Evaluation of LOXL1 polymorphisms in eyes with exfoliation glaucoma in Japanese.

Abstract

To investigate the lysyl oxidase-like 1 (LOXL1) gene for single nucleotide polymorphism (SNP) variations in Japanese patients with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) and to examine the phenotypes of the patients with these variations.
Fifty-six unrelated Japanese patients with XFS, including 36 patients with XFG, were studied. Genomic DNA was extracted from the leukocytes of peripheral blood, and three SNPs (rs1048661; p.Arg141Leu, rs3825942; p.Gly153Asp, and rs2165241) were identified. These SNPs were amplified by polymerase chain reaction (PCR), directly sequenced, and genotyped.
Two nonsynonymous variants in exon 1 of LOXL1,rs1048661 and rs3825942, were found to be strongly associated with XFS including XFG. The frequency of the T allele (0.964) in rs1048661 in eyes with XFS was much higher in controls (0.507) with a p value of 7.7x10(-18). The odds ratio for the T allele in rs1048661 was 26.0 (95% confidence interval, 18.3-37.1). In the haplotype analysis, T-G was overrepresented in XFS subjects (p=7.7x10(-18)), showing a highly significant difference in frequency between primary open-angle glaucoma (POAG) and the control group (p=0.07), but the G-G and G-A haplotypes were less represented in XFS subjects (p=1.1x10(-11) and p=1.0x10(-4), respectively). However, an earlier study reported the strongest associated SNP with XFS and XFG, rs2165241, showed no association.
SNPs of LOXL1 (rs1048661; Arg141Leu and rs3825942; Gly153Asp) are highly associated with XFS in the Japanese population. However, unidentified genetic or environmental factors independent of LOXL1 will most likely influence the phenotypic expression of the syndrome.

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Evaluation of LOXL1 polymorphisms in eyes with exfoliation
glaucoma in Japanese
Nobuo Fuse, Akiko Miyazawa, Toru Nakazawa, MingGe Mengkegale, Takaaki Otomo, Kohji Nishida
(The first two authors contributed equally to this publication.)
Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan
Purpose: To investigate the lysyl oxidase-like 1 (LOXL1) gene for single nucleotide polymorphism (SNP) variations in
Japanese patients with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) and to examine the phenotypes of
the patients with these variations.
Methods: Fifty-six unrelated Japanese patients with XFS, including 36 patients with XFG, were studied. Genomic DNA
was extracted from the leukocytes of peripheral blood, and three SNPs (rs1048661; p.Arg141Leu, rs3825942;
p.Gly153Asp, and rs2165241) were identified. These SNPs were amplified by polymerase chain reaction (PCR), directly
sequenced, and genotyped.
Results: Two nonsynonymous variants in exon 1 of LOXL1, rs1048661 and rs3825942, were found to be strongly
associated with XFS including XFG. The frequency of the T allele (0.964) in rs1048661 in eyes with XFS was much
higher in controls (0.507) with a p value of 7.7x10−18. The odds ratio for the T allele in rs1048661 was 26.0 (95% confidence
interval, 18.3–37.1). In the haplotype analysis, T-G was overrepresented in XFS subjects (p=7.7x10−18), showing a highly
significant difference in frequency between primary open-angle glaucoma (POAG) and the control group (p=0.07), but
the G-G and G-A haplotypes were less represented in XFS subjects (p=1.1x10−11 and p=1.0x10−4, respectively). However,
an earlier study reported the strongest associated SNP with XFS and XFG, rs2165241, showed no association.
Conclusions: SNPs of LOXL1 (rs1048661; Arg141Leu and rs3825942; Gly153Asp) are highly associated with XFS in
the Japanese population. However, unidentified genetic or environmental factors independent of LOXL1 will most likely
influence the phenotypic expression of the syndrome.
Exfoliation syndrome (XFS; OMIM 177650) is a
generalized disorder of the extracellular matrix characterized
clinically by the pathological accumulation of abnormal
fibrillar material in the anterior segment of the eye
predisposing the eye to glaucomatous optic neuropathy [1-3].
XFS has also been associated with weakness of the lens zonule
fibers, severe chronic open-angle glaucoma, cataract
formation, and a spectrum of other serious spontaneous
intraocular defects. There is also evidence that XFS is
associated with cardiovascular and cerebrovascular morbidity
[2,4,5].
