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. 2011 Jul 27;25(4):347–352. doi: 10.1016/j.sjopt.2011.07.001

Review: The role of LOXL1 in exfoliation syndrome/glaucoma

Benjamin T Whigham a, R Rand Allingham b,⁎
PMCID: PMC3729321  PMID: 23960948

Abstract

Exfoliation syndrome is a common cause of open-angle glaucoma. It is characterized by microscopic flakes of protein-rich material being deposited in both ocular and non-ocular tissues. While its mechanism is poorly understood, family- and population-based studies have established that the disorder has a strong genetic component. A further understanding of the relevant gene variants might help reveal the molecular mechanism behind exfoliation. The most-strongly associated genetic variants are found in the lysyl oxidase-like 1 (LOXL1) gene. However, two major risk alleles in the LOXL1 coding region are reversed between ethnic groups. It now appears the strong association between LOXL1 and XFS is due to non-coding variants that have not yet been identified. Such variants might alter LOXL1 expression, which is decreased in the late stages of exfoliation syndrome/glaucoma. Here we discuss LOXL1 as a risk gene for exfoliation syndrome and glaucoma.

Keywords: Exfoliation, Pseudoexfoliation, Glaucoma, Genetics, LOXL1

1. Introduction

Exfoliation syndrome (XFS) is the most common identifiable cause of open-angle glaucoma (Ritch, 1994). The resulting glaucoma, termed exfoliation glaucoma (XFG), is a blinding disorder characterized by whitish flakes in the anterior chamber of the eye, increased intraocular pressures, and optic nerve damage. The clinical presentation of XFG has been described in great detail in previous articles (Ritch and Schlotzer-Schrehardt, 2001; Vesti and Kivela, 2000). XFG currently carries a worse prognosis than primary open-angle glaucoma (POAG). XFG accounts for approximately 25% of open-angle glaucoma worldwide and is more concentrated in certain regions and ethnic groups (Ritch and Schlotzer-Schrehardt, 2001). The risk of developing glaucoma in patients with XFS is increased with longer duration. Approximately half of the eyes with XFS will develop glaucoma within 15 years of diagnosis (Jeng et al., 2007).

XFS is a systemic disorder that involves abnormal deposition of microscopic fibrils in numerous ocular and non-ocular tissues (Schlotzer-Schrehardt and Naumann, 2006). The etiology of XFS is not fully understood but appears to be related to the excessive production and abnormal crosslinking of elastic fibers (Schlotzer-Schrehardt, 2011). Deposition of these fibers is known to occur in the trabecular meshwork which likely contributes to reduced facility of aqueous outflow, elevated IOP, and can ultimately lead to the development of glaucoma (Ritch et al., 2003). While the etiology of XFS/XFG remains unknown, the disease appears to depend on risk genetic factors around the lysyl oxidase-like 1 (LOXL1) gene. A full understanding of this association could be a powerful clue to the pathology of XFS and its associated glaucoma.

2. XFS has complex inheritance pattern

XFS has a strong hereditary component. Family studies have consistently supported a role for genetic factors XFS risk (Allingham et al., 2001; Damji et al., 1998; Forsman et al., 2007). The pattern of inheritance is not clear however, and may be due to late onset of disease and incomplete penetrance (Forsman et al., 2007). These factors make it difficult to identify segregation patterns in families. In addition to these factors there may be important environmental factors involved in the pathogenesis of XFG/XFS (Challa, 2009).

The prevalence of XFS/XFG is highly variable among different racial or ethnic groups. Rates in the Native American Navajo population have been reported at 38% (Friederich, 1982). The Nordic populations have rates of XFS above 15% in individuals over 60 years of age (Arnarsson et al., 2007). Some Arab and Greek populations have rates of XFS above 25% in people over 70 (Summanen and Tonjum, 1988; Topouzis et al., 2007). The reports in Arabs also found a significant burden of XFS in younger groups, nearing 8% in patients between ages 50 and 60 (Summanen and Tonjum, 1988). In contrast, XFS/XFG is rare among the West African and Eskimo populations (Forsius, 1988; Ntim-Amponsah et al., 2004). Although environmental factors may play a role in XFS or XFG, it is interesting to note that African Americans, largely descended from West African populations, also share the low prevalence of XFS/XFG despite living in a region where the prevalence is substantially higher (Cashwell and Shields, 1988).

