genetic etiologies of glaucoma

SPECIAL ARTICLE

Genetic Etiologies of GlaucomaJaney L. Wiggs, MD, PhD

G laucoma can be inherited as a mendelian autosomal-dominant or autosomal-recessive trait, or as a complex multifactorial trait. Genetic approaches have helpeddefine the underlying molecular events responsible for some mendelian forms of thedisease and have identified the chromosome locations of genes that are likely to con-

tribute to common complex forms. Future directions include the discovery of new glaucoma genes,determining the clinical phenotypes associated with specific genes and mutations, investigatingenvironmental factors that may contribute to the disease, investigating gene-environment inter-actions and gene-gene interactions, and developing a mutation database that can be used for di-agnostic and prognostic testing. Arch Ophthalmol. 2007;125:30-37

Glaucoma is the third most prevalent causeof visual impairment and blindness amongwhite Americans and is the leading causeof blindness among black Americans.1 Allforms of glaucoma have in common op-tic nerve degeneration characterized bytypical visual field defects and are usu-ally associated with elevated intraocularpressure (IOP). In most instances, the el-evation of IOP results from impaired drain-age of aqueous humor (produced by theciliary body) through the trabecular mesh-work outflow pathways. Glaucoma causesirreversible blindness that can only be pre-vented by therapeutic intervention at earlystages of the disease.

A family history of the disease has longbeen recognized as a major risk factor forglaucoma, suggesting that specific gene de-fects contribute to the pathogenesis of thedisorder.2 Glaucoma may be inherited asmendelian-dominant or mendelian-recessive traits (usually early-onset formsof the disease), or may exhibit a heritablesusceptibility consistent with complex traitinheritance (typically adult-onset forms ofthe disease).

GENETIC APPROACHES

The identification of the molecular eventsresponsible for glaucoma has been diffi-cult because of a general lack of knowl-edge about the cellular and biochemicalevents that are necessary for the normal

regulation of IOP and retinal ganglion cellfunction. Access to diseased human tissueis also difficult and animal models have onlyrecently been developed and character-ized.3 The advantage of a genetic approachis that the responsible protein can be iden-tified without access to diseased tissue. Theidentification of genes (and their proteinproducts) that can cause or contribute toglaucoma will help define the underlyingpathophysiology, as well as lead to the de-velopment of new DNA-based diagnostictests and novel therapeutic approaches.

The availability of predictive tests wouldprovide a mechanism for early detection andtreatment. Those individuals at risk who areidentified early in the course of the dis-ease and who begin therapy prior to sig-nificant damage to the optic nerve will havethe best chance of maintaining useful sight.

Genes associated with forms of glau-coma that exhibit autosomal-dominant,autosomal-recessive, and other mende-lian inheritance patterns can be located inthe human genome using large affectedpedigrees (typically at least 11 members)and standard linkage analysis. Once thechromosomal location of the gene is de-termined, the genes found within the link-age region can be evaluated for associa-tion with the disease. The simplicity of thisoverall approach has lead to substantialsuccess and most of the genes currentlyknown to be associated with various formsof glaucoma were identified using thesemethods (Table).

Common forms of adult-onset glau-coma, including primary open-angle glau-

Author Affiliation: Department of Ophthalmology, Harvard Medical School,Boston, Mass.

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coma (POAG), typically do not ex-hibit mendelian inheritance patterns.These common age-related ocular dis-orders do have a significant herita-bility; however, the genetic contribu-tions to these disorders are complex,resulting from interactions of mul-tiple genetic factors, and are suscep-tible to the influence of environmen-tal exposures. Discovering genes thatcontribute to disorders with com-plex inheritance is more difficult.Among the factors that contribute tothe challenge of discovering com-plex disease genes are the underly-ing molecular heterogeneity, impre-cise definition of phenotypes,inadequately powered study de-signs, and the inability of standard setsof microsatellite markers to extractcomplete information about inherit-ance. Genome scans using familiesdemonstrating clustering of com-plex diseases (largely sibpairs) typi-cally lead to the identification of anumber of large genetic intervals con-taining many possible candidategenes.4-6 Using families affected withrare mendelian forms of complex dis-eases is another path to the desiredgenes. This approach has been suc-cessful in the identification of someocular disease genes7-9; however, mostof the identified genes do not appear

to have a major role in the complexphenotype.10-13 Recent efforts usingwhole genome–association methodsand very large numbers of singlenucleotide polymorphisms have suc-cessfully identified genetic factorsconferring susceptibility to complexdiseases, such as age-related macu-lar degeneration,14-18 and it is ex-pected that this will be a useful ap-proach for adult-onset glaucoma.

