Fan, B. J., Pasquale, L., Grosskreutz, C. L., Rhee, D., Chen, T., Deangelis, M. M. 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. 9, 5

Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.
BMC Medical Genetics (Impact Factor: 2.08). 02/2008; 9(1):5. DOI: 10.1186/1471-2350-9-5
Source: PubMed


Pseudoexfoliation syndrome is a major risk factor for glaucoma in many populations throughout the world. Using a U.S. clinic-based case control sample with broad ethnic diversity, we show that three common SNPs in LOXL1 previously associated with pseudoexfoliation in Nordic populations are significantly associated with pseudoexfoliation syndrome and pseudoexfoliation glaucoma.
Three LOXL1 SNPs were genotyped in a patient sample (206 pseudoexfoliation, 331 primary open angle glaucoma, and 88 controls) from the Glaucoma Consultation Service at the Massachusetts Eye and Ear Infirmary. The SNPs were evaluation for association with pseudeoexfoliation syndrome, pseudoexfoliation glaucoma, and primary open angle glaucoma.
The strongest association was found for the G allele of marker rs3825942 (G153D) with a frequency of 99% in pseudoexfoliation patients (with and without glaucoma) compared with 79% in controls (p = 1.6 x 10-15; OR = 20.93, 95%CI: 8.06, 54.39). The homozygous GG genotype is also associated with pseudoexfoliation when compared to controls (p = 1.2 x 10-12; OR = 23.57, 95%CI: 7.95, 69.85). None of the SNPs were significantly associated with primary open angle glaucoma.
The pseudoexfoliation syndrome is a common cause of glaucoma. These results indicate that the G153D LOXL1 variant is significantly associated with an increased risk of pseudoexfoliation and pseudoexfoliation glaucoma in an ethnically diverse patient population from the Northeastern United States. Given the high prevalence of pseudooexfoliation in this geographic region, these results also indicate that the G153D LOXL1 variant is a significant risk factor for adult-onset glaucoma in this clinic based population.