3. Variants in LOXL1 associate with XFS

The lysyl oxidase-like 1 (LOXL1) gene was first associated with XFS/XFG in a genome-wide association study (GWAS) (Thorleifsson et al., 2007). Three single-nucleotide polymorphisms (SNPs) were found to be highly associated with XFG and later with XFS. All three SNPs were located within the LOXL1 gene. One SNP, rs2165241, was located in intron 1 of LOXL1. The other two SNPs, rs1048661 and rs3825942, were missense variants located in exon 1. For both coding SNPs, the ‘G’ allele was associated with a higher risk of XFS and XFG.

The relationship between the LOXL1 SNPs and XFS has now been studied in numerous populations including Swedish (Thorleifsson et al., 2007), US Caucasian (Aragon-Martin et al., 2008; Challa et al., 2008; Fan et al., 2008; Fingert et al., 2007; Yang et al., 2008), Australian (Hewitt et al., 2008), German (Wolf et al., 2010), Italian (Pasutto et al., 2008), Central European (Mossbock et al., 2008), Finnish (Lemmela et al., 2009), Chinese (Chen et al., 2009; Lee et al., 2009), Japanese (Fuse et al., 2008; Hayashi et al., 2008; Mabuchi et al., 2008; Mori et al., 2008; Ozaki et al., 2008; Tanito et al., 2008), Indian (Ramprasad et al., 2008), South African (Rautenbach et al., 2011; Williams et al., 2010), and Saudi Arabian (Abu-Amero et al., 2010). Observed SNP frequencies for the two missense variants are shown in Table 1.

Table 1.

Summary of the genetic association of two coding variants in LOXL1 gene with XFS/XFG.

Studied population rs1048661 ‘G’ allele
 Significant association rs3825942 ‘G’ allele
 Significant association References
Case Control Case Control
Icelandic 0.781 0.651 Yes 0.984 0.847 Yes Thorleifsson et al. (2007)
Swedish 0.834 0.682 Yes 0.995 0.879 Yes Thorleifsson et al. (2007)
American 0.819 0.600 Yes 0.986 0.880 Yes Fingert et al. (2007)
American 0.787 0.665 Yes 0.939 0.844 Yes Challa et al. (2008)
American NA NA NA 1.000 0.856 Yes Yang et al. (2008)
American 0.843 0.703 Yes 0.959 0.798 Yes Aragon-Martin et al. (2008)
American 0.829 0.719 No 0.988 0.795 Yes Fan et al. (2008)
Australian 0.78 0.660 Yes 0.95 0.84 Yes Hewitt et al. (2008)
Austrian 0.841 0.671 Yes 0.994 0.817 Yes Mossbock et al. (2008)
Germany 0.844 0.660 Yes 0.992 0.856 Yes Wolf et al. (2010)
Germany 0.818 0.644 Yes 0.951 0.857 Yes Pasutto et al. (2008)
Finnish 0.825 0.683 Yes 0.968 0.823 Yes Lemmela et al. (2009)
Italian 0.825 0.693 Yes 1.000 0.821 Yes Pasutto et al. (2008)
Saudi Arabian 0.876 0.762 Yes 0.968 0.817 Yes Abu-Amero et al. (2010)
Indian 0.721 0.634 No 0.923 0.742 Yes Ramprasad et al. (2008)
Chinese 0.542 0.444 No 0.992 0.918 Yes Lee et al. (2009)
Chinese 0.110 0.480 Yes 1.000 0.900 Yes Chen et al. (2009)
Japanese 0.036 0.493 Yes 1.000 0.877 Yes Fuse et al. (2008)
Japanese 0.008 0.460 Yes 1.000 0.857 Yes Hayashi et al. (2008)
Japanese 0.006 0.450 Yes 0.994 0.853 Yes Mabuchi et al. (2008)
Japanese 0.005 0.474 Yes 0.995 0.850 Yes Mori et al. (2008)
Japanese 0.005 0.497 Yes 0.986 0.863 Yes Ozaki et al. (2008)
Japanese 0.005 0.554 Yes 0.993 0.806 Yes Tanito et al. (2008)
South African 0.990 0.810 Yes 0.130 0.620 Yes Williams et al. (2010)
South African 1.000 0.883 Yes 0.140 0.617 Yes Rautenbach et al. (2011)
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NA: not available; LOXL1: lysyl oxidase-like 1; XFS: exfoliation syndrome; XFG: exfoliation glaucoma.