GENES ASSOCIATED WITHFORMS OF GLAUCOMA WITHMENDELIAN INHERITANCE

Typically, early-onset forms of glau-coma are inherited as mendelian-dominant or mendelian-recessivetraits, including early-onset open-angle glaucoma19-23; congenital glau-coma24; development glaucomas, in-cluding Rieger syndrome,2 5 - 2 8

glaucoma associated with nail-patella syndrome,29 and nanophthal-mos30; and glaucoma associated withpigment dispersion syndrome.31-34

Congenital Glaucoma

In patients with congenital glau-coma, the development of the ante-rior segment of the eye and aque-ous humor outflow pathways is

abnormal, causing high IOP. Con-genital glaucoma can be inherited asan autosomal-recessive trait and isprevalent in countries where con-sanguinity is common.35,36 Usingconsanguineous pedigrees fromSaudi Arabia and Turkey, defects inthe CYP1B1 gene coding for a pro-tein that is a member of the cyto-chrome P450 family were found in in-dividuals affected with congenitalglaucoma.Subsequently,mutations inthis gene have also been found in pa-tients with congenital glaucoma frommany countries including Slovakia(gypsies) and Japan, and from coun-tries with more heterogeneous popu-lations, such as the United States andBrazil. A loss of protein function isprobably the underlying geneticmechanism, as most of the muta-tions are deletions, insertions, or mis-sense mutations occurring in highlyconserved protein regions that arenecessary for its function.37 Recur-rent mutations have been found inpatients from varied ethnic back-grounds. Recent work indicates therecurrent mutations are on ancientchromosomes that have a commonhaplotype.38 The cytochrome P450that is the product of the CYP1B1gene participates in the metabolismof many compounds, including 17�-

Table. Chromosomal Locations of Genes Associated With Glaucoma

Chromosome Location Condition Locus (Gene) Inheritance Pattern

1q23 Early- and adult-onset POAG GLC1A (MYOC) Early-onset; ADAdult-onset; complex

1p36 Congenital glaucoma GLC3B AR2p21 Congenital glaucoma GLC3A (CYP1B1) AR2cen-2q13 Adult-onset POAG GLC1B AD3q21-24 Adult-onset POAG GLC1C AD4q25 Rieger syndrome RIEG1 (PITX2) AD5q22 Adult-onset POAG GLC1G (WDR36) AD; complex6p25 Iridodysgenesis IRID1 (FOXC1) AD7q35 Adult-onset POAG GLC1F AD7q35-q36 Pigment dispersion syndrome GPDS1 AD8q23 Adult-onset POAG GLC1D AD9q22 Early-onset POAG GLC1J AD9q34 Glaucoma associated with nail-patella syndrome (LMX1B) AD10p15-p14 Adult-onset POAG; low-tension glaucoma GLC1E (OPTN) AD11p Nanophthalmos NNO1 AD11p13 Aniridia AN2 (PAX6) AD11q12 Nanophthalmos VMD2 AD11q23 Nanophthalmos MFRP AR13q14 Rieger syndrome RIEG2 AD14q11 Adult-onset POAG Locus pending Complex15q11-q13 Adult-onset POAG GLC1I Complex20p12 Early-onset POAG GLC1K AD

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; POAG, primary open-angle glaucoma.




estradiol. It has been hypothesizedthat alterations in the metabolism ofestrogens may be the basis for the ocu-lar abnormalities associated with de-fects in this gene.39,40

Most patients with congenitalglaucoma caused by mutations inCYP1B1 have a severe case of the dis-ease; however, there are some fami-lies with significant variation in phe-notypic severity and even reducedpenetrance, which is evident fromthe observation of apparently unaf-fected homozygote carriers.41 Inmice, tyrosinase activity has beenshown to modify the severity of theanterior segment defects caused byCYP1B1 deficiency42; however, thisresult has not been found in hu-mans.43 Linkage studies have iden-tified at least 1 other chromosomalregion that is likely to harbor a genefor congenital glaucoma (1p36)44;numerous cytogenetic reports indi-cate other chromosome regions thatmay harbor congenital glaucomagenes.45 In addition, autosomal-dominant forms of congenital glau-coma have been identified.46

Developmental Syndromes(Axenfeld-Rieger, Nail-patella

Syndrome, Aniridia, andNanophthalmos)

In addition to congenital glau-coma, other forms of glaucoma areassociated with abnormal develop-ment of the anterior segment of theeye. Axenfeld-Rieger syndrome,characterized by posterior embryo-toxon, iris hypoplasia, and iridocor-neal adhesions, can be caused bymutations in the PITX2 gene.47 De-fects in the FOXC1 gene are foundin patients with anterior segmentdysgenesis.48,49 Patients with de-fects in both of these genes may alsohave associated systemic defects in-volving the teeth, facial bones, heart,and umbilicus. Abnormalities in thePAX6 gene cause aniridia, as well asa spectrum of iris abnormalities re-lated to glaucoma.50 Nail-patella syn-drome is a systemic developmentaldisease associated with glaucomacaused by defects in LMX1B.51 Anautosomal-dominant form ofnanophthalmos associated with vit-roretinochoroidopathy has beenshown to be caused by abnormali-ties in the VMD2 gene.52

The genes responsible for thesedisorders participate in the regula-tion of gene expression during de-velopment,53-55 specifically in the de-velopment of the periocularmesenchyme, which includes neu-ral crest– and cranial paraxial me-soderm–derived cells.55-57 These de-velopmental disorders are allinherited as autosomal-dominanttraits, and in general, the DNA de-fects lead to loss of function of theprotein and haploinsufficiency.47-51

Intrafamilial variability in dis-ease severity is commonly encoun-tered in pedigrees carrying defectsin these genes. The variable pheno-typic expressivity may be caused bydosage effects or by the coexist-ence of other genes that can modifythe expression of the trait.

