoma. Here, we carried out an updated meta-analysis of the association between LOXL1 gene polymorphisms and XFS/XFG susceptibility, involving 13984 participants. We identified three polymorphisms, rs1048661, rs3825942, and rs2165241, that met the inclusion criteria for meta-analysis. XFS/XFG analysis by ethnicity revealed a significantly high association between the G allele of rs1048661, the allele T of rs2165241 and the allele G of rs3825942, and XFS/XFG risk in Caucasians. We found that the G allele of rs1048661 may have potentially negative effects on XFS/XFG in Africans, and the G allele of rs3825942 may protect from XFS/XFG in Africans. In Asians, a significantly increased XFS/XFG risk was associated with the G allele of rs3825942. However, we also found that the G allele of rs1048661 was associated with reduced XFS/XFG risk in Asians. In Asians, there was no significant association between the T allele of rs2165241 and XFS/XFG risk. Additionally, there was a significant association between LOXL1 gene polymorphisms and susceptibility to various disease types. These results affirmed the association between LOXL1 gene polymorphisms and XFS and XFG. Notably, we found a high frequency of risk alleles (rs1048661, rs2165241, and rs3825942) in non-XFG/XFS individuals, especially in Caucasians. Some studies have reported that these polymorphisms affect the proteolytic activity of LOXL1, and LOXL1 is an important matrix cross-linking enzyme that is required for elastic fiber formation and confer risk for the development of XFS/XFG [71]. However, the contribution of the risk alleles to XFS/XFG is complicated. Certain genetic variants of LOXL1, which has a prominent role in elastin fiber production, are not a single causative factor as many genetically affected individuals do not develop XFS or XFG [72]. It is likely that additional genetic or environmental factors modulate the penetrance of LOXL1 susceptibility alleles [52]. This meta-analysis found that LOXL1 gene polymorphisms may contribute to XFS/XFG susceptibility in different populations, and the differences in genetic susceptibility might be affected by ethnic factors, lifestyle factors and environmental exposures. Unfortunately, there are few studies concerning the association between LOXL1 gene polymorphisms (rs3825942 and 1048661) and XFS/XFG in Africans, and no data were available for the SNP rs2165241 in Africans. This may lead to bias in the conclusion and generalization of the relationship between LOXL1 gene polymorphisms and XFS/XFG in Africans. Thus, many such original studies are needed to confirm these findings as the currently included case-control studies are based on small sample sizes, especially for African populations.

The mechanisms by which LOXL1 gene polymorphisms affect XFS/XFG susceptibility remain unclear. Multiple studies [63, 73] have shown that LOXL1 mediates the formation and maintenance of elastic tissues, as well as maintenance of extracellular matrix homeostasis, by regulating cross-linking reactions between collagen and elastin. LOXL1 has also been reported to be involved in elastin renewal and XFS/XFG development [71, 74]. Sharma et al. [59] reported that the coding variants rs1048861 and rs3825942 may alter protein function and binding, wherein molecular modeling displayed that positions 141(rs1048661) and 153(rs3825942) of the LOXL1 protein are likely surface residues and hence possible recognition sites for protein-protein interactions. Alterations at these residues might change the capacity of LOXL1 to bind other proteins related to its cleavage as well as processing. Nevertheless, the difference in processing of the LOXL1 protein variants detected in their research does not completely interpret susceptibility to XFS/XFG among carriers of these variants as each of the variants confer the XFS/XFG risk in various ethnicities. The detailed mechanism whereby LOXL1 gene polymorphisms lead to the XFS/XFG, remains poorly understood. Therefore, further studies are required to elucidate the mechanism on how the LOXL1 gene polymorphisms impact the occurrence and development of XFS/XFG. Moreover, the distinct genetic background of Caucasians from Asians may modify LOXL1-mediated genetic susceptibility; hence, the effects of rs2165241 and rs1048661 are opposite in Asians and Caucasians. Genetic and/or environmental factors may modify the effects of gene polymorphisms in different ethnic groups.