The association between the ‘G’ risk alleles and XFS has been largely consistent across all tested populations. However there have been important exceptions. For example, the ‘G’ allele for rs1048661 was not significantly associated with XFG in an Indian (Ramprasad et al., 2008) and Chinese (Lee et al., 2009) population. Furthermore, the ‘G’ allele of rs1048661 was found to actually be protective in another Chinese population (Chen et al., 2009) and several Japanese populations (Fuse et al., 2008; Hayashi et al., 2008; Mabuchi et al., 2008; Mori et al., 2008; Ozaki et al., 2008; Tanito et al., 2008). The inconsistent association between XFG and rs1048661 was also observed for the intronic SNP, rs2165241 (Chen et al., 2010). For this reason, it was concluded that this SNP is not a functional variant for XFS/XFG.

The inconsistencies with rs1048661 and rs2165241 left the third SNP, rs3825942, as the most promising functional candidates for XFS. The rs3825942 SNP appeared to contribute to XFS for two reasons. First, similar to rs1048661, the ‘G’ allele for rs3825942 causes a missense change, G153D, in the LOXL1 protein, a change that may have functional consequences for the LOXL1 protein (Abu-Amero et al., 2010). Second, the ‘G’ allele of rs3825942 was strongly, and consistently, associated with XFS in a diverse set of populations. However, recently two reports have found that the opposite ‘A’ allele for rs3825942 is the risk allele in the South African black population (Williams et al., 2010; Rautenbach et al., 2011). Given the South African result, it now appears that rs3825942 does not contribute to XFS. It now appears most likely that these SNPs are in association with the actual functional allele (Williams et al., 2010). The LOXL1 coding sequence has now been completely sequenced in multiple populations with no consistent risk alleles emerging (Abu-Amero et al., 2010; Williams et al., 2010). Attention is now turning to non-coding, regulatory regions of LOXL1. These regions might contain functional variants that contribute to XFS/XFG.

4. Biochemical rationale for LOXL1 in XFS

Efforts have begun to understand how the pathogenesis of XFS could be influenced by LOXL1. LOXL1 is a member of the lysyl oxidase gene family, a group of enzymes involved in the synthesis and maintenance of elastic fibers (Csiszar, 2001; Kagan and Li, 2003). LOXL1 appears to be particularly important in the renewal of elastic tissues. This is supported by LOXL1’s strong colocalization with elastin in vivo and also by observations in LOXL1-knockout mice (Liu et al., 2004). These mice develop multiple abnormalities of elastic tissue that include lax skin, diverticula, enlarged airspaces, and prolapse of the rectum and pelvis. Female mice lacking LOXL1 initially have normal appearing elastic tissue; however, they are unable to deposit new elastic tissues after pregnancy and birth. Collectively, these data suggest that LOXL1 is responsible for targeted renewal of elastic fibers (Liu et al., 2004).