Early-Onset POAG

Defects in the MYOC gene coding forthe myocilin protein were first as-sociated with early-onset POAG. Upto 20% of patients with early-onsetPOAG and 3%-5% of patients withadult-onset POAG have defects inthis gene.10,11 Some mutations arespecifically associated with early-onset disease, while others are morecommon in adult-onset patients.One study has suggested that het-erozygous defects of the CYP1B1gene can influence the severity ofdisease caused by mutations inMYOC.58 This result may indicatethat these 2 proteins affect the samebiochemical pathway.

In patients with both early- andlate-onset disease, the majority of thecausative mutations are found in theolfactomedin domain of the protein,which is encoded by sequences foundin the third exon of the gene.11 Myo-cilin is one member of a family of ol-factomedin domain–containing pro-teins that are, ingeneral, glycoproteinsthat function in the extracellular en-vironment.59

Although the clustering of glau-coma-associated mutations in theolfactomedin domain and the partici-pation of olfactomedins in extra-cellular processes suggests that themyocilin protein functions in the ex-tracellular matrix, the role of the nor-mal protein in the outflow pathwaysis not well understood. Several stud-ies suggest that myocilin is not needed

for normal aqueous humor out-flow.60-62 The normal protein has beendetected in the extracellular ma-trix,63,64 suggesting it is secreted fromthecell; studieshave indicated that themutant forms of the protein are notsecreted.65-67

It is likely that mutant forms ofthe myocilin protein have an abnor-mal function that may result in re-tention of the abnormal form of theprotein in the cell.68,69 Mutant myo-cilin proteins form heterodimers andheteromultimers with wild-typemyocilin and these heteromulti-meric complexes remain seques-tered intracellularly.70

Disease-causing myocilin mu-tants appear to be misfolded and arehighly aggregation prone, causinglarge-protein aggregates to accumu-late in the endoplasmic reticulum.Secretion of mutant myocilin hasbeen shown to be temperature sen-sitive, which supports the hypoth-esis that myocilin-induced glau-coma is a protein-conformationaldisease.71,72 Mutations associatedwith glaucoma also inhibit an intra-cellular endoproteolytic cleavage ofmyocilin that normally releases theolfactomedin domain.73 Mutantforms of the protein may be toxic tothe trabecular cells or may preventthe processing and secretion of otherproteins that are necessary for thenormal function of the trabecularoutflow pathways. Further studieswill be required to determine the ac-tual mechanism of myocilin-associated glaucoma.

NEW GENES ASSOCIATEDWITH MENDELIAN FORMS OFGLAUCOMA SUPPORTED BY

LINKAGE STUDIES

For a number of glaucoma-associ-ated genes, the chromosomal loca-tion of the gene has been deter-mined by linkage studies. The genehas yet to be identified.

Anterior Segment DysgenesisSyndromes

Linkage studies and chromosome-deletion analyses suggest that genesresponsible for anterior segment de-velopmental abnormalities are lo-cated on chromosomes 13q14,28

4p,74 16q,75 and 20p.76 In mice, sev-




eral genes have been suggested as re-sponsible for ocular developmentaldefects leading to glaucoma, includ-ing Bmp4,77,78 Foxe3,79 and Tgfb2.80

Pigment Dispersion Syndrome

Of the individuals with clinical evi-dence of pigment dispersion syn-drome, approximately 50% will de-velop glaucoma. In humans thedisease can be sporadic or inher-ited, with most pedigrees demon-strating autosomal-dominant inher-itance patterns.31-33 Specific genesresponsible for the human condi-tion have not yet been identified;however, linkage studies suggest that1 gene is located on chromosome7q36.33 The DBA2 mouse spontane-ously develops a syndrome similarto human pigment dispersion syn-drome and pigmentary glaucoma.81

Two genes in the mouse contributeto the disease: TYRP1 (Tyrosinase-related protein 1) and Gpnmb (Gly-coprotein NMB).82 Both of thesegenes are involved in pigment pro-duction and/or stabilization of mel-anosomes. Neither of these genescontribute to the disease in hu-mans.83

