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Ophthalmic Molecular Genetics |

An Investigation Into LOXL1 Variants in Black South African Individuals With Exfoliation Syndrome FREE

Robyn M. Rautenbach, MBChB, DipOphth(SA); Soraya Bardien, PhD; Justin Harvey, MCom(Mathematical Statistics); Ari Ziskind, MBChB, FCSOphth(SA), MSc, BSc
[+] Author Affiliations

Author Affiliations: Division of Ophthalmology, Stellenbosch University and Tygerberg Hospital (Drs Rautenbach and Ziskind); and Division of Molecular Biology and Human Genetics, Faculty of Health Sciences (Dr Bardien) and Centre for Statistical Consultation, Department of Statistics and Actuarial Science, Stellenbosch University (Dr Harvey), Cape Town, South Africa.


Section Editor: Janey L. Wiggs, MD, PhD

More Author Information
Arch Ophthalmol. 2011;129(2):206-210. doi:10.1001/archophthalmol.2010.349.
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Published online

Objective  To investigate the association between 2 lysyl oxidase–like 1 (LOXL1) polymorphisms, rs1048661 (R141L) and rs3825942 (G153D), and exfoliation syndrome (XFS) in black South African individuals.

Methods  A total of 43 black patients with XFS and 47 ethnically matched controls were recruited for genetic analysis. Samples were analyzed for presence of the LOXL1–R141L and G153D variants using restriction fragment length polymorphism analysis. A case-control association study was performed.

Results  The R141L and G153D single-nucleotide polymorphisms (SNPs) were both significantly associated with XFS (P = .00582 and P < .00001, respectively). Consistent with findings in white populations but not in Asian cohorts, the GG genotype of the R141L SNP was present in significantly more XFS cases than controls (P = .00582). However, in this black South African study population, the AA genotype of G153D was present in an overwhelming majority of cases with XFS (P < .00001; odds ratio, 17.10; 95% confidence interval, 4.91-59.56), contrary to all previous articles in which the GG genotype was strongly associated with the disease phenotype.

Conclusion  The LOXL1 SNPs R141L and G153D are significantly associated with XFS in this black South African population. The AA genotype of G153D confers XFS risk in this population, as opposed to the GG genotype described in all other populations, suggesting that unidentified genetic or environmental factors independent of these LOXL1 SNPs may influence phenotypic expression of the syndrome.

Clinical Relevance  Elucidation of the role of genetic factors, including the LOXL1 gene, in XFS will facilitate identification of individuals predisposed to developing this condition.

Exfoliation syndrome (XFS) is a generalized disorder of the extracellular matrix characterized by the pathological deposition and accumulation of fibrillar material throughout the eye. The origin of this fibrillar material is unknown but believed to be derived from abnormal basement membranes of aging epithelial cells in ocular structures.1 In addition to its occurrence within the eye, exfoliative fibrillopathy has been reported in the skin, blood vessels, and visceral organs, suggesting that XFS may in fact be an ocular manifestation of a systemic disorder.24

This condition is associated with an array of ocular manifestations, most frequently a severe and progressive form of chronic open-angle glaucoma. Exfoliation syndrome is acknowledged as the most common identifiable cause of open-angle glaucoma, accounting for approximately 25% of cases worldwide.5

The prevalence of XFS increases with age, and a number of studies have reported geographical clustering of this condition based on race and ethnicity.6 Familial aggregation studies have suggested a significant genetic contribution to XFS.7 Despite these findings, a simple inheritance model is not evident, suggesting that XFS is the result of a complex inheritance pattern with multiple contributing genetic and/or environmental factors.

