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Originally published In Press as doi:10.1167/iovs.08-1805 on April 30, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:3976-3980.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-1805
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Association of LOXL1 Gene Polymorphisms with Pseudoexfoliation in the Japanese

Mineo Ozaki,1,2 Kelvin Y. C. Lee,2,3 Eranga N. Vithana,2,3 Victor H. Yong,3 Anbupalam Thalamuthu,4 Takanori Mizoguchi,5 Anandalakshmi Venkatraman,3 and Tin Aung3,6

1From the Ozaki Eye Hospital and Dept of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; the 3Singapore Eye Research Institute and Singapore National Eye Centre, Singapore; the 4Genome Institute of Singapore, Singapore; the 5Mizoguchi Eye Clinic, Sasebo, Japan; and the 6Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
PURPOSE. The single nucleotide polymorphisms (SNPs) rs1048661, rs3825942, and rs2165241 within the LOXL1 gene were recently found to confer risk of pseudoexfoliation glaucoma (XFG) through pseudoexfoliation syndrome (XFS) in Caucasians. The purpose of this study was to test this association in Japanese subjects with XFS/XFG.

METHODS. Japanese subjects with clinically diagnosed XFS/XFG and normal control subjects were recruited. Genomic DNA was extracted and the three SNPs of the LOXL1 gene were genotyped by bidirectional sequencing. The association of individual SNPs with XFG/XFS was evaluated by using {chi}2 and the Fisher exact test.

RESULTS. Two hundred nine Japanese patients (106 XFG and 103 XFS) and 172 control subjects were studied. Strong associations were observed for all three SNPs of LOXL1 for XFS (odds ratio [OR] = 13.56, P = 3.39 x 10–28 for allele T of rs1048661; OR = 10.71, P = 1.49 x 10–7 for allele G of rs3825942; and OR = 4.55, P = 5.33 x 10–4 for allele C of rs2165241) and XFG (OR = 25.21, P = 1.44 x 10–34 for allele T of rs1048661; OR = 11.02, P = 1.40 x 10–7 for allele G of rs3825942; and OR = 11.89, P = 4.76 x 10–6 for allele C of rs2165241). The risk-associated alleles of rs1048661 and rs2165241 differed between the Japanese and Caucasians, whereas allele G of rs3825942 was associated with disease in both populations. Conditional analysis indicated that rs3825942 was not independent but correlated highly with rs1048661. The at-risk haplotype T-G-C was present at an approximately two times higher rate (94.7% vs. 50.6%, P = 4.22 x 10–43) in cases than in control subjects and conferred a 2.9-fold (95% confidence interval [CI], 2.357–3.464) increased likelihood of XFS.

CONCLUSIONS. Polymorphisms in the LOXL1 gene confer risk to XFS/XFG in the Japanese, but there are different risk-associated alleles and haplotypes in the Japanese.

Glaucoma, the leading cause of irreversible blindness in the world,1 is a group of heterogeneous disorders that result in progressive optic nerve damage and visual field loss. Pseudoexfoliation syndrome (XFS), a condition characterized by abnormal accumulation of microfibrillar deposits on the surfaces of the pupillary border of the iris, anterior lens capsule, ciliary body, zonular fibers, and anterior chamber angle,2 is the most common identifiable cause of open-angle glaucoma worldwide.3 The prevalence of XFS increases with age,4 and worldwide prevalence rates have been found to vary among populations. Nordic countries are reported to have the highest prevalence rates of XFS of up to 40%,5 compared with much lower prevalence rates in Anglo-Celtic Caucasians.4 6 7 The prevalence of XFS in the Japanese population has been reported to be from 0.8% to 3.2%.8 9

XFS is associated with ocular manifestations like cataract, zonular weakness, and secondary glaucoma (or pseudoexfoliation glaucoma [XFG]),10 as well as systemic associations such as aneurysms and vascular abnormalities.11 12 13 14 15 A report of a recent study indicated that the 15-year probability of XFS conversion to XFG is 44%.16 XFG is characterized by rapid progression of glaucomatous optic nerve damage, high resistance to medical therapy and a worse prognosis than primary open-angle glaucoma.17 The mechanical obstruction by pseudoexfoliative material from accumulation in the juxtacanalicular tissue (JCT), followed by endothelial cell dysfunction and disorganization of JCT and Schlemm’s canal have been postulated to be the causative factors in development of XFG.18 Family history is an important risk factor for both glaucoma and XFS, pointing to a role of genetic factors in the risk of these conditions.19