Nanophthalmos

Nanophthalmos can be inherited asan autosomal-recessive or autoso-mal-dominant trait, and affected pa-tients are at risk for angle-closureglaucoma. One gene, MFRP (mem-brane-type Frizzled-related pro-tein), located on chromosome11q23, has been shown to be asso-ciated with autosomal-recessivenanopthlamos.84 Mutations in a sec-ond gene, VMD2 (vitelliform macu-lar dystrophy 2, also known as be-strophin), located on chromosome11q13 have been found in patientswith an autosomal-dominant formof nanophthalmos, also associatedwith viteroretinochroidopathy.52 Fi-nally, a third gene on chromosome11 has been located but not yet dis-covered.30

Early-Onset POAG

Although mutations in myocilin arecurrently the most identifiable causeof early-onset POAG, most cases(80%) are not caused by myocilin

mutations.10,11,85 Three new chro-mosome locations of genes respon-sible for POAG have been identi-fied on chromosomes 9q22 (GLC1J)and 20p12 (GLC1K),86 and on chro-mosome 5q.87

GENES ASSOCIATED WITHFORMS OF GLAUCOMA WITH

COMPLEX INHERITANCE

Adult-onset forms of glaucoma, in-cluding POAG, low-tension glau-coma, and glaucoma associated withpseudoexfoliation, are inherited ascomplex traits. A positive family his-tory is a major risk factor for theseconditions, which suggests that spe-cific gene defects are likely to con-tribute.88-92 However, a simple modeinheritance is not evident, and asingle underlying susceptibility geneis not likely. It is more likely thatmultiple genes contribute to thesephenotypes and that environmen-tal conditions may also participate.Because a genetic model cannot bedefined, methods to identify genesresponsible for these conditions aremore complex than those used formendelian disorders. Genome scansand model-free analyses have beenperformed using families demon-strating clustering of complex dis-eases (largely sibpairs), as well asfamilies affected with rare formsshowing apparent mendelian inher-itance.

Low-tension Glaucoma

In patients with low-tension glau-coma, degeneration of the opticnerve occurs even though the IOPsare not abnormally elevated. In pa-tients with low-tension glaucoma,the clinical appearance of the opticnerve is similar to the appearance ofthe optic nerve in the Kjer form ofautosomal-dominant optic atro-phy. Loss of function mutations inthe OPA1 gene are responsible forKjer autosomal-dominant optic at-rophy; polymorphisms in the OPA1gene may be associated with low-tension glaucoma in some cases.92

Low-tension glaucoma has alsobeen associated with mutations in anovel gene, OPTN.9 The protein op-tineurin is expressed in many ocu-lar and nonocular tissues, includ-ing the trabecular meshwork,

nonpigmented ciliary epithelium,retina, brain, heart, liver, skeletalmuscle, kidney, and pancreas. Op-tineurin may participate in the tis-sue necrosis factor � signaling path-way, which has been proposed to beone pathway involved in retinal gan-glion cell apoptosis in patients withlow-tension glaucoma and in pa-tients with POAG.93,94 It has beenspeculated that the optineurin pro-tein may function to protect the op-tic nerve from tissue necrosis fac-tor �–mediated apoptosis and thatthe loss of function of this proteinmay decrease the threshold for gan-glion cell apoptosis in patients withglaucoma.

Missense mutation in optineurinis an infrequent cause of low-tension glaucoma, with a possible in-crease in prevalence in the Japanesepopulation.95,96 The E50K mutation,although exceedingly rare, has beenassociated with a severe form of low-tension glaucoma, characterized bysignificant loss of optic nerve func-tion at relatively early ages.97,98 Sur-prisingly, researchers have not foundoptineurin mutations at an in-creased frequency in patients withtypical high-pressure glaucoma, ar-guing that this gene does not contrib-ute to adult-onset POAG.13,99

Studies of lymphocytes in pa-tients with low-tension glaucomahave demonstrated altered expres-sion of the p53 gene, a known regu-lator of apoptosis.100 Abnormal regu-lation of apoptosis may be onemechanism of low-tension glau-coma. Although not true for op-tineurin, the possibility remains thatgenes that predispose patients tolow-tension glaucoma may also con-tribute to nerve degeneration in pa-tients with POAG associated with in-creased IOP.

Adult-Onset POAG

Primary open-angle glaucoma com-monly occurs after age 50 years andis usually associated with elevatedIOP. The relationship between pres-sure elevation and optic nerve dis-ease is not linear, suggesting thatvariability in optic nerve suscepti-bility exists among glaucoma pa-tients. Adult-onset glaucoma oftenoccurs in multiple family members(familial aggregation) but does not




usually follow a clear mendelian in-heritance pattern, suggesting that in-herited risk factors can result in asusceptibility to the disease but aloneare not necessarily causative. Mul-tiple risk factors and/or environmen-tal factors may be responsible for thisdisease in older individuals.