The prevalence of XFS varies markedly among
populations and is highest in the Scandinavian population and
markedly lower in Anglo-Celtic Caucasians [6-9]. The
prevalence increases with age and is highest between 70 and
80 years of age [7]. Forty percent of Icelandic individuals 80
years or older in the Reykjavik Eye Study [10] and 22% of the
population 70 years or older in the Finnish population were
found to have XFS [11]. In the Japanese, the prevalence of
XFS is reported to be between 1.1% (XFS with and without
Correspondence to: Dr. N. Fuse, Department of Ophthalmology,
Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi,
Aoba-ku, Sendai, Miyagi, 980-8574, Japan; Phone: 81-22-717-7294;
FAX: 81-22-717-7298; email: fusen@oph.med.tohoku.ac.jp
glaucoma, and glaucoma suspected of those over 40 years) to
4.8% (XFS with and without glaucoma, and glaucoma
suspected of those over 80 years), which is much lower than
the prevalence in the Scandinavian population [12,13].
Thorleifsson et al. [14] established a strong association
between single nucleotide polymorphisms (SNPs) in the lysyl
oxidase–like 1 (LOXL1) gene and XFS in the Swedish and
Icelandic populations using a genome-wide scan. They
identified two nonsynonymous
Arg141Leu and rs3825942; Gly153Asp) in exon 1 and one
intronic SNP (rs2165241) in LOXL1, which conferred an
attributable risk of 99% to Icelandic and Swedish individuals
[14]. This association was recently confirmed in United States
[15-17], Australian [18], and South Indian populations [19].
In addition, the SNPs, rs1048661 and rs3825942, of LOXL1
seem to be highly associated with XFS in the Japanese
population [20].
SNPs (rs1048661;
LOXL1 is a member of the lysyl oxidase family of
proteins that catalyzes the oxidative deamination of lysine
residues of tropoelastin [21]. Elastic fiber homeostasis
requires lysyl oxidase-like 1 protein [22], and this family of
proteins has important roles in elastogenesis. Thus, it is
biologically reasonable that defects in LOXL1 may cause
features of XFS because of the aberrant production of elastin
Molecular Vision 2008; 14:1338-1343 <http://www.molvis.org/molvis/v14/a161>
Received 9 April 2008 | Accepted 14 July 2008 | Published 21 July 2008
© 2008 Molecular Vision
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and accumulation of fibrillar material in the anterior segment
of the eye.
The purpose of this study was to investigate the lysyl
oxidase-like 1 (LOXL1) gene for SNP variations in Japanese
patients with XFS including those with exfoliation glaucoma
(XFG) and compare them to patients with primary open-angle
glaucoma (POAG) as well as to examine the phenotypes of
the patients with these variations.
METHODS
Patients: Fifty-six unrelated Japanese patients with XFS (31
men and 25 women; mean age 74.75±6.15 years) including
36 (23 men and 13 women) patients with XFG were studied.
All of the patients resided in the northern part of Japan and
were examined at the Ophthalmic clinic of the Tohoku
University Hospital (Sendai, Japan). The purpose and
procedures were explained to all patients, and an informed
consent was obtained from each of them. This study was
approved by the Tohoku University Institutional Review
Board, and the procedures conformed to the tenets of the
Declaration of Helsinki. Routine ophthalmic examinations
were performed on all patients.
The criterion used for classifying a patient as having XFS
was an open anterior chamber angle with accumulation of
abnormal fibrillar material in the anterior segment of the eye.
Patients who were diagnosed with XFG met the criterion of
XFS and also had 1) applanation intraocular pressure (IOP)
greater than 22 mmHg in each eye, 2) glaucomatous cupping
in each eye including a cup-to-disc ratio greater than 0.7, and
3) presence of visual field defects determined by Goldmann
perimetry and/or Humphrey field analyzer consistent with the
glaucomatous cupping in at least one eye. The mean IOP at
diagnosis was 35.0±12.0 mmHg in the 36 patients with XFG
and 17.9±6.7 mmHg in the 20 patients with XFS but without
glaucoma. Control subjects (76 men and 62 women; mean age
68.0±7.7 years) had the following characteristics 1) no
accumulation of abnormal fibrillar material in the anterior
segment of the eye, 2) IOP less than 22 mmHg, 3) normal optic
discs, and 4) no family history of glaucoma. The mean IOP at
the initial examination was 14.3±3.4 mmHg in the138 control
patients.