High heterogeneity was found in our study. For exploring the underlying source of heterogeneity, a subgroup analysis and sensitivity analysis were performed. Unfortunately, although subgroup and sensitivity analyses were performed, obvious heterogeneity still existed in certain genetic models, and it is difficult to explain the heterogeneity completely. Thus, we speculated that living environment and other complications might lead to heterogeneity. Publication bias was assessed using Begg’s funnel plot and Egger’s test; no significant publication bias was found in this meta-analysis. Moreover, all genotype distributions of controls were in -absolute accordance with the HWE, indicating that our results are stable and reliable.

We acknowledge several limitations of this study. First, in subgroup analysis by ethnicity and disease type, some subgroups consisted of less than three case-control studies, which may be too small to detect associations. Second, data were not stratified by other factors, such as gender, age, gene-environment/gene-gene interactions, and lifestyle, because sufficient information could not be extracted from primary publications. Third, we mainly focused on LOXL1 gene polymorphisms, and did not take into consideration potential linkage disequilibrium with other mutations in this gene, or gene-gene and gene-environment interactions. Moreover, language bias may have occurred as only articles published in Chinese or English were included in the study. However, we minimized the likelihood of bias using a rigorous protocol, study identification, data selection, and statistical analysis.

Conclusion

In conclusion, our findings indicate that rs1048661, rs3825942, and rs2165241 LOXL1 polymorphisms may contribute to XFS/XFG susceptibility, especially in Caucasians. Furthermore, well-designed studies with large sample sizes focusing on ethnicity or disease types are needed to confirm these findings.

Supporting information

Acknowledgments

We sincerely appreciated to all authors contributed to this article and Editage for English language editing.

References

  1. 1. Zenkel M, Schlötzer-Schrehardt U. Expression and regulation of LOXL1 and elastin-related genes in eyes with exfoliation syndrome. J Glaucoma. 2014; 23(8 Suppl 1): S48–50. pmid:25275906.
  2. 2. Yilmaz SG, Palamar M, Onay H, Ilim O, Aykut A, Ozkinay FF, et al. LOXL1 gene analysis in Turkish patients with exfoliation glaucoma. Int Ophthalmol. 2016; 36(5): 629–635. pmid:26758070.
  3. 3. Hashemi H, Khabazkhoob M, Emamian MH, Jafari A, Mohazeb-Torabi S, Fotouhi A. The Prevalence of Exfoliation Syndrome in an Iranian Population Aged 45–69 Years. Ophthalmic Epidemiol. 2016; 23(5): 303–308. pmid:27253831.
  4. 4. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014; 311(18): 1901–1911. pmid:24825645.
  5. 5. Liu Y, Whigham BT, Wheeler J, Williams SE, Rautenbach RM, Ziskind A, et al. The role of lysyl oxidase-like 1 DNA copy number variants in exfoliation glaucoma. Mol Vis. 2012; 18: 2976–2981. http://doi.org/10.1186/1471-2415-12-64 pmid:23288989.
  6. 6. Mocan MC, Kasim B, Muz E, Irkec M, Orhan M, Karabulut E, et al. Intraocular Pressure Characteristics of Exfoliative Glaucoma and Exfoliation Syndrome as Determined With the Water Drinking Test. J Glaucoma. 2016; 25(3): 301–305. pmid:25642816.
  7. 7. Ritch R. Exfoliation syndrome: beyond glaucoma. Arch Ophthalmol. 2008; 126(6): 859–861. pmid:18541854.
  8. 8. Ritch R, Schlötzer-Schrehardt U, Konstas AG. Why is glaucoma associated with exfoliation syndrome? Prog Retin Eye Res. 2003; 22(3): 253–275. pmid:12852486.
  9. 9. Kasım B, İrkeç M, Alikaşifoğlu M, Orhan M, Mocan MC, Aktaş D. Association of LOXL1 gene polymorphisms with exfoliation syndrome/glaucoma and primary open angle glaucoma in a Turkish population. Mol Vis. 2013; 19: 114–120. http://doi.org/10.1186/1471-2415-13-1 pmid:23378724.