Defects in MYOC coding for myo-cilin are found in 3% to 5% of pa-tients with adult-onset POAG.10,11

Certain MYOC mutations are morecommonly found in older-onset pa-tients than in early-onset patients.101

In particular, the nonsense mu-tation Q368X, which results in atruncated polypeptide, is more fre-quently found in patients with adult-onset POAG than in patients withearly-onset POAG.102 Studies haveshown that the Q368X mutation dem-onstrates a founder effect in whitepatients, which is possibly one expla-nation for its higher prevalence.103 Inan in vitro assay that correlates thesolubility of mutant forms of myoci-lin with clinical severity, the Q368Xmutation is less likely to form a pre-cipitate, supporting the suggestionthat the Q368X mutation causes amilder form of the disease.68

Recently, DNA sequence changeshave been identified in the WDR36gene, located within the chromo-somal region defined as GLC1G.104

Although the function of the pro-tein product is unknown and the roleof the protein in glaucoma remainsto be confirmed,105 prior studies sug-gest that it may participate in im-mune responses106; other studieshave also suggested that glaucomamay be influenced by immune re-activity.107 Interestingly, recent evi-dence suggests that mutations in theWDR36 gene are not an indepen-dent cause of glaucoma but maymodify the severity of the disease inan affected person.108

NEW GENES ASSOCIATEDWITH COMPLEX FORMS OFGLAUCOMA SUPPORTED BY

LINKAGE STUDIES

Adult-Onset POAG

Using mendelian (model-depen-dent) linkage approaches andsmall numbers of large pedigreesaffected by POAG, 7 genetic locihave been described for POAG

(GLC1A-G),21,104,109-113 and glaucoma-predisposing genes have been iden-tified in 3 of these loci: GLC1A, myo-cilin7; GLC1E, optineurin9; andGLC1G, WDR36.104 Each of thesegenes is only responsible for a smallfraction of cases of POAG, reflect-ing the small percentage of POAGthat is inherited as a mendelian traitrather than as a complex trait.

Genomic studies using model-free linkage analysis (complex dis-ease gene approaches) have identi-fied the chromosome locations ofadult-onset POAG susceptibilitygenes. Using mainly white US sib-ling pairs affected by POAG, 7 ge-nomic regions were identified,6 andrecent follow-up information on thispopulation demonstrates additionalevidence for POAG-susceptibility locion chromosomes 14q11 (locus pend-ing) (J.L.W., unpublished data, 2006)and 15q (GLC1I).114,115 A study of sib-ling pairs from Barbados affected byPOAG has identified 2 regions onchromosomes 2q and 10p as highlysignificant for POAG in this popula-tion,116 and a study of West Africansselected for elevated IOP have foundloci on 5q and 14q.117 Because thesestudies were conducted using a largenumber of families affected by typi-cal late-onset glaucoma, the geneslocated in these chromosome re-gions are likely to be significant riskfactors for POAG. Single nucleotidepolymorphism–basedapproachesareproving successful for complex dis-eases,14-18 and theapplicationof thesetechnologies to adult-onset POAG isthe focus of current studies.

Pseudoexfoliation

Although a linkage study has not yetbeen completed for pseudoexfolia-tion glaucoma, systemic abnormali-ties, including elevation of homocys-teine, have been identified in affectedpatients.118-120 Evaluating the ge-netic factors that contribute to thesesystemic problems may lead to newinsights about this common form ofglaucoma.

GENES ASSOCIATEDWITH PRIMARY

OPTIC NEUROPATHIES

Inherited disorders of the optic nerveinclude degenerative processes (pri-

marily glaucoma, as described pre-viously), as well as primary disor-ders causing optic nerve atrophy.121

Mitochondrial function is a criticalelement in optic nerve disease:Leber hereditary optic neuropathyis caused by missense mutations inmitochondrial DNA,122 while Kjerautosomal-dominant optic atrophyis caused by mutations in the OPA1gene. The protein product of OPA1,a dynamin-related GTPase, also hasa role in mitochondrial function.123

OPA1 DNA sequence variants maybe associated with low-tension glau-coma in some patients.92

FUTURE DIRECTIONS

Genotype-PhenotypeCorrelations and Clinical

Outcomes Studies

The clinical features that define glau-coma phenotypes associated withspecific mutations (genotypes) mustbe established before useful clini-cal information can be acquired fromDNA-based diagnostic testing. Forthe genes that have been identifiedas responsible for glaucoma, or as-sociated with glaucoma, clinicalinformation about the onset of dis-ease, course of disease, and re-sponse to therapy needs to be col-lected. As new genes responsible fordifferent forms of inherited glau-coma are discovered, clinical dis-ease features should be correlatedwith specific mutations. These geno-type-phenotype studies will in-clude the answers to the followingquestions: (1) What is the range ofphenotypic variation of a given mu-tation, ie, can one predict the prog-nosis of the disease knowing the spe-cific mutation responsible for thedisease? (2) Are certain mutationsassociated with particular aspects ofthe disease phenotype? (3) Are cer-tain mutations necessary but not suf-ficient to cause the disease? Suchmutations would require other ad-ditional genetic defects or environ-mental factors to be fully manifest.The development of genotype-phenotype databases for glaucomagenes and mutations will be an im-portant step toward clinically use-ful DNA-based diagnostic testing forglaucoma.