Genomic DNA was extracted from peripheral blood
leukocytes and purified with the Qiagen QIAamp Blood Kit
(Qiagen, Valencia, CA), and the three SNPs (rs1048661,
rs3825942, and rs2165241) were amplified by polymerase
chain reaction (PCR), directly sequenced, and genotyped. For
PCR, two primer sets (for rs1048661 and rs3825942 in exon
1: 5'-CTC AGC GCT CCG AGA GTA G-3' and 5'-ACA CGA
AAC CCT GGT CGT AG-3'; for rs2165241 in intron 1: 5'-
ACC AGG TAC TTG CAG CAT CC-3' and 5'-TGC TTG
CCT AAT CAC AGC AC-3') were used under standard PCR
conditions. The amplifications were performed at 60° C
annealing temperature for the two SNPs in exon 1 and 58° C
annealing temperature for the two SNPs in intron 1. The PCR
fragments were purified by ExoSAP-IT (USB, Cleveland,
OH) and sequenced by the BigDyeTM Terminator Cycle
Sequencing Ready Reaction Kit (Perkin-Elmer, Foster City,
CA) on an automated DNA sequencer (ABI PRISMTM 3100
Genetic Analyzer, Perkin-Elmer).
The allelic frequencies, genotypes, and haplotypes of the
patients with the LOXL1 SNPs were determined. The allelic
and genotypic frequencies were compared with two-tailed p
values using χ2 analyses.
Statistical analysis: The χ2 test, depending on cell counts, was
used to determine if the genotype frequency differences
between the cases and controls were significant. Odds ratios
(approximating to relative risk) were calculated as a measure
of the association between the LOXL1 genotype and the
phenotype of XFS. For each odds ratio, the p values and 95%
confidence intervals were calculated. The inferred haplotypes,
quantified between all pairs of biallelic loci, were estimated
using the SNPAlyze program version 4.0 (Dynacom,
Yokohama, Japan). Additionally, a permutation test was
performed to test the deviation of allelic frequencies of SNPs
and haplotypes [23]. The significance of the association was
determined by contingency table analysis using the χ2 test. The
Hardy–Weinberg equilibrium was analyzed using gene
frequencies obtained by simple gene counting and the χ2 test
with Yates' correction for comparing observed and expected
values.
RESULTS
The allelic frequencies, genotypes, and haplotypes of the three
LOXL1 SNPs (rs1048661, p.Arg141Leu; rs3825942,
p.Gly153Asp; and rs2165241 in intron 1) were determined in
the cohort of subjects from the northern region of Japan.
Distribution of LOXL1 variants in exfoliation syndrome
patients and control subjects: The T allele of the rs1048661
SNP was detected at a significantly higher frequency in
patients with XFG and XFS without glaucoma than in the
control subjects (p=1.7x10−12 and p=1.5x10−8, respectively;
Table 1). Similarly, all of the XFS subjects had the G allele of
rs3825942 SNP. The G allele was also associated with XFG
and XFS without glaucoma (p=5.2x10−3 and p=0.027,
respectively).
The genotypic frequencies for each of the two LOXL1
SNPs were compared between XFS patients and control
subjects (Table 2). The frequency of the T/T variant in the
rs1048661 SNP was significantly higher in XFS patients than
in control subjects (94.6% versus 21.7%), but the frequency
of the T/G variant was significantly lower in the XFS patients
than control subjects (3.6% versus 58.0%; p=1.6x10−19).
There was no statistical difference between patients with
POAG and control subjects.
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All of the patients with XFS had the G/G variant of
rs3825942, which was higher in the XFS patients than in the
control subjects (100% versus 78.3%; p=7.5x10−4). There was
no significant difference between POAG patients and control
subjects.
Interestingly, there was no statistically significant
difference between XFS and XFG patients in the allelic
frequencies of rs1048661 (p>0.05), and all the genotypes for
rs3825942 were G-G in both XFS and XFG patients (Table
1). The strongest association of the SNPs with XFS was for
the T allele of rs2165241, as in the original report [14].
However, there was no statistical difference between XFS,
XFG, and controls in the allelic frequency of rs2165241
(Table 2). All SNPs adhered to the Hardy–Weinberg
expectations (p>0.05).
Haplotype analysis of LOXL1 in the Japanese
population: The inferred haplotypes between all pairs of
biallelic loci were estimated (Table 3). Two SNPs, rs1048661
and rs3825942, were significantly associated with XFS
(p<0.05). The haplotype-based associations were tested with
a 1,000 iterated permutation test. Three major haplotypes, G-
G, T-G, and G-A (each frequency greater than 5%), were
found in the subjects, but the T-A haplotype was not found
(Table 3). The T-G haplotype was overrepresented in all XFS
patients, XFG patients, and XFS patients that did not have
glaucoma (p=7.7x10−18, p=1.7x10−12, and p=1.5x10−8,
respectively), showing a highly significant difference in
frequency from the POAG and control groups, but the G-G
and G-A haplotypes were less represented in all XFS patients,
XFG patients, and XFS patients without glaucoma (Table3).