  10. 10. Jaimes M, Rivera-Parra D, Miranda-Duarte A, Valdés G, Zenteno JC. Prevalence of high-risk alleles in the LOXL1 gene and its association with pseudoexfoliation syndrome and exfoliation glaucoma in a Latin American population. Ophthalmic Genet. 2012; 33(1): 12–17. pmid:21970694.
  11. 11. Sagong M, Gu BY, Cha SC. Association of lysyl oxidase-like 1 gene polymorphisms with exfoliation syndrome in Koreans. Mol Vis. 2011; 17: 2808–2817. http://doi.org/10.1186/1476-511X-10-192 pmid:22128228.
  12. 12. Ramprasad VL, George R, Soumittra N, Sharmila F, Vijaya L, Kumaramanickavel G. Association of non-synonymous single nucleotide polymorphisms in the LOXL1 gene with pseudoexfoliation syndrome in India. Mol Vis. 2008; 14: 318–322. http://doi.org/10.1017/S0952523808080504 pmid:18334947.
  13. 13. Gayathri R, Coral K, Sharmila F, Sripriya S, Sripriya K, Manish P, et al. Correlation of Aqueous Humor Lysyl Oxidase Activity with TGF-ß Levels and LOXL1 Genotype in Pseudoexfoliation. Curr Eye Res. 2016; 41(10): 1331–1338. pmid:27116380.
  14. 14. Chiras D, Tzika K, Kokotas H, Oliveira SC, Grigoriadou M, Kastania A, et al. Development of novel LOXL1 genotyping method and evaluation of LOXL1, APOE and MTHFR polymorphisms in exfoliation syndrome/glaucoma in a Greek population. Mol Vis. 2013; 19: 1006–1016. http://www.molvis.org/molvis/v19/1006 pmid:23687437.
  15. 15. Wu M, Zhu XY, Ye J. Associations of polymorphisms of LOXL1 gene with primary open-angle glaucoma: a meta-analysis based on 5,293 subjects. Mol Vis. 2015; 21: 165–172. http://www.molvis.org/molvis/v21/165 pmid:25750511.
  16. 16. Thorleifsson G, Magnusson KP, Sulem P, Walters GB, Gudbjartsson DF, Stefansson H, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science. 2007; 317(5843): 1397–1400. pmid:17690259.
  17. 17. Dubey SK, Hejtmancik JF, Krishnadas SR, Sharmila R, Haripriya A, Sundaresan P. Lysyl oxidase-like 1 gene in the reversal of promoter risk allele in pseudoexfoliation syndrome. JAMA Ophthalmol. 2014; 132(8): 949–955. pmid:24809751.
  18. 18. Tanito M, Minami M, Akahori M, Kaidzu S, Takai Y, Ohira A, et al. LOXL1 variants in elderly Japanese patients with exfoliation syndrome/glaucoma, primary open-angle glaucoma, normal tension glaucoma, and cataract. Mol Vis. 2008; 14: 1898–1905. http://doi.org/10.1186/1471-2199-9-94 pmid:18958304.
  19. 19. Ozaki M, Lee KY, Vithana EN, Yong VH, Thalamuthu A, Mizoguchi T, et al. Association of LOXL1 gene polymorphisms with pseudoexfoliation in the Japanese. Invest Ophthalmol Vis Sci. 2008; 49(9): 3976–3980. pmid:18450598.
  20. 20. Fuse N, Miyazawa A, Nakazawa T, Mengkegale M, Otomo T, Nishida K. Evaluation of LOXL1 polymorphisms in eyes with exfoliation glaucoma in Japanese. Mol Vis. 2008; 14: 1338–1343. http://doi.org/10.1104/pp.103.026880 pmid:18648524.
  21. 21. Hayashi H, Gotoh N, Ueda Y, Nakanishi H, Yoshimura N. Lysyl oxidase-like 1 polymorphisms and exfoliation syndrome in the Japanese population. Am J Ophthalmol. 2008; 145(3): 582–585. pmid:18201684.