Identification of New Genes

Genetic factors are at least in part re-sponsible for all forms of glaucoma,with the exception of glaucoma re-lated to trauma and infection. Cur-rently, the genetic origins of the ma-jorityofglaucomacasesareunknown,as the known genes account for onlya small fraction of heritable cases.With the advent of single nucleotidepolymorphism–based technologies, itis likelythatanumberofgenesrespon-sible for glaucoma will be identifiedinthenext5years.Genesthatcontrib-ute toglaucomamay influenceeleva-tion of IOP or susceptibility to opticnervedegeneration,orboth.Itishighlylikely, as inanycomplexdisease, thatcomplex forms of glaucoma, such asadult-onset POAG, result not onlyfromthe independentactionsofmul-tiple genes but also from the interac-tion of multiple genes (epistasis).

Gene-Environment Interactions

For late-onsetdiseases it is likely thatthe genetically determined diseasefeatures are more sensitive to envi-ronmental influences because of dis-ruption of normal physiologic ho-meostatic mechanisms. Currently,little is known about environmentalfactors that may influence the onsetor progression of adult-onset POAG.Recentstudiessuggest that factors re-lated to glaucoma metabolism andtype IIdiabetesmellitusmay increasethe risk of glaucoma.124 Another in-teresting gene-environment interac-tionthatpredisposespatients toglau-coma is steroid responsiveness, bothfromendogeneoussteroids(ie,stress)andpharmacologicsteroids.125 Evalu-ation of environmental factors thatmay be associated with POAG is on-going,andinvestigations intospecificgene-environment interactions inpa-tients with adult-onset POAG is alsounder way.

Developing a Diagnostic Panelfor Patients at Risk for Glaucoma

One of the goals of disease gene dis-covery is the development of predic-tivediagnostic tests.Foradisease suchas glaucoma, where early treatmentcan be beneficial, diagnostic tests de-signed to identify individuals at riskfor the disease can be particularly

valuable. Current testing for glau-coma genes is limited to genes that areknown to be associated with glau-coma and is primarily diagnostic,rather than prognostic. Except forspecific mutations in the MYOC andOPTN genes, details regarding thepredicted clinical course associatedwith a glaucoma gene mutation can-not be provided. Genotype-pheno-type studies as outlined earlier willhelp define the prognostic aspects ofcurrentlyknownglaucomagenemu-tations. Ultimately the goal is to dis-cover a complete panel of genes thatcontribute to glaucoma and developdiagnostic and prognostic correlatesfor themutations found ineachgene.Suchapanelwouldprovideamecha-nismto identify individualsat risk forthe disease and initiate timely treat-ment before irreversible optic nervedegeneration and blindness occurs.

Submitted for Publication: August4, 2006; final revision received Sep-tember 24, 2006; accepted Septem-ber 26, 2006.Correspondence: Janey L. Wiggs,MD, PhD, Department of Ophthal-mology, Massachusetts Eye and EarInfirmary, 243 Charles St, Boston,MA 02114 ([email protected]).Financial Disclosure: None re-ported.

REFERENCES

1. Friedman DS, Wolfs RC, O’Colmain BJ, et al.Prevalence of open-angle glaucoma among adultsin the United States. Arch Ophthalmol. 2004;122:532-538.

2. Weih LM, Nanjan M, McCarty CA, Taylor HR.Prevalence and predictors of open-angle glau-coma: results from the visual impairment project.Ophthalmology. 2001;108:1966-1972.

3. Inman DM, Sappington RM, Horner PJ, CalkinsDJ. Quantitative correlation of optic nerve pa-thology with ocular pressure and corneal thick-ness in the DBA/2 mouse model of glaucoma.Invest Ophthalmol Vis Sci. 2006;47:986-996.

4. Fisher SA, Abecasis GR, Yashar BM, et al. Meta-analysis of genome scans of age-related macu-lar degeneration. Hum Mol Genet. 2005;14:2257-2264.

5. Stambolian D, Ibay G, Reider L, et al. Genome-wide linkage scan for myopia susceptibility lociamong Ashkenazi Jewish families show evi-dence of linkage on chromosome 22q12. Am JHum Genet. 2004;75:448-459.

6. Wiggs JL, Allingham RR, Hossain A, et al. Ge-nome-wide scan for adult onset primary openangle glaucoma. Hum Mol Genet. 2000;9:1109-1117.

7. Stone EM, Fingert JH, Alward WL, et al. Identi-

fication of a gene that causes primary open angleglaucoma. Science. 1997;275:668-670.

8. Allikmets R, Singh N, Sun H, et al. A photore-ceptor cell-specific ATP-binding transportergene (ABCR) is mutated in recessive Stargardtmacular dystrophy. Nat Genet. 1997;15:236-246.