Phenotypes of exfoliation glaucoma patients in our
population: The phenotypes of our 36 XFG patients were high
IOP (35.0±12.0 mmHg), poor response to topical medication
(number of eye drops; 2.4±0.4 bottles), aggressive course
without treatment, and moderate response to filtration
surgery. Among the XFS subjects, only one patient, a 76-year-
old man with XFG, had a unique haplotype of G-G.
TABLE 1. LOXL1 ALLELIC FREQUENCIES OF RS1048661 AND RS3825942 IN JAPANESE PATIENTS WITH EXFOLIATION SYNDROME AND CONTROLS.
SNPp.R141L (rs1048661 G/T)
Odds ratio
(95%CI)
p value p.G153D (rs3825942 G/A)
Odds ratio
(95% CI)
p value
AlleleTGGA
Japanese population in this study
XFS all (n=56) 0.9640.036 26.0
(18.3–37.1)
7.7x10−18
10-4.1x10−4
XFG (n=36) 0.9580.042 22.2
(15.9–30.9)
1.7x10−12
10-5.2x10−3
XFS no glaucoma
(n=20)
0.9750.025 37.9
(25.0–57.5)
1.5x10−8
10-0.027
POAG (n=62) 0.6050.395 1.49
(1.25–1.78)
0.11 0.911
(1.07–1.91)
0.089 1.43 0.37
Control (n=138) 0.507 0.493 0.8770.123
Japanese population in the Western Japanesestudy*
XFS all (n=59)
XFG (n=27)
XFS no glaucoma(n=32) 0.984
Control (n=189)
0.992
1
0.008 N/A 3.0x10−19
0 N/A 1.1x10−10
0.016 N/A 1.7x10−11
0.46
1
1
1
0
0
0
-
-
-
1.4x10−5
3.0x10−3
1.3x10−3
0.54 0.8570.143

Icelandic population**
XFG (n=75)0.1730.827 2.56
(1.74–3.77)
1.8x10−6
0.987
(5.59–31.29)
0.013 13.234.1x10−9
XFS no glaucoma
(n=55)
POAG (n=90)
0.2110.789 2.02
(1.32–3.09)
1.3x10−3
0.982
(4.02–25.36)
0.8720.128 1.25
(0.81–1.91)
0.8470.153
0.018 10.108.5x10−7
0.2890.711 1.32
(0.96–1.82)

0.0850.32
Control (n=14,474) 0.3490.651

The single asterisk indicates the data were reported by Hayashi et al. [20], and the double asterisk denotes that the data were
reported by Thorleifsson et al. [14]. The significance of the association was determined by a contingency table analysis
using the χ 2 test. CI=confidence interval; N/A=Not applicable in the original report.
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DISCUSSION
We confirmed the findings of Thorleifsson and colleagues
[14] that two coding SNPs in LOXL1 were strongly associated
with XFS in our Japanese population. In recent studies, the
frequencies of LOXL1 SNP alleles, genotypes, and haplotypes
detected in cohorts in Iowa and Australian were remarkably
similar to those reported in Scandinavian populations [15,
18]. The G allele of each of the LOXL1 SNPs was highly
associated with XFS, and the risk for disease in those
populations was associated most strongly with the G-G
haplotype.
However, the distribution of the rs1048661 alleles and
haplotypes in patients were quite different between
Scandinavian, Australian, American, and Japanese subjects.
In the Northern Japanese in this study, the T allele of the
rs1048661 SNP was dominant in controls, and more than 90%
of XFS subjects had the T allele. These results reconfirmed
the previous study in the Japanese population derived from
the western part of Japan [20]. The frequency and position of
the SNPs are different among various populations. So, it is
difficult to apply the genome information of a polymorphism
of Caucasians to that of East Asians. However, as for the
Japanese population, the genetic background is homogeneous,
and Table 1 showed the similarity between the Japanese
population.
In general, Japanese patients with XFG associated with a
LOXL1 SNP show late-onset of glaucoma after 65 years of
age. XFG would be a relatively uncommon age-related
disease characterized by a generalized fibrillar degeneration
of elastin-containing tissues. In our study, the age at onset was
mainly older than 60 years of age (two case showed an onset
of 55 and 58 years). The phenotypes of our XFG patients with
the two variants were high IOP, poor response to topical
medication, aggressive course without treatment, and
probably moderate response to filtration surgery.