A recent study demonstrated that three single nucleotide polymorphisms (SNPs)—rs1048661 (R141L), rs3825942 (G153D), and rs2165241 (intronic)—located in the first exon of the LOXL1 gene on chromosome 15q24.1 confer risk of XFG secondary to XFS.20 The T allele of rs2165241 was associated with an odds ratio (OR) > 3 in XFG versus control subjects in two independent study groups (Iceland and Sweden). The two nonsynonymous SNPs rs1048661 and rs3825942 were also significantly associated with XFG (OR = 2.46 and 20.10, respectively). Recent studies in Caucasian patients from Iowa in the United States and Australia replicated the association of these two nonsynonymous SNPs with XFS.21 22

The purpose of our study was to confirm the association of these SNPs in the LOXL1 gene with XFS and XFG in Japanese patients from Kyushu, the southernmost of the four main islands of Japan.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Study Subjects
Japanese patients with clinically diagnosed XFS/XFG and normal Japanese control subjects were recruited from two hospitals in Kyushu, Japan. Written informed consent was obtained from all subjects, the study protocol had the approval of the hospitals’ ethics committee, and it was performed according to the tenets of the Declaration of Helsinki.

All subjects underwent detailed ophthalmic examination by ophthalmologists, including slit lamp biomicroscopy examination, gonioscopy, dilated pupil examination of the lens and funduscopy, and slit lamp photography. Subjects with XFS were defined as those with clinical and photographic evidence of pseudoexfoliation in the pupil margin, anterior lens surface, or other anterior segment structures, with intraocular pressure (IOP) less than 21 mm Hg and no clinical evidence of glaucomatous optic neuropathy. Subjects with XFG were defined as those with clinical evidence of XFS and glaucomatous optic neuropathy (defined as loss of neuroretinal rim with a vertical cup-to-disc ratio of >0.7) with compatible visual field loss. Japanese subjects with normal anterior segment and optic nerve examination and without clinical signs of XFS/XFG were recruited as control subjects.

Genotyping
Genomic DNA was extracted from peripheral white blood cells of all subjects. Three SNPs in the LOXL1 gene—rs2165241, rs1048661, and rs3825942—were amplified by polymerase chain reaction (PCR; model 9700 thermocycler; Applied Biosystems [ABI], Foster City, CA). PCR reactions were performed in 50-µL volumes containing 10 mM Tris HCl (pH 8.9), 50 mM KCl, 1.5 mM MgCl2, 25 picomoles of each primer, 200 µM each dNTP, 50 to 100 ng of patient genomic DNA, and 0.7 units of Taq thermostable DNA polymerase (Promega, Madison, WI). Cycling parameters were 3 minutes at 95°C, followed by 35 cycles of 30 seconds at 95°C, 30 seconds at the melting temperature (Tm) of the primers (52°C–62°C), and 30 seconds to 1 minute at 72°C with a final 5-minute extension at 72°C. The products were purified with PCR clean-up columns (GFX; GE Healthcare, Piscataway, NJ). Sequence variations were identified by automated bidirectional sequencing (BigDye terminator ver. 3.1 chemistries; ABI). An automated DNA sequencer (Prism 3100; ABI) was used. Primers for sequence reactions were the same as those for the PCR reaction.

Statistical Analysis
The Fisher exact test was used to test the allelic and genotypic associations of all the SNPs with XFG and XFS. Conditional analysis using logistic regression was performed to examine the independent effect of an SNP conditional on another SNP. Hardy-Weinberg equilibrium (HWE) of the genotypic frequencies among cases and separately among the control subjects was also examined. The analyses were performed with the R23 and PLINK24 software programs. Haploview was used to compute linkage disequilibrium (LD) statistics.25 Haplotype association analysis was performed using the software package WHAP.26 Joint associations of all the haplotypes and haplotype-specific and sole variant associations were performed using this program. Haplotype-specific test of association is used to examine the independent effect of any specific haplotype. For this test, under the null model none of the haplotypes is used and under the alternative model the specific haplotype effect is entered. A likelihood ratio test is then constructed to assess the significance of the haplotype-specific effect. When the global test is found to be significant, a sole-variant test of a specific haplotype can be performed to examine the contribution of this haplotype to the global association. This test examines the effect of all the other haplotypes excluding the one under consideration. Additional details regarding the haplotype associations implemented in the program can be found within cited reference articles.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Two hundred nine Japanese patients with pseudoexfoliation (103 XFS and 106 XFG) and 172 Japanese control subjects were recruited in the study. The mean age of the patients (XFG and XFS) was 78.0 ± 6.1 years (range, 60–91) and that of the normal control subjects was 73.8 ± 7.9 years (range, 44–93). The demographic characteristics of the study population are shown in Table 1 .