A landmark genome-wide association study by Thorleifsson et al8 identified 3 common single-nucleotide polymorphisms (SNPs) in the lysyl oxidase–like 1 (LOXL1) gene on chromosome 15q24.1 that were strongly associated with XFS and exfoliation glaucoma in Scandinavian populations. The LOXL family of proteins play a vital role in the homeostasis of elastic tissues, acting as cross-linking enzymes and thereby ensuring spatially defined deposition of elastin fibrils.9,10 The identification of the LOXL1 protein in pseudoexfoliation deposits verifies its involvement in abnormal fibrinogenesis in pseudoexfoliative tissues.11,12

Two of these SNPs, rs1048661 (R141L) and rs3825942 (G153D), are located within exon 1 of LOXL1 and cause amino acid missense changes in the protein. This exon codes for the N-terminal portion of the protein, which may have a role in directing the LOXL1 protein to sites of elastogenesis. The third LOXL1 SNP, rs2165241, is located in the first intron of the gene and is presumed not to have any biological consequence. All 3 of these SNPs were in significant linkage disequilibrium in the studied population.8 These genetic findings have been replicated to a large extent, with some important variations, in numerous studies throughout North America,1317 Australia,18 Europe,19 and Asia.2026

This study investigates the association of these LOXL1 gene polymorphisms with XFS among black South Africans, a geographical cluster with a high prevalence of XFS and exfoliation glaucoma.27,28

PATIENT POPULATION

An ethnically matched cohort of 43 elderly black patients with exfoliation syndrome and 47 control individuals were identified from the outpatient ophthalmology service at the East London Hospital Complex (Eastern Cape, South Africa) for this study. The study was approved by the Stellenbosch University Committee for Human Research (N08/08/208), and all patients and controls were recruited after informed consent. All cases and controls underwent an anterior segment evaluation after pupillary dilatation to confirm the presence or absence of the characteristic fibrillar material diagnostic of XFS. Venous blood samples were collected from all study participants.

GENOTYPING

DNA was extracted from the peripheral venous blood samples according to established methods. Polymerase chain reaction primers were designed to amplify the region containing the LOXL1 R141L and G153D variants (forward: 5′-GCA GGT GTA CAG CTT GCT CA-3′ and reverse: 5′-GGC CGG TAG TAC ACG AAA CC-3′), which produced a product of 474 base pairs. Restriction fragment–length polymorphism analysis was used to genotype the 2 SNPs. The Smal (fermentas) and Eco24I (fermentas) restriction endonuclease enzymes were used for R141L and G153D, respectively. Following digestion, the polymerase chain reaction products were resolved on 12% polyacrylamide gels and the bands visualized using silver staining. The genotyping method was verified by sequencing randomly selected samples using the BigDye Terminator Sequence Ready Reaction kit version 3.1 (Applied Biosystems, Foster City, California) and analyzed on a 3130xl Genetic Analyzer (Applied Biosystems). BioEdit version 7.0.1 software was used for analysis of the sequencing electropherograms.29

STATISTICAL ANALYSIS

A power analysis was performed prior to analysis of the data. It was found that the sample size had sufficient power (85.345%) to detect a clinically significant association between the presence or absence of a specific polymorphism and XFS. Data was analyzed using SAS version 9.1 (SAS Institute Inc, Cary, North Carolina). Descriptive statistics were computed for patient age, and comparison between the mean ages of cases and controls was performed by t test for 2 groups. Furthermore, the primary outcome variables were analyzed by contingency tables. Associations between the cases and controls and the different allele, genotype, and haplotype frequencies was examined using Pearson χ2 test. Odds ratios and relative risk estimates were also produced to examine further interactions between the disease and specific alleles and genotypes. Confidence intervals (CIs) for these estimates were also produced. A P < .05 represented statistical significance in hypothesis testing and 95% confidence intervals were used to describe the estimation of unknown parameters.

Hardy-Weinberg equilibrium of the allele and genotype frequencies of cases and control subjects was examined, both separately and in combination, using χ2 and Fisher exact tests.

Of the 43 patients with XFS, 15 had exfoliation glaucoma. Of the 47 controls; 13 had primary open-angle glaucoma but no evidence of exfoliation. The cases and controls were age-matched with a mean (SD) age of 72.37 (9.57) in XFS cases and 71.81 (7.56) in controls without XFS, with no significant difference found between the means of these 2 groups (P = .75621).