On a molecular level, LOXL1 appears to polymerize tropoelastin monomers into growing elastin polymers (Kagan and Li, 2003; Liu et al., 2004). To accomplish this, LOXL1 is first targeted to sites of elastogenesis by a pro-region located near its N-terminus (Thomassin et al., 2005). LOXL1 is then activated by removal of the pro-region by a proteinase. This cleavage activates a catalytic domain towards the C-terminus of LOXL1. Once activated, LOXL1 deaminates lysine residues in the tropoelastin molecule, allowing it to join the growing elastin polymer.

From the genetic studies cited above, it now appears that LOXL1 protein is involved in the pathogenesis of XFS, a disorder of elastic tissues (Schlotzer-Schrehardt, 2009). XFS fibrils also contain additional proteins involved in elastic fiber synthesis and structure (Ovodenko et al., 2007). In immunohistochemistry studies, XFS fibrils have been found to stain positively for the LOXL1 protein and its substrate tropoelastin (Schlotzer-Schrehardt et al., 2008). Interestingly, an important binding partner of LOXL1, fibulin-5, was absent in PEX deposits (Thomassin et al., 2005).

5. Altered LOXL1 expression is a possible pathological mechanism

Altered LOXL1 expression might contribute to the development of XFS. Current evidence suggests that LOXL1 expression is altered in XFG. In cadaveric ocular tissues, the expression of LOXL1 was found increased in early-stage XFS but decreased in late-stage XFS and in XFG (Schlotzer-Schrehardt et al., 2008). Subsequent studies regarding the expression of LOXL1 in XFS/XFG have had mixed results (Khan et al., 2010; Mori et al., 2008).

Several SNPs have been investigated for their effects on LOXL1 expression. Both coding SNPs identified in the initial GWAS were studied for effects on LOXL1 expression. The coding SNP rs1048661 is associated with altered expression of LOXL1. Its ‘G’ allele was associated with a 7.7% decrease of LOXL1 expression in adipose tissue (Thorleifsson et al., 2007) and approximately 20% in postmortem ocular tissue (Schlotzer-Schrehardt et al., 2008). In contrast, the most strongly associated SNP, rs3825942, was not associated with a net increase or decrease of LOXL1 expression in adipose or ocular tissue (Schlotzer-Schrehardt et al., 2008; Thorleifsson et al., 2007).

Another SNP, rs16958477, was found to alter LOXL1 expression in vitro (Ferrell et al., 2009). This SNP is located 659 base pairs upstream of LOXL1. It appears to influence the promoter activity of the one kilobase region upstream of LOXL1. Its ‘C’ allele was associated with increased promoter activity in a commercial plasmid. This SNP was originally investigated for a connection to pelvic organ prolapse but no significant correlation was observed (Ferrell et al., 2009). The SNP also did not associate with XFG in black South Africans (Williams et al., 2010). The ‘A’ allele did associate with XFS in a large Caucasian cohort with an OR 2.05 (1.54–2.72) (Jian Fan et al., 2011). However, this association was much weaker than rs3825942, which yielded an OR of 25 (8.3–50) in the same cohort.

Collectively, these data leave several questions about the role of expression in XFS and how to investigate it. First is the odd situation that there is no recognized correlation between the most-strongly associated variant, rs3825942, and LOXL1 expression. One possible explanation is that rs3825942, and any variant in LD with rs3825942, might alter expression patterns of LOXL1 without causing a net change of mRNA levels. Such a scenario could relate to the repeated observation that LOXL1 expression does not decrease until late in the pathogenesis of XFS and might actually be increased in early stages of XFS (Schlotzer-Schrehardt et al., 2008).

6. Other possible mechanisms for LOXL1 in XFS

The connection between LOXL1 and XFS could also possibly result from another mechanism that does not center on expression. One possibility is that a variant in the LOXL1 region could have an effect on LOXL1 splicing. Evidence now supports that a non-coding SNP can influence mRNA splicing (Tazi et al., 2009). For example, the dopamine D2 receptor gene carries two intronic SNPs that decrease the expression of one splice product (Zhang et al., 2007). There is some evidence to suggest that many GWAS associations for human traits may be the result of splicing effects (Heinzen et al., 2008). In the case of LOXL1, an intronic SNP might alter LOXL1 splicing. The LOXL1 intronic sequence has not been studied in previous reports, but it does contain at least one SNP, rs2165241, that is strongly associated with XFS in some populations (Jian Fan et al., 2011; Thorleifsson et al., 2007).