  22. 22. Park DY, Won HH, Cho HK, Kee C. Evaluation of lysyl oxidase-like 1 gene polymorphisms in pseudoexfoliation syndrome in a Korean population. Mol Vis. 2013; 19: 448–453. http://doi.org/10.1016/j.jmb.2012.12.001 pmid:23441117.
  23. 23. Chen L, Jia L, Wang N, Tang G, Zhang C, Fan S, et al. Evaluation of LOXL1 polymorphisms in exfoliation syndrome in a Chinese population. Mol Vis. 2009; 15: 2349–2357. http://doi.org/10.1016/0956-716X(93)90323-K pmid:19936304.
  24. 24. de Juan-Marcos L, Escudero-Domínguez FA, Hernández-Galilea E, Cabrillo-Estévez L, Cruz-González F, Cieza-Borrella C, et al. Association of Lysyl Oxidase-Like 1 Gene Polymorphisms in Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma in a Spanish Population. Ophthalmic Genet. 2016; 37(1): 25–30. pmid:24892565.
  25. 25. Rautenbach RM, Bardien S, Harvey J, Ziskind A. An investigation into LOXL1 variants in black South African individuals with exfoliation syndrome. Arch Ophthalmol. 2011; 129(2): 206–210. pmid:21320968.
  26. 26. Williams SE, Whigham BT, Liu Y, Carmichael TR, Qin X, Schmidt S, et al. Major LOXL1 risk allele is reversed in exfoliation glaucoma in a black South African population. Mol Vis. 2010; 16: 705–712. http://doi.org/10.1186/1471-2415-10-11 pmid:20431720.
  27. 27. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010; 25(9): 603–605. pmid:20652370.
  28. 28. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol. 2008; 61(10): 991–996. pmid:18538991.
  29. 29. Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000; 53(11): 1119–1129. pmid:11106885.
  30. 30. Fan BJ, Pasquale L, Grosskreutz CL, Rhee D, Chen T, DeAngelis MM, et al. DNA sequence variants in the LOXL1 gene are associated with pseudoexfoliation glaucoma in a U.S. clinic-based population with broad ethnic diversity. BMC Med Genet. 2008; 9: 5. pmid:18254956.
  31. 31. Mori K, Imai K, Matsuda A, Ikeda Y, Naruse S, Hitora-Takeshita H, et al. LOXL1 genetic polymorphisms are associated with exfoliation glaucoma in the Japanese population. Mol Vis. 2008; 14: 1037–1040. http://doi.org/10.1186/1476-4598-7-51 pmid:18552979.
  32. 32. Chakrabarti S, Rao KN, Kaur I, Parikh RS, Mandal AK, Chandrasekhar G, et al. The LOXL1 gene variations are not associated with primary open-angle and primary angle-closure glaucomas. Invest Ophthalmol Vis Sci. 2008; 49(6): 2343–2347. pmid:18223248.
  33. 33. Gong WF, Chiang SW, Chen LJ, Tam PO, Jia LY, Leung DY, et al. Evaluation of LOXL1 polymorphisms in primary open-angle glaucoma in southern and northern Chinese. Mol Vis. 2008; 14: 2381–2389. http://doi.org/10.1167/8.7.28 pmid:19098994.
  34. 34. Wang L, Yu Y, Fu S, Zhao W, Liu P. LOXL1 Gene Polymorphism With Exfoliation Syndrome/Exfoliation Glaucoma: A Meta-Analysis. J Glaucoma. 2016; 25(1): 62–94. pmid:25304275.
  35. 35. Lan L, Lei F. Analysis of LOXL1 gene polymorphism in exfoliated glaucoma. Journal of Experimental and Laboratory Medicine. 2020;38(3):423–425,429.
  36. 36. Taghavi E, Daneshvar R, Noormohammadi Z, Modarresi SM, Sedaghat MR. Association of LOXL1 Gene Polymorphisms with Exfoliation Glaucoma Patients. Iran J Public Health. 2019; 48(10): 1827–1837. http://doi.org/10.18502/ijph.v48i10.3490 pmid:31850260.