The G allele of SNP rs1048661 (R141L) was detected in a statistically higher frequency in patients with XFS than controls (P = .00106). The relative risk of having no disease given the presence of the G allele vs the T allele for this SNP was 0.49 (95% CI. 0.42-0.57). The A allele of SNP rs3825942 (G153D) was strongly associated with exfoliation syndrome (P < .00001) in this sample, with patients being 9.94 times more likely to have an A allele than a G allele (odds ratio, 9.94; 95% CI, 4.75-20.79) (Table 1).

Table Graphic Jump LocationTable 1. LOXL1 Allele and Genotype Frequencies by Single-Nucleotide Polymorphism in XFS Cases and Controls

The genotype frequencies for the rs1048661 (R141L) SNP and the rs3825942 (G153D) SNP confirmed statistically significant differences between the XFS cases and controls. The GG genotype of R141L was present in significantly more XFS cases than controls (P = .00582), with a relative risk of having no disease (GG vs GT/TT) of 0.46 (95% CI, 0.37-0.59). In this study population, we found that the AA genotype of G153D was present in an overwhelming majority of cases with XFS (P < .00001), with an odds ratio (AA vs GG) of 17.10 (95% CI, 4.91-59.56) (Table 1).

The haplotypes composed of the 2 LOXL1 SNPs rs1048661 and rs3825942 were determined, with the frequencies of the 2-SNP haplotypes differing significantly between the patients with XFS and the controls (P < .00001). The GA haplotype was associated with the highest risk of XFS in which a patient is 9.94 times more likely to have XFS if haplotype GA is present than if either haplotypes TG or GG are present (odds ratio, 9.94; 95% CI, 4.75-20.79). The TG haplotype was not detected among the group with XFS (Table 2).

Table Graphic Jump LocationTable 2. LOXL1 Haplotypes in XFS Cases and Controls

Hardy-Weinberg analysis of allele and genotype frequencies in cases and controls of both SNPs found Hardy-Weinberg equilibrium in all of the subpopulations, with the exception of the G153D cases (P = .00002). This was confirmed using both χ2 and Fisher exact tests and after checking for genotyping errors.

This study's participants are representative of the South African Xhosa population, who represent the southernmost extension of the Bantu-speaking nations that began to migrate southwards from an area near present-day Cameroon approximately 4000 years ago. They are fairly homogenous culturally and reside primarily in an area of South Africa known as the Eastern Cape Province. A previous study on genetic substructure in South African Bantu speakers has found that these groups cluster according to linguistic groupings (Xhosa, Zulu, etc).30 Exfoliation syndrome is common in this population; a recent study conducted in a related tribal grouping reported a prevalence of 6.6%.26

Our finding in the South African Xhosa population is that the AA genotype of the rs3825942 (G153D) SNP is strongly associated with XFS, which is different from the GG genotype noted in all other population groups reported to date. This is unexpected, especially in light of the strength of the associations described previously. In addition, in our study the association for G153D is with the minor allele, which is distinct from all other articles (Table 3).

Table Graphic Jump LocationTable 3. Comparative Data of LOXL1 Risk Alleles and Minor Allele Frequencies

A recent publication corroborates the findings of this study. Williams and colleagues31 investigated LOXL1 SNPs in black South African patients with exfoliation glaucoma and also found that the A (and not the G allele) of G153D, in contrast to all other studies, is significantly associated with XFS and exfoliation glaucoma in black South African individuals. An advantage of our compared with that of Williams et al is that our study focused on only 1 ethnic subgroup, the Xhosa-speaking Bantu population (our cases and controls were recruited exclusively from an area where Xhosa-speaking black South African individuals predominantly reside).

The allele frequencies observed in our study compare favorably with the data observed in HapMap (http://hapmap.ncbi.nlm.nih.gov/) and dbSNP (http://www.ncbi.nlm.nih.gov/SNP/) as well as the aforementioned study of another black South African population.30 For G153D (rs3825942), the G allele has been found at frequencies ranging from 58% to 63% in various black populations in the Southwestern United States, Kenya, Nigeria, and South Africa. The frequency of the G allele observed in the control population in the present study was 62%. This is in contrast with the frequency observed in white populations from the United States and Italy, Asians from China, Japan, and the United States, and Indians from the United States, which ranged from 78% to 88%. For R141L (rs1048661), the frequency that we observed for the G allele of 88% is similar to the other recent study in black South African individuals (81%)30 but different from that observed in American white (96%) and Japanese individuals(44%). Because R141L is not present in HapMap and Williams et al30 did not evaluate haplotype data, no comparison can currently be made for the haplotype frequencies of the 2 SNPs identified in this study.