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  		TABLE 1. Demographic Features of Study Subjects

 
The distribution of the allele frequencies for SNPs rs2165241, rs1048661, and rs3825942 within the LOXL1 gene are given in Table 2 . The genotype frequencies in control subjects were in HWE. The genotype frequencies of the SNPs rs3825942 and rs2165241 were also in HWE in the combined, XFG, and XFS, groups. However, there was a slight departure from HWE expectations in the observed genotype frequencies for SNP rs1048661, in the combined (P = 8.863 x 10–5), XFG (P = 0.009), and XFS cases (P = 0.0097). This deviation does not indicate a problem with genotyping or population structure but most likely indicates an association between this marker and disease susceptibility. Previous work has shown that deviation from HWE in affected individuals may be indicative of the presence of susceptibility loci.27 28


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  		TABLE 2. Distribution of LOXL1 Alleles in Pseudoexfoliation and Control Subjects

 
The SNPs showed significant association with XFG (OR = 25.21, P = 1.44 x 10–34 for allele T of rs1048661; OR = 11.02, P = 1.40 x 10–7 for allele G of rs3825942; and OR = 11.89, P = 4.76 x 10–6 for allele C of rs2165241). In the XFS group, OR = 13.56, P = 3.39 x 10–28 for allele T of rs1048661; OR = 10.71, P = 1.49 x 10–7 for allele G of rs3825942; and OR = 4.55, P = 5.33 x 10–4 for allele C of rs2165241 were observed. When the data were analyzed for the combined group, the association was stronger with OR = 17.79, P = 6.41 x 10–48 for allele T of rs1048661. Of interest, the risk-associated allele of rs1048661 and rs2165241 differed between our Japanese study and the original Icelandic study.20 The G allele of rs1048661 that was associated with the risk of XFG in the Icelandic population was present at a much lower frequency at 5.3%, in our combined sample set that included individuals with XFS with and without glaucoma. In several studies, XFS and XFG have been reported to be more prevalent in the women than in the men. Accordingly, more affected Japanese women were also investigated in our study. However, the allele frequencies of SNPs rs1048661, rs3825942, and rs2165241 did not differ significantly between the sexes in the combined sample set that included individuals with XFS with and without glaucoma (Table 3) .


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  		TABLE 3. Sex-Specific Allelic Distributions for LOXL1 Variants in Subjects with Pseudoexfoliation

 
We used step-wise logistic regression to determine the independence of the two nonsynonymous SNPs in their effect on disease (Table 4) . With conditioning on rs1048661, rs3825942 was found not to be significantly associated with disease, indicating that rs3825942 is not independent but is highly correlated with rs1048661. However, with conditioning on rs3825942, rs1048661 remained associated with disease risk (P = 1.67 x 10–20) indicating that rs1048661 (or another perfect proxy) accounts for the association signal observed at this locus.


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  		TABLE 4. Conditional Association between LOXL1 Variants and Pseudoxfoliation Syndrome

 
Pair-wise LD analysis also showed that the two nonsynonymous SNPs rs1048661 and rs3825942 were in strong LD with each other (D' = 1; 95% confidence interval [CI], 0.8–1.0). Haplotype analysis using rs2165241, rs1048661, and rs3825942 revealed only four different haplotypes, after the rare haplotypes were removed with frequencies less than 1% among the patient and control individuals. The estimated haplotype frequencies are presented in Table 5 . Each haplotype was significantly associated with pseudoexfoliation (with and without glaucoma) either as a protective or an at risk haplotype. The at-risk haplotype T-G-C (P = 4.22 x 10–43) was present approximately two times higher (94.7% vs. 50.6%) in cases than control subjects and conferred a 2.9 (95% CI, 2.357–3.464) fold increased likelihood of XFS. The three other haplotypes that did not contain the risk allele T of rs1048661 were all protective against XFS, despite some containing the risk allele G of rs3825942 (Table 5) . Furthermore, the sole-variant test for the haplotype T-G-C gave a P > 0.5, which suggests that this is the only risk haplotype. For the other three haplotypes, the P for the sole-variant tests was found to be highly significant, indicating that they do not confer independent risk of the disease.