  37. 37. Pandav SS, Chakma P, Khera A, Chugh N, Gupta PC, Thattaruthody F, et al. Lack of association between lysyl oxidase-like 1 polymorphism in pseudoexfoliation syndrome and pseudoexfoliation glaucoma in North Indian population. Eur J Ophthalmol. 2019; 29(4): 431–436. pmid:30189755.
  38. 38. Shihadeh W, Khabour O, Khalil MB, Al-Dabbagh A, Al-Hashimi M. Association of LOXL1 gene common sequence variants in Jordanian patients with exfoliation syndrome and exfoliative glaucoma. Int J Ophthalmol. 2018; 11(10): 1583–1587. pmid:30364215.
  39. 39. Yaz Y, Yıldırım N, Aydın Yaz Y, Çilingir O, Yüksel Z, Mutlu F. Three Single Nucleotide Polymorphisms of LOXL1’ in a Turkish Population with Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma. Turk J Ophthalmol. 2018; 48(5): 215–220. pmid:30405941.
  40. 40. Asfuroglu M, Cavdarli B, Koz OG, A AY, Ozdemir EY. Association of Lysyl Oxidase-Like 1 Gene Polymorphism in Turkish Patients With Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma. J Glaucoma. 2017; 26(2): e54–e57. pmid:27753755.
  41. 41. Álvarez L, García M, González-Iglesias H, Escribano J, Rodríguez-Calvo PP, Fernández-Vega L, et al. LOXL1 gene variants and their association with pseudoexfoliation glaucoma (XFG) in Spanish patients. BMC Med Genet. 2015; 16: 72. pmid:26319397.
  42. 42. Qiu CL, The relationship between LOXL1 promoter haplotypes with exfoliation syndrome in the Uygur population. Journal of Xinjiang Medical University. 2015;1(4):138–145.
  43. 43. Anastasopoulos E, Coleman AL, Wilson MR, Sinsheimer JS, Yu F, Katafigiotis S, et al. Association of LOXL1 polymorphisms with pseudoexfoliation, glaucoma, intraocular pressure, and systemic diseases in a Greek population. The Thessaloniki eye study. Invest Ophthalmol Vis Sci. 2014; 55(7): 4238–4243. pmid:24917141.
  44. 44. Micheal S, Khan MI, Akhtar F, Ali M, Ahmed A, den Hollander AI, et al. Role of Lysyl oxidase-like 1 gene polymorphisms in Pakistani patients with pseudoexfoliative glaucoma. Mol Vis. 2012; 18: 1040–1044. http://doi.org/10.1186/1476-4598-11-23 pmid:22605916.
  45. 45. Mayinu Chen X. Evaluation of LOXL1 polymorphisms in exfoliation syndrome in the Uygur population. Mol Vis. 2011; 17: 1734–1744. http://doi.org/10.1097/ICU.0b013e32834787bb pmid:21738402.
  46. 46. Malukiewicz G, Lesiewska-Junk H, Linkowska K, Mielnik M, Grzybowski T, Sulima N. Analysis of LOXL1 single nucleotide polymorphisms in Polish population with pseudoexfoliation syndrome. Acta Ophthalmol. 2011; 89(1): e64–66. pmid:21272281.
  47. 47. Wolf C, Gramer E, Müller-Myhsok B, Pasutto F, Gramer G, Wissinger B, et al. Lysyl oxidase-like 1 gene polymorphisms in German patients with normal tension glaucoma, pigmentary glaucoma and exfoliation glaucoma. J Glaucoma. 2010; 19(2): 136–141. pmid:19373106.
  48. 48. Abu-Amero KK, Osman EA, Dewedar AS, Schmidt S, Allingham RR, Al-Obeidan SA. Analysis of LOXL1 polymorphisms in a Saudi Arabian population with pseudoexfoliation glaucoma. Mol Vis. 2010; 16: 2805–2810. http://doi.org/10.1186/1476-511X-9-143 pmid:21197115.
  49. 49. Lemmelä S, Forsman E, Onkamo P, Nurmi H, Laivuori H, Kivelä T, et al. Association of LOXL1 gene with Finnish exfoliation syndrome patients. J Hum Genet. 2009; 54(5): 289–297. pmid:19343041.