Although the allele and genotype frequencies in this study were in Hardy-Weinberg equilibrium for the control groups of both SNPs and the cases in the rs1048661 (R141L) analysis, the allele and genotype frequencies for the rs3825942 (G153D) were not in Hardy-Weinberg equilibrium (P = .00002) for cases with XFS. In light of the fact that the same genotyping platform was used in all the genetic analyses, and that similar findings have occasionally been described in other case-control studies of XFS involving these same SNPs20,24 as well as in similar studies of other conditions, it is our opinion that this is a real finding despite deviation from Hardy-Weinberg equilibrium. We are, however, uncertain of its implications regarding Hardy-Weinberg assumptions in our population. As the sample population is identical for both SNPs, it is unlikely that this finding is related in any way to small sample size, inbreeding, or assortative mating of any kind but might be a reflection of an association between this marker and disease susceptibility.32

The AA genotype of G153D confers XFS risk in this South African population. This observation, together with findings in several Chinese and Japanese populations that the TT genotype of the rs1048661 (R141L) SNP is strongly associated with XFS contrasts the association of the GG genotype reported in all other North American and European studies as well as our study (Table 3), suggesting that the original assumption that these 2 SNPs in LOXL1 are causative of XFS is in need of revision. Several possible hypotheses can be proposed for this finding. The most likely explanation is that, although a LOXL1 polymorphism is intimately involved with the pathogenesis of XFS, it is neither the R141L or G153D but another variant in linkage disequilibrium with these SNPs that may not have been included in the original genome-wide association study. Other possible hypotheses compatible with these findings would assume that the R141L and G153D polymorphisms are themselves integral to the pathogenesis of XFS but that either the genomic environment of LOXL1, the molecular biological environment of elastin fibril metabolism, or the broader environment in which the pathway functions act to increase the complexity of the relationship between LOXL1 and XFS, resulting in these paradoxical associations. Progress in understanding this relationship is dependent on further research in all of these areas.

In summary, the LOXL1 SNPs rs1048661 (R141L) and rs3826942 (G153D) are significantly associated with XFS in the black South African population. The AA genotype of G153D confers XFS risk in this population, as opposed to the GG genotype reported in all previously described populations.

The fact that the disease-associated haplotype differs across various populations (GA in black South African individuals, TG in Japanese individuals, and GG in white individuals) indicates that these are not the disease-causing variants but that they are in linkage disequilibrium with the actual pathogenic variants.

Correspondence: Robyn M. Rautenbach, MBChB, DipOphth(SA), Ophthalmology Department, Tygerberg Academic Hospital, Private Bag X3, Tygerberg 7505, South Africa (robynrautenbach@gmail.com).

Submitted for Publication: March 14, 2010; final revision received June 1, 2010; accepted June 7, 2010.

Author Contributions: Dr Rautenbach had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: This study was supported by research funds from the Division of Ophthalmology at Stellenbosch University, Cape Town, South Africa.

Additional Contributions: We thank the study participants for taking part in this study and the staff of the ophthalmology out-patient services in East London for their assistance with patient counselling and data collection.