9. Rezaie T, Child A, Hitchings R, et al. Adult-onset primary open-angle glaucoma caused bymutations in optineurin. Science. 2002;295:1077-1079.

10. Wiggs JL, Allingham RR, Vollrath D, et al. Preva-lence of mutations in TIGR/Myocilin in patients withadult and juvenile primary open-angle glaucoma.Am J Hum Genet. 1998;63:1549-1552.

11. Fingert JH, Heon E, Liebmann JM, et al. Analy-sis of myocilin mutations in 1703 glaucoma pa-tients from five different populations. Hum MolGenet. 1999;8:899-905.

12. De La Paz MA, Guy VK, Abou-Donia S, et al.Analysis of the Stargardt disease gene (ABCR)in age-related degeneration. Ophthalmology.1999;106:1531-1536.

13. Wiggs JL, Auguste J, Allingham RR, et al. Lackof association of mutations in optineurin with dis-ease in patients with adult-onset primary open-angle glaucoma. Arch Ophthalmol. 2003;121:1181-1183.

14. Haines JL, Hauser MA, Schmidt S, et al. Comple-ment factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419-421.

15. Edwards AO, Ritter R III, Abel KJ, Manning A,Panhuysen C, Farrer LA. Complement factor Hpolymorphism and age-related maculardegeneration. Science. 2005;308:421-424.

16. Klein RJ, Zeiss C, Chew EY, et al. Complementfactor H polymorphism in age-related maculardegeneration. Science. 2005;308:385-389.

17. Hageman GS, Anderson DH, Johnson LV, et al.A common haplotype in the complement regu-latory gene factor H (HF1/CFH) predisposes in-dividuals to age-related macular degeneration.Proc Natl Acad Sci U S A. 2005;102:7227-7232.

18. Zareparsi S, Branham KE, Li M, et al. Strong as-sociation of the Y402H variant in complementfactor H at 1q32 with susceptibility to age-related macular degeneration. Am J Hum Genet.2005;77:149-153.

19. Allen TD, Ackerman WG. Hereditary glaucomain a pedigree of three generations. ArchOphthalmol. 1942;27:139-157.

20. Johnson AT, Drack AV, Kwitek AE, Cannon RL,Stone EM, Alward WL. Clinical features and link-age analysis of a family with autosomal domi-nant juvenile glaucoma. Ophthalmology. 1993;100:524-529.

21. Sheffield VC, Stone EM, Alward WLM, et al.Genetic linkage of familial open-angle glau-coma to chromosome 1q21-q31. Nat Genet.1993;4:47-50.

22. Richards JE, Lichter PR, Boehnke M, et al.Mapping of a gene for autosomal dominant ju-venile-onset open-angle glaucoma to chromo-some Iq. Am J Hum Genet. 1994;54:62-70.

23. Wiggs JL, Del Bono EA, Schuman JS, Hutchin-son BT, Walton DS. Clinical features of five pedi-grees genetically linked to the juvenile glau-coma locus on chromosome 1q21-q31.Ophthalmology. 1995;102:1782-1789.

24. Gencik A. Epidemiology and genetics of pri-mary congenital glaucoma in Slovakia: descrip-tion of a form of primary congenital glaucomain gypsies with autosomal dominant inherit-




ance and complete penetrance. Dev Ophthalmol.1989;16:76-115.

25. Fitch N, Kaback M. The Axenfeld syndrome andthe Rieger syndrome. J Med Genet. 1978;15:30-34.

26. Murray JC, Bennett SR, Kwitek AE, et al. Link-age of Rieger syndrome to the region of the epi-dermal growth factor gene on chromosome 4.Nat Genet. 1992;2:46-49.

27. Mears AJ, Mirzayans F, Gould DB, et al. Auto-somal dominant iridogoniodysgensis anomalymaps to 6p25. Am J Hum Genet. 1996;59:1321-1327.

28. Phillips JC, del Bono EA, Haines JL, et al. A sec-ond locus for Rieger syndrome maps to chro-mosome 13q14. Am J Hum Genet. 1996;59:613-619.

29. Lichter PR, Richards JE, Downs CA, StringhamHM, Boehnke M, Farley FA. Cosegregation ofopen-angle glaucoma and the nail-patellasyndrome. Am J Ophthalmol. 1997;124:506-515.

30. Othman MI, Sullivan SA, Skuta GL, et al. Auto-somal dominant nanophthalmos (NNO1) withhigh hyperopia and angle-closure glaucoma mapsto chromosome 11. Am J Hum Genet. 1998;63:1411-1418.

31. Mandelkorn RM, Hoffman ME, Olander KW, Zim-merman TJ, Harsha D. Inheritance and the pig-mentary dispersion syndrome. Ann Ophthalmol.1983;15:577-582.