  50. 50. Lee KY, Ho SL, Thalamuthu A, Venkatraman A, Venkataraman D, Pek DC, et al. Association of LOXL1 polymorphisms with pseudoexfoliation in the Chinese. Mol Vis. 2009; 15: 1120–1126. http://doi.org/10.1017/S0952523809990198 pmid:19503743.
  51. 51. Hewitt AW, Sharma S, Burdon KP, Wang JJ, Baird PN, Dimasi DP, et al. Ancestral LOXL1 variants are associated with pseudoexfoliation in Caucasian Australians but with markedly lower penetrance than in Nordic people. Hum Mol Genet. 2008; 17(5): 710–716. pmid:18037624.
  52. 52. Challa P, Schmidt S, Liu Y, Qin X, Vann RR, Gonzalez P, et al. Analysis of LOXL1 polymorphisms in a United States population with pseudoexfoliation glaucoma. Mol Vis. 2008; 14: 146–149. http://doi.org/10.1016/j.visres.2007.12.008 pmid:18334928.
  53. 53. Mabuchi F, Sakurada Y, Kashiwagi K, Yamagata Z, Iijima H, Tsukahara S. Lysyl oxidase-like 1 gene polymorphisms in Japanese patients with primary open angle glaucoma and exfoliation syndrome. Mol Vis. 2008; 14: 1303–1308. http://doi.org/10.1126/scisignal.125re5 pmid:18636115.
  54. 54. Mossböck G, Renner W, Faschinger C, Schmut O, Wedrich A, Weger M. Lysyl oxidase-like protein 1 (LOXL1) gene polymorphisms and exfoliation glaucoma in a Central European population. Mol Vis. 2008; 14: 857–861. http://doi.org/10.1016/j.visres.2008.04.022 pmid:18483563.
  55. 55. Aragon-Martin JA, Ritch R, Liebmann J, O’Brien C, Blaaow K, Mercieca F, et al. Evaluation of LOXL1 gene polymorphisms in exfoliation syndrome and exfoliation glaucoma. Mol Vis. 2008; 14: 533–541. http://doi.org/10.1016/j.carres.2007.12.003 pmid:18385788.
  56. 56. Pasutto F, Krumbiegel M, Mardin CY, Paoli D, Lämmer R, Weber BH, et al. Association of LOXL1 common sequence variants in German and Italian patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma. Invest Ophthalmol Vis Sci. 2008; 49(4): 1459–1463. pmid:18385063.
  57. 57. Yang X, Zabriskie NA, Hau VS, Chen H, Tong Z, Gibbs D, et al. Genetic association of LOXL1 gene variants and exfoliation glaucoma in a Utah cohort. Cell Cycle. 2008; 7(4): 521–524. pmid:18287813.
  58. 58. Kobakhidze N, Tabagari S, Chichua G. LOXL1 GENE VARIANTS IN ASSOCIATION WITH EXFOLIATION SYNDROME IN GEORGIAN POPULATION. Georgian Med News. 2019; (286): 32–36. pmid:30829585
  59. 59. Sharma S, Martin S, Sykes MJ, Dave A, Hewitt AW, Burdon KP, et al. Biological effect of LOXL1 coding variants associated with pseudoexfoliation syndrome. Exp Eye Res. 2016; 146: 212–223. pmid:26997634.
  60. 60. Sekeroglu MA, Irkec M, Mocan MC, Ileri E, Dikmenoglu N, Seringec N, et al. The association of ocular blood flow with haemorheological parameters in primary open-angle and exfoliative glaucoma. Acta Ophthalmol. 2011; 89(5): 429–434. pmid:19878104.
  61. 61. Ren R, Ding J, Wang N, Teng CC, de Moraes GV, Jonas JB, et al. Clinical Signs and Characteristics of Exfoliation Syndrome and Exfoliative Glaucoma in Northern China. Asia Pac J Ophthalmol (Phila). 2015; 4(2): 86–88. pmid:26065350.