Gottfried  OHNaumann  MDShlotser-Schrehardt  UKuchle  M Pseudoexfoliation syndrome for the comprehensive ophthalmologist: intraocular and systemic manifestations. Ophthalmology 1998;105 (6) 951- 968
PubMed
Schlötzer-Schrehardt  UMKoca  MRNaumann  GOVolkholz  H Pseudoexfoliation syndrome: ocular manifestation of a systemic disorder? Arch Ophthalmol 1992;110 (12) 1752- 1756
PubMed
Streeten  BWLi  ZYWallace  RNEagle  RC  JrKeshgegian  AA Pseudoexfoliative fibrillopathy in visceral organs of a patient with pseudoexfoliation syndrome. Arch Ophthalmol 1992;110 (12) 1757- 1762
PubMed
Schlötzer-Schrehardt  UM Molecular pathology of pseudoexfoliation syndrome/glaucoma: new insights from LOXL1 gene associations. Exp Eye Res 2009;88 (4) 776- 785
PubMed
Ritch  R Exfoliation syndrome: the most common identifiable cause of open-angle glaucoma. J Glaucoma 1994;3 (2) 176- 177
PubMed
Gifford  H  Jr A clinical and pathologic study of exfoliation of the lens capsule. Am J Ophthalmol 1958;46 (4) 508- 524
PubMed
Forsius  H Exfoliation syndrome in various ethnic populations. Acta Ophthalmol Suppl 1988;18471- 85
PubMed
Thorleifsson  GMagnusson  KPSulem  P  et al.  Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 2007;317 (5843) 1397- 1400
PubMed
Liu  XZhao  YGao  J  et al.  Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nat Genet 2004;36 (2) 178- 182
PubMed
Decitre  MGleyzal  CRaccurt  M  et al.  Lysyl oxidase-like protein localizes to sites of de novo fibrinogenesis in fibrosis and in the early stromal reaction of ductal breast carcinomas. Lab Invest 1998;78 (2) 143- 151
PubMed
Schlötzer-Schrehardt  UPasutto  FSommer  P  et al.  Genotype-correlated expression of lysyl oxidase-like 1 in ocular tissues of patients with pseudoexfoliation syndrome/glaucoma and normal patients. Am J Pathol 2008;173 (6) 1724- 1735
PubMed
Sharma  SChataway  TBurdon  KP  et al.  Identification of LOXL1 protein and apolipoprotein E as components of surgically isolated pseudoexfoliation material by direct mass spectrometry. Exp Eye Res 2009;89 (4) 479- 485
PubMed
Fingert  JHAlward  WLMKwon  YH  et al.  LOXL1 mutations are associated with exfoliation syndrome in patients from the midwestern United States. Am J Ophthalmol 2007;144 (6) 974- 975
PubMed
Fan  BJPasquale  LGrosskreutz  CL  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;95
PubMed
Yang  XZabriskie  NAHau  VS  et al.  Genetic association of LOXL1 gene variants and exfoliation glaucoma in a Utah cohort. Cell Cycle 2008;7 (4) 521- 524
PubMed
Aragon-Martin  JARitch  RLiebmann  J  et al.  Evaluation of LOXL1 gene polymorphisms in exfoliation syndrome and exfoliation glaucoma. Mol Vis 2008;14533- 541
PubMed
Challa  PSchmidt  SLiu  Y  et al.  Analysis of LOXL1 polymorphisms in a United States population with pseudoexfoliation glaucoma. Mol Vis 2008;14146- 149
PubMed
Hewitt  AWSharma  SBurdon  KP  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
PubMed
Pasutto  FKrumbiegel  MMardin  CY  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
PubMed
Ramprasad  VLGeorge  RSoumittra  NSharmila  FVijaya  LKumaramanickavel  G Association of non-synonymous single nucleotide polymorphisms in the LOXL1 gene with pseudoexfoliation syndrome in India. Mol Vis 2008;14318- 322
PubMed
Lee  KYHo  SLThalamuthu  A  et al.  Association of LOXL1 polymorphisms with pseudoexfoliation in the Chinese. Mol Vis 2009;151120- 1126
PubMed
Chen  LJia  LWang  N  et al.  Evaluation of LOXL1 polymorphisms in exfoliation syndrome in a Chinese population. Mol Vis 2009;152349- 2357
PubMed
Fuse  NMiyazawa  ANakazawa  TMengkegale  MOtomo  TNishida  K Evaluation of LOXL1 polymorphisms in eyes with exfoliation glaucoma in Japanese. Mol Vis 2008;141338- 1343
PubMed
Hayashi  HGotoh  NUeda  YNakanishi  HYoshimura  N Lysyl oxidase-like 1 polymorphisms and exfoliation syndrome in the Japanese population. Am J Ophthalmol 2008;145 (3) 582- 585
PubMed
Mori  KImai  KMatsuda  A  et al.  LOXL1 genetic polymorphisms are associated with exfoliation glaucoma in the Japanese population. Mol Vis 2008;141037- 1040
PubMed
Ozaki  MLee  KYVithana  EN  et al.  Association of LOXL1 gene polymorphisms with pseudoexfoliation in the Japanese. Invest Ophthalmol Vis Sci 2008;49 (9) 3976- 3980
PubMed
Ritch  R Exfoliation syndrome: beyond glaucoma. Arch Ophthalmol 2008;126 (6) 859- 861
PubMed
Van Wyk  RDJoseph  DAStulting  AAVan Rooyen  FC Prevalence of pseudoexfoliation syndrome in patients attending the eye clinics in central South Africa. SA Ophthalmology Journal 2009;4 (2) 18- 24
Hall  TA BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp Ser 1999;4195- 98
Lane  ABSoodyall  HArndt  S  et al.  Genetic substructure in South African Bantu-speakers: evidence from autosomal DNA and Y-chromosome studies. Am J Phys Anthropol 2002;119 (2) 175- 185
PubMed
Williams  SEIWhigham  BTLiu  Y  et al.  Major LOXL1 risk allele is reversed in exfoliation glaucoma in a black South African population. Mol Vis 2010;16705- 712
PubMed
Nielsen  DMEhm  MGWeir  BS Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. Am J Hum Genet 1998;63 (5) 1531- 1540
PubMed