7. Other genes associated with XFS

Other genes appear to have a role in XFS and XFG. While LOXL1 variants associate strongly with XFS, the high-risk alleles are often found in older unaffected individuals (Table 1). This failure to develop XFS might partly result from other genes that influence XFS pathogenesis. Several other genes have been investigated. From these studies, a few possible population-specific risk factors have emerged (Schlotzer-Schrehardt, 2011).

A study in German patients looked at variants across six genes that appear to have a functional role in the pathogenesis of XFS (Krumbiegel et al., 2009). A total of 50 SNPs were genotyped across these genes. Of the 50, only one SNP was found to associate with XFS in the German cohort with an OR of 1.34. The SNP was located in the 8th intron of the clusterin (CLU) gene. This one variant was then tested in a second German cohort where it was still significant. However, in an Italian cohort, the SNP was not significant (Krumbiegel et al., 2009). It is possible that this allele has varying effects based on ethnic background. Other genes have been investigated because of a suspected role in the development of XFS or transition from XFS to XFG (Schlotzer-Schrehardt, 2011). To date, most investigations have found negative results. Significant associations have often been limited to studies in one population but not another (Schlotzer-Schrehardt, 2011).

A recent GWAS in German patients found an association with variants of the CNTNAP2 gene with risk of exfoliation (Krumbiegel et al., 2011). CNTNAP2 is a neuronal membrane protein that is expressed in numerous ocular tissues involved in XFS (Krumbiegel et al., 2011). This result was replicated in a second German cohort, with a combined odds ratio (OR) of about 1.4. However, CNTNAP2 was not associated with XFS in an Italian cohort (Krumbiegel et al., 2011). Therefore, it appears that CNTNAP2 may also be a population-specific risk factor.

8. Potential impact of LOXL1 variants on XFS management

Genetic screens for XFS are currently impractical due to the low-specificity of known risk alleles (Challa, 2009). For instance, in Caucasians, the rs3825942 risk allele has an 88% frequency in controls (Fingert et al., 2007). Effective risk screening will require the identification of new risk variants, either in the LOXL1 region or in other genes.

The LOXL1 region might carry more genetic information to aid in risk stratification. To date, most studies have focused on the missense variants, which alone do not allow for meaningful risk stratification. However, it appears that the LOXL1 region contains other SNPs that confer risk of XFS independently of the missense variants. For example, a promoter SNP identified in US Caucasians was found to increase of risk of XFS even when controlling for rs3825942 genotype (Jian Fan et al., 2011).

An understanding of all genetic contributions to XFS, both inside the LOXL1 region and in other genes, might allow for improved risk stratification. However, the impact of environmental factors and the influence of random chance might limit the predictive value of XFS risk variants. Only with a better understanding of both genetic and environmental contributions could accurate risk stratification be achieved. Even then, a screen for risk-variants might only be cost-effective in certain ethnicities.

Genetic insights might also aid in the treatment of XFG. A mechanism to explain the LOXL1-XFG association could allow for new targets for intervention. For example, XFG patients might benefit from increased LOXL1 expression since they tend to have reduced expression in the eye (Khan et al., 2010). More research might unveil additional targets for molecular interventions.

9. Conclusions

The LOXL1 region contains variants that are strongly associated with XFS and XFG. Previous risk allele reversals observed in Asian and African populations suggest that the functional variants near LOXL1 have not been identified. Identification of the functional variants near LOXL1 will allow for a comprehensive study of the mechanisms that underlie XFS and XFG. Such knowledge might impact the diagnosis and management of these conditions.

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