  62. 62. Tryggvason G, Jonasson F, Cotch MF, Li CM, Hoffman HJ, Themann CL, et al. Hearing in older adults with exfoliation syndrome/exfoliation glaucoma or primary open-angle glaucoma. Acta Ophthalmol. 2016; 94(2): 140–146. pmid:26547142.
  63. 63. Ovodenko B, Rostagno A, Neubert TA, Shetty V, Thomas S, Yang A, et al. Proteomic analysis of exfoliation deposits. Invest Ophthalmol Vis Sci. 2007; 48(4): 1447–1457. pmid:17389470.
  64. 64. Ritland JS, Utheim TP, Utheim OA, Espeseth T, Lydersen S, Semb SO, et al. Effects of APOE and CHRNA4 genotypes on retinal nerve fibre layer thickness at the optic disc and on risk for developing exfoliation syndrome. Acta Ophthalmol Scand. 2007; 85(3): 257–261. pmid:17488453.
  65. 65. Shimizu A, Takano Y, Shi D, Yokokura S, Yokoyama Y, Zheng X, et al. Evaluation of CNTNAP2 gene polymorphisms for exfoliation syndrome in Japanese. Mol Vis. 2012; 18: 1395–1401. http://doi.org/10.3109/09273948.2012.659369 pmid:22690117
  66. 66. Tsironi EE, Pefkianaki M, Tsezou A, Kotoula MG, Dardiotis E, Almpanidou P, et al. Evaluation of MMP1 and MMP3 gene polymorphisms in exfoliation syndrome and exfoliation glaucoma. Mol Vis. 2009; 15: 2890–2895. pmid:20038976.
  67. 67. Yilmaz A, Tamer L, Ates NA, Yildirim O, Yildirim H, Atik U. Is GST gene polymorphism a risk factor in developing exfoliation syndrome? Curr Eye Res. 2005; 30(7): 575–581. pmid:16020292.
  68. 68. Guadarrama-Vallejo D, Miranda-Duarte A, Zenteno JC. The T allele of lysyl oxidase-like 1 rs41435250 is a novel risk factor for pseudoexfoliation syndrome and pseudoexfoliation glaucoma independently and through intragenic epistatic interaction. Mol Vis. 2013; 19: 1937–1944. http://www.molvis.org/molvis/v19/1937. http://doi.org/10.1186/1476-511X-12-135 pmid:24068861.
  69. 69. Tang C, Li JS. Meta-analysis of association between LOXL1 polymorphisms and exfoliation syndrome/glaucoma, Chinese Journal of Pathophysiology. 2014;30(5):914–922.
  70. 70. Chen H, Chen LJ, Zhang M, Gong W, Tam PO, Lam DS, et al. Ethnicity-based subgroup meta-analysis of the association of LOXL1 polymorphisms with glaucoma. Mol Vis. 2010; 16: 167–177. http://www.molvis.org/molvis/v16/a21. http://doi.org/10.1124/jpet.111.189225 pmid:20142848.
  71. 71. Schlötzer-Schrehardt U, Zenkel M. The role of lysyl oxidase-like 1 (LOXL1) in exfoliation syndrome and glaucoma. Exp Eye Res. 2019; 189: 107818. pmid:31563608.
  72. 72. Bernstein AM, Ritch R, Wolosin JM. LOXL1 folding in exfoliation glaucoma. Adv Protein Chem Struct Biol. 2019; 118: 273–288. pmid:31928728.
  73. 73. Jameson SA, Swaminathan G, Dahal S, Couri B, Kuang M, Rietsch A, et al. Elastin homeostasis is altered with pelvic organ prolapse in cultures of vaginal cells from a lysyl oxidase-like 1 knockout mouse model. Physiol Rep. 2020; 8(11): e14436. pmid:32533648.
  74. 74. Jonasson F. From epidemiology to lysyl oxidase like one (LOXL1) polymorphisms discovery: phenotyping and genotyping exfoliation syndrome and exfoliation glaucoma in Iceland. Acta Ophthalmol. 2009; 87(5): 478–487. pmid:19664108.