Figures

Tables

Table Graphic Jump LocationTable 1. LOXL1 Allele and Genotype Frequencies by Single-Nucleotide Polymorphism in XFS Cases and Controls
Table Graphic Jump LocationTable 2. LOXL1 Haplotypes in XFS Cases and Controls
Table Graphic Jump LocationTable 3. Comparative Data of LOXL1 Risk Alleles and Minor Allele Frequencies

References

Gottfried  OHNaumann  MDShlotser-Schrehardt  UKuchle  M Pseudoexfoliation syndrome for the comprehensive ophthalmologist: intraocular and systemic manifestations. Ophthalmology 1998;105 (6) 951- 968
PubMed
Schlötzer-Schrehardt  UMKoca  MRNaumann  GOVolkholz  H Pseudoexfoliation syndrome: ocular manifestation of a systemic disorder? Arch Ophthalmol 1992;110 (12) 1752- 1756
PubMed
Streeten  BWLi  ZYWallace  RNEagle  RC  JrKeshgegian  AA Pseudoexfoliative fibrillopathy in visceral organs of a patient with pseudoexfoliation syndrome. Arch Ophthalmol 1992;110 (12) 1757- 1762
PubMed
Schlötzer-Schrehardt  UM Molecular pathology of pseudoexfoliation syndrome/glaucoma: new insights from LOXL1 gene associations. Exp Eye Res 2009;88 (4) 776- 785
PubMed
Ritch  R Exfoliation syndrome: the most common identifiable cause of open-angle glaucoma. J Glaucoma 1994;3 (2) 176- 177
PubMed
Gifford  H  Jr A clinical and pathologic study of exfoliation of the lens capsule. Am J Ophthalmol 1958;46 (4) 508- 524
PubMed
Forsius  H Exfoliation syndrome in various ethnic populations. Acta Ophthalmol Suppl 1988;18471- 85
PubMed
Thorleifsson  GMagnusson  KPSulem  P  et al.  Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 2007;317 (5843) 1397- 1400
PubMed
Liu  XZhao  YGao  J  et al.  Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nat Genet 2004;36 (2) 178- 182
PubMed
Decitre  MGleyzal  CRaccurt  M  et al.  Lysyl oxidase-like protein localizes to sites of de novo fibrinogenesis in fibrosis and in the early stromal reaction of ductal breast carcinomas. Lab Invest 1998;78 (2) 143- 151
PubMed
Schlötzer-Schrehardt  UPasutto  FSommer  P  et al.  Genotype-correlated expression of lysyl oxidase-like 1 in ocular tissues of patients with pseudoexfoliation syndrome/glaucoma and normal patients. Am J Pathol 2008;173 (6) 1724- 1735
PubMed
Sharma  SChataway  TBurdon  KP  et al.  Identification of LOXL1 protein and apolipoprotein E as components of surgically isolated pseudoexfoliation material by direct mass spectrometry. Exp Eye Res 2009;89 (4) 479- 485
PubMed
Fingert  JHAlward  WLMKwon  YH  et al.  LOXL1 mutations are associated with exfoliation syndrome in patients from the midwestern United States. Am J Ophthalmol 2007;144 (6) 974- 975
PubMed
Fan  BJPasquale  LGrosskreutz  CL  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;95
PubMed
Yang  XZabriskie  NAHau  VS  et al.  Genetic association of LOXL1 gene variants and exfoliation glaucoma in a Utah cohort. Cell Cycle 2008;7 (4) 521- 524
PubMed