Recently, the most promising locus for diagnosing XFS
was assigned to 18q12.1–21.33, and the susceptible loci were
proposed to be 2q, 17p, and 19q in the Finnish population in
TABLE 2. FREQUENCY OF GENOTYPES, P.R141L, P. G153D, AND RS2165241, OF LOXL1 IN PATIENTS WITH
XFS, XFG, AND CONTROLSUBJECTS.
XFS all XFG XFS no
glaucoma(n=20)
(n=56)Genotype
POAG Control
(n=138)
(n=62)
LOXL1 p.R141L (rs1048661) variant
T/T
T/G
G/G
p value*
53 (94.6%)
2 (3.6%)
1 (1.8%)
1.6x10−19
34 (94.4%)
1 (2.8%)
1 (2.8%)
7.8x10−15
19 (95.0%)
1 (5.0%)
0
3.0x10−10
23 (37.1%)
29 (46.8%)
10 (16.1%)
0.15
30 (21.7%)
80 (58.0%)
28 (20.3%)
LOXL1 p.G153D (rs3825942) variant
G/G
G/A
A/A
p value*
56 (100%)
0
0
7.5x10−4
36 (100%)
0
0
8.8x10−3
20 (100%)
0
0
0.068
51 (82.3%)
11 (17.7%)
0
0.58
108 (78.3%)
26 (18.8%)
4 (2.9%)
LOXL1 rs2165241variant
C/C
C/T
T/T
54(96,4%)
2(3.6%)
0
0.08
34(94.4%)
2(5.6%)
0
0.29
20(100%)
0
0
0.11
56(91.3%)
6(9.7%)
0
0.69
122(88.4%)
16(11.6%)
0
p value*
The asterisk indicates that the significance of the association was determined by a contingency table analysis using the χ2 test.
TABLE 3. LOXL1 HAPLOTYPES IN PATIENTS WITH EXFOLIATION SYNDROMEAND IN CONTROLS.
rs1048661
-rs3825942
Haplotype
XFS all
(n=56)
p valueXFG (n=36)p value XFS no glaucoma
(n=20)
p value POAG (n=62) p valueControl (n=138)
G-G
T-G
G-A
0.0357
0.9643
0
1.1x10−11
7.7x10−18
1.0x10−4
0.0417
0.9583
0
4.1 x10−8
1.7x10−12
1.7x10−3
0.025
0.975
0
1.0 x10−5
1.5 x10−8
0.02
0.3115
0.5984
0.0902
0.21
0.07
0.34
0.3768
0.5
0.1232
The inferred haplotypes, quantified between all pairs of biallelic loci, were estimated using the SNPAlyze program version 4.0
(Dynacom, Yokohama, Japan).
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an autosomal dominant mode of inheritance with incomplete
penetrance [24]. In a microarray study, it was reported that the
differentially expressed genes with a high level of
reproducibility in patients with XFS were mainly related to
extracellular matrix metabolism and cellular stress [25].
Hewitt et al. [18] described a remarkably similar LOXL1
allelic architecture in the Blue Mountains Eye Study (BMES)
where XFS is a relatively uncommon disease compared to that
in Australia and to that of the Nordic population in which the
XFS is extremely common. This strongly suggests that an as
yet unidentified genetic or environmental factor independent
of LOXL1 strongly influences the phenotypic expression of
the syndrome.
High risk LOXL1 haplotypes account for a significant
fraction of patients with XFS and thus may be useful in genetic
screening tests. However, because many patients that carry
LOXL1 risk alleles do not have XFS, genetic testing for these
alleles may be of limited usefulness at present. An unaffected
control group with the highest risk diplotype (50%) would be
expected to contain affected but not yet diagnosed individuals
with XFS. Identification of XFS-associated SNPs of such
magnitude that is clearly identifiable will allow early
detection even before elevation of IOP at a later age or
irreversible visual impairment due to damage of the optic
nerve. More studies of the functions and genotype-phenotype
correlation of LOXL1 are required to determine the
pathophysiology of XFS, and more studies such as meta-
analysis with a greater number of subjects would be needed
to confirm these genetic data.
ACKNOWLEDGMENTS
This study was supported in part by a Grant-In-Aid for
Scientific Research from the Ministry of Education, Science,
and Culture of the Japanese Government (N.F.; C-18591905),
Tokyo, Japan. This study was supported by a grant to N.F.
from the Suda Memorial Fund for Glaucoma Research. The
authors thank Dr. Takashi Shiono, Dr. Yoshihiko Imai, Dr.
Sei-ichi Watanabe, and Dr. Kumiko Sato for collecting the
samples. The authors thank Dr. Duco I. Hamasaki for editing
the manuscript.
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