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    • "However, LOXL1, in and of itself, fails to sufficiently explain the complex mechanism of the disease progression of XFG through XFS. This observation is also supported from the point of view of genetics, as many replication studies using populations derived from different genetic backgrounds (Caucasians from the US789 and Europe1011, Asians from Japan1213141516 and China1718, and Africans from South Africa19) have succeeded in replicating the association of the LOXL1 variants, although the allele frequency of the variants varied among the ethnicities. In fact, the risk allele of one of the exonic variants (rs1048661) has been found to be inverted between Japanese12 and Nordic populations5. "
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    ABSTRACT: The common variants in lysyl oxidase-like 1 gene (LOXL1) are associated with exfoliation glaucoma (XFG) patients developed through exfoliation syndrome (XFS). However, the risk allele of a variant in LOXL1 has been found to be inverted between Asian and Caucasian populations. Therefore, we newly performed a genome-wide association study using 201 XFS/XFG and 697 controls in Japanese, and identified 34 genome-wide significant single-nucleotide polymorphisms (SNPs) distributing in not only LOXL1 but also TBC1D21 and PML at the 15q24.1 locus. These SNPs were confirmed by an independent population consisted of 121 XFS/XFG and 263 controls in Japanese. Moreover, further analyses revealed a unique haplotype structure only from the combination of TBC1D21 and LOXL1 variants showing a high XFS/XFG susceptibility specific for the Asian population. Although there still should be other gene(s) in the other region(s) contributing to the disease process, these results suggested that the combination of newly discovered variants in these genes might be useful for precise XFG risk assessment, as well as for elucidating the molecular mechanism of XFG pathogenesis through XFS.
    Full-text · Article · Jun 2014 · Scientific Reports
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    • "For rs1048661, the G allele was reported as a risk allele for XFS in most Caucasians including Nordic, American, German, Italian, Australian, and Finnish populations [4,8,10,12,28], while the opposite T allele was reported to increase the risk of XFS in Asian populations such as Japanese and Chinese [15,16,19]. For rs3825942, the G allele was significantly associated with XFS in most populations including Caucasians and Asians [4,7,8,10,12,15,18,19,21,28], but recent reports on black South Africans revealed that the opposite A allele was associated with XFS [13,14]. For rs2165241, the T allele was reported as a risk allele in Caucasians [4-7,12], while the C allele was reported to increase the risk for XFS in Japanese and Chinese populations [15,20,22]. "
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    ABSTRACT: The purpose of this study was to evaluate association profiles of lysyl oxidase-like 1 (LOXL1) gene polymorphisms with pseudoexfoliation syndrome (XFS) in a Korean population. A total of 110 Korean patients with XFS and 127 control subjects were included in this study. Genotypes of three single nucleotide polymorphisms (SNPs) of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed with direct sequencing, and a case-control association study was performed. Genotype frequencies of each SNP were compared according to the XFS phenotypes. All three SNPs were significantly associated with XFS. The T allele at rs1048661 (odds ratio [OR]=14.29, 95% confidence interval [CI]=6.25-33.3) and the C allele at rs2165241 (OR=7.14, 95% CI=1.59-33.3) were risk alleles in Korean subjects, which was consistent with findings in other Asian populations. However, our findings were opposite to results from Caucasian populations in which the risk alleles at rs1048661 and rs2165241 were G and T, respectively. At the rs3825942, the G allele (OR=12.50, 95% CI=2.94-50.0) was a risk allele for XFS, which was similar to results from most other ethnic groups except black South Africans in whom the A allele increased the risk. In the haplotype analysis, the T-G-C haplotype composed of all three risk alleles was significantly overrepresented in XFS and conferred an 11.36 fold (95% CI=5.97-23.49) increased likelihood of XFS. There was no significant association between the genotype frequencies of the three SNPs and the XFS phenotypes. Three SNPs of LOXL1 (rs1048661, rs3825942, and 2,165,241) are highly associated with XFS in a Korean population. The risk alleles of these SNPs were similar to those of other Asian populations, such as Japanese or Chinese, but differed from non-Asian populations, suggesting that still unidentified genetic or environmental factors may contribute to disease expression.
    Full-text · Article · Feb 2013 · Molecular vision
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    • "Previously, we performed a GWAS to identify the common POAG-associated genetic factors (Nakano et al. 2009) and found a number of SNPs significantly associated with POAG. GWAS for POAG has also been performed by several other research groups (Meguro et al. 2010; Thorleifsson et al. 2010; Burdon et al. 2011), and we also recently published additional GWAS research results on POAG (Nakano et al. 2012). However, compared with the genetic risk for another type of glaucoma, Exfoliation Glaucoma (EG), which was carried out by deCODE using only two SNPs (, "
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    ABSTRACT: Primary open-angle glaucoma (POAG) is one of the major causes of blindness worldwide and considered to be influenced by inherited and environmental factors. Recently, we demonstrated a genome-wide association study for the susceptibility to POAG by comparing patients and controls. In addition, the serum cytokine levels, which are affected by environmental and postnatal factors, could be also obtained in patients as well as in controls, simultaneously. Here, in order to predict the effective diagnosis of POAG, we developed an "integration approach" using different attribute data which were integrated simply with several machine learning methods and random sampling. Two data sets were prepared for this study. The one is the "training data set", which consisted of 42 POAG and 42 controls. The other is the "test data set" consisted of 73 POAG and 52 controls. We first examined for genotype and cytokine data using the training data set with general machine learning methods. After the integration approach was applied, we obtained the stable accuracy, using the support vector machine method with the radial basis function. Although our approach was based on well-known machine learning methods and a simple process, we demonstrated that the integration with two kinds of attributes, genotype and cytokines, was effective and helpful in diagnostic prediction of POAG.
    Full-text · Article · Oct 2012 · SpringerPlus
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