Aragon-Martin  JARitch  RLiebmann  J  et al.  Evaluation of LOXL1 gene polymorphisms in exfoliation syndrome and exfoliation glaucoma. Mol Vis 2008;14533- 541
PubMed
Challa  PSchmidt  SLiu  Y  et al.  Analysis of LOXL1 polymorphisms in a United States population with pseudoexfoliation glaucoma. Mol Vis 2008;14146- 149
PubMed
Hewitt  AWSharma  SBurdon  KP  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
PubMed
Pasutto  FKrumbiegel  MMardin  CY  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
PubMed
Ramprasad  VLGeorge  RSoumittra  NSharmila  FVijaya  LKumaramanickavel  G Association of non-synonymous single nucleotide polymorphisms in the LOXL1 gene with pseudoexfoliation syndrome in India. Mol Vis 2008;14318- 322
PubMed
Lee  KYHo  SLThalamuthu  A  et al.  Association of LOXL1 polymorphisms with pseudoexfoliation in the Chinese. Mol Vis 2009;151120- 1126
PubMed
Chen  LJia  LWang  N  et al.  Evaluation of LOXL1 polymorphisms in exfoliation syndrome in a Chinese population. Mol Vis 2009;152349- 2357
PubMed
Fuse  NMiyazawa  ANakazawa  TMengkegale  MOtomo  TNishida  K Evaluation of LOXL1 polymorphisms in eyes with exfoliation glaucoma in Japanese. Mol Vis 2008;141338- 1343
PubMed
Hayashi  HGotoh  NUeda  YNakanishi  HYoshimura  N Lysyl oxidase-like 1 polymorphisms and exfoliation syndrome in the Japanese population. Am J Ophthalmol 2008;145 (3) 582- 585
PubMed
Mori  KImai  KMatsuda  A  et al.  LOXL1 genetic polymorphisms are associated with exfoliation glaucoma in the Japanese population. Mol Vis 2008;141037- 1040
PubMed
Ozaki  MLee  KYVithana  EN  et al.  Association of LOXL1 gene polymorphisms with pseudoexfoliation in the Japanese. Invest Ophthalmol Vis Sci 2008;49 (9) 3976- 3980
PubMed
Ritch  R Exfoliation syndrome: beyond glaucoma. Arch Ophthalmol 2008;126 (6) 859- 861
PubMed
Van Wyk  RDJoseph  DAStulting  AAVan Rooyen  FC Prevalence of pseudoexfoliation syndrome in patients attending the eye clinics in central South Africa. SA Ophthalmology Journal 2009;4 (2) 18- 24
Hall  TA BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp Ser 1999;4195- 98
Lane  ABSoodyall  HArndt  S  et al.  Genetic substructure in South African Bantu-speakers: evidence from autosomal DNA and Y-chromosome studies. Am J Phys Anthropol 2002;119 (2) 175- 185
PubMed
Williams  SEIWhigham  BTLiu  Y  et al.  Major LOXL1 risk allele is reversed in exfoliation glaucoma in a black South African population. Mol Vis 2010;16705- 712
PubMed
Nielsen  DMEhm  MGWeir  BS Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. Am J Hum Genet 1998;63 (5) 1531- 1540
PubMed

Correspondence

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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Indicate what change(s) you will implement in your practice, if any, based on this CME course.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
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