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  		TABLE 5. Haplotype Analysis of LOXL1 Polymorphisms in Pseudoexfoliation and Control Subjects

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
In this study, we confirmed the findings of Thorleifsson et al.20 that the three variants within LOXL1 gene are strongly associated with both XFG and XFS. In our Japanese cohort, the T allele of rs1048661, the observed SNP with the strongest association, conferred a 25.2-fold increased risk of XFG. The population-attributable risk (PAR) for this variant as estimated from the combined sample cohort was 90%.

Of note, the risk-associated alleles of rs1048661 and rs2165241 differed in the Japanese subjects (T and C alleles, respectively) in this study and in the Caucasian and Icelandic populations (G and T alleles, respectively), whereas allele G of rs3825942 was associated with disease in all populations. Hayashi et al.29 also reported an association of LOXL1 SNPs rs1048661 and rs3825942 with XFS in the Japanese population and observed a low frequency of the G allele of rs1048661 (0.8%). Taken together, the evidence suggests that rs3825942 within LOXL1 is the source of the association of LOXL1 with XFS. The independent origin of the rs3825942 (G153D) variant on different genetic backgrounds may explain the difference in alleles flanking the causal G allele of rs3825942 in the Asian and Caucasian populations. Alternatively, this SNP may have arisen much earlier and could be an ancient mutation, with recombination events around this region resulting in the different flanking alleles and frequencies observed in the Caucasian and Japanese populations. However, our conditional analysis showed that rs3825942 is not independent, but correlates highly with rs1048661. This finding was further supported by the haplotype analysis, which showed that haplotypes without the T allele of rs1048661 were all protective against XFS, despite some containing the risk allele G of rs3825942. Therefore, we cannot rule out the possibility that another variant, in strong LD with both these variants, may be the causal variant of XFS at this locus.

The LOXL1 gene is a member of the lysyl oxidase family of proteins that catalyzes oxidative deamination of lysine residues of tropoelastin, which leads to their spontaneous cross-linking with consequential formation of elastin polymer fibers.30 31 Expression of LOXL1 in the anterior segment of the eye has been demonstrated with RT-PCR and Western blot analysis.21 Several studies have demonstrated that the LOXL1 propeptide binds to both tropoelastin and fibulin-5 and that these interactions are essential for directing the deposition of the enzyme onto elastic fibers.30 32 The product of the LOXL1 gene modifies elastin fibers that are a major constituent of the intraocular lesions in XFG. The two coding SNPs, rs1048661 and rs3825942, lead to an amino acid change at position 141 (Arg to Leu) and 153 (Gly to Asp) respectively, both located at the N-terminal propeptide. It is noteworthy that these alterations or mutations, which could affect both the catalytic activity of the protein through modifications of propeptide cleavage and binding to substrates such as tropoelastin and fibulin-532 are protective against XFG in Nordic and Caucasian populations and that the common ancestral wild-type allele at each SNP is associated with disease.20 21 22 In the Japanese however, the "mutant" T allele of rs1048661 is associated with disease. Despite these conflicting individual allelic associations, the T-G haplotype for rs1048661 and rs3825942 has been shown to be a risk haplotype in both Nordic and Japanese populations.20 29 Therefore an investigation should compare the properties (i.e., catalytic activity and stability) of the resultant protein isoform (141Leu-Gly153) relative to the wild-type form (141Arg-Gly153) to explore fully how it may lead to the chronic accumulation of abnormal fibrillar material and the XFS phenotype.

In summary, we have demonstrated the association of LOXL1 with XFS and XFG in our population of Japanese patients. Of the three SNPs in LOXL1, only the G allele of rs3825942 (G153D) has been shown to be highly associated in XFS/XFG in the Japanese and Caucasians. However, the three SNPs analyzed in this study could still be proxy to the real causal variation in LOXL1 that is yet to be discovered. We propose that a detailed sequence comparison of the entire LOXL1 gene, inclusive of its intronic and promoter sequences, be performed in affected and unaffected individuals and also that individuals from populations that show less extensive LD be examined, to identify the causative variants within LOXL1.


   Footnotes
 
2 Contributed equally to the work and should be considered equivalent authors. Back

Supported by a grant from the Singapore Eye Research Institute.

Submitted for publication January 28, 2008; revised March 17, 2008; accepted June 20, 2008.

Disclosure: M. Ozaki, None; K.Y.C. Lee, None; E. N. Vithana, None; V.H. Yong, None; A. Thalamuthu, None; T. Mizoguchi, None; A. Venkatraman, None; T. Aung, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Tin Aung, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751; tin11{at}pacific.net.sg.


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 Abstract
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