32. Paglinauan C, Haines JL, DelBono EA, Schu-man J, Stawski SK, Wiggs JL. Exclusion of chro-mosome 1q21-q31 from linkage to three pedi-grees affected by the pigment dispersionsyndrome. Am J Hum Genet. 1995;56:1240-1243.

33. Andersen JS, Pralea AM, DelBono EA, et al.A gene responsible for the pigment dispersionsyndrome maps to chromosome 7q35-q36. ArchOphthalmol. 1997;115:384-388.

34. Bovell AM, Damji KF, Dohadwala AA, Hodge WG,Allingham RR. Familial occurrence of pigmentdispersion syndrome. Can J Ophthalmol. 2001;36:11-17.

35. Stoilov I, Akarsu AN, Sarfarazi M. Identificationof three different truncating mutations in cyto-chrome P4501B1 (CYP1B1) as the principalcause of primary congenital glaucoma (Buph-thalmos) in families linked to the GLC3A locuson chromosome 2p21. Hum Mol Genet. 1997;6:641-647.

36. Bejjani BA, Lewis RA, Tomey KF, et al. Muta-tions in CYP1B1, the gene for P4501B1, are thepredominant cause of primary congenital glau-coma in Saudi Arabia. Am J Hum Genet. 1998;62:325-333.

37. Stoilov I, Akarsu AN, Alozie I, et al. Sequenceanalysis and homology modeling suggest thatprimary congenital glaucoma on 2p21 resultsfrom mutations disrupting either the hinge re-gion or the conserved core structures of cyto-chrome P4501B1. Am J Hum Genet. 1998;62:573-584.

38. Sena DF, Finzi S, Rodgers K, Del Bono E, HainesJL, Wiggs JL. Founder mutations of CYP1B1 genein patients with congenital glaucoma from theUnited States and Brazil. J Med Genet. 2004;41:e6.

39. Tsuchiya Y, Nakajima M, Kyo S, Kanaya T, In-oue M, Yokoi T. Human CYP1B1 is regulated byestradiol via estrogen receptor. Cancer Res. 2004;64:3119-3125.

40. Jansson I, Stoilov I, Sarfarazi M, Schenkman JB.Effect of two mutations of human CYP1B1, G61E

and R469W, on stability and endogenous ste-roid substrate metabolism. Pharmacogenetics.2001;11:793-801.

41. Bejjani BA, Stockton DW, Lewis RA, et al. Mul-tiple CYP1B1 mutations and incomplete pen-etrance in an inbred population segregating pri-mary congenital glaucoma suggest frequent denovo events and a dominant modifier locus. HumMol Genet. 2000;9:367-374.

42. Libby RT, Smith RS, Savinova OV, et al. Modi-fication of ocular defects in mouse developmen-tal glaucoma models by tyrosinase. Science.2003;299:1578-1581.

43. Bidinost C, Hernandez N, Edward DP, et al.Of mice and men: tyrosinase modification ofcongenital glaucoma in mice but not inhumans. Invest Ophthalmol Vis Sci. 2006;47:1486-1490.

44. Akarsu AN, Turacli ME, Aktan SG, et al. A sec-ond locus (GLC3B) for primary congenital glau-coma (Buphthalmos) maps to the 1p36 region.Hum Mol Genet. 1996;5:1199-1203.

45. Cohn AC, Kearns LS, Savarirayan R, Ryan J, CraigJE, Mackey DA. Chromosomal abnormalities andglaucoma: a case of congenital glaucoma withtrisomy 8q22-qter/monosomy 9p23-pter. Oph-thalmic Genet. 2005;26:45-53.

46. Simha N, Verin P, Gauthier L. Congenital glau-coma of dominant autosomal transmission ap-ropos of a family [in French]. Bull Soc Ophtal-mol Fr. 1989;89:1149-1151.

47. Semina EV, Reiter R, Leysens NJ, et al. Cloningand characterization of a novel bicoid-related ho-meobox transcription factor gene, RIEG, in-volved in Rieger syndrome. Nat Genet. 1996;14:392-399.

48. Nishimura DY, Searby CC, Alward WL, et al.A spectrum of FOXC1 mutations suggests genedosage as a mechanism for developmental de-fects of the anterior chamber of the eye. Am JHum Genet. 2001;68:364-372.

49. Mears AJ, Jordan T, Mirzayans F, et al. Muta-tions of the forkhead/winged-helix gene, FKHL7,in patients with Axenfeld-Rieger anomaly. Am JHum Genet. 1998;63:1316-1328.

50. Van Heyningen V, Williamson KA. PAX6 in sen-sory development. Hum Mol Genet. 2002;11:1161-1167.

51. Hamlington JD, Jones C, McIntosh I. Twenty-two novel LMX1B mutations identified in nail pa-tella syndrome (NPS) patients. Hum Mutat. 2001;18:458.

52. Yardley J, Leroy BP, Hart-Holden N, et al. Mu-tations of VMD2 splicing regulators causenanophthalmos and autosomal dominant vitreo-retinochoroidopathy (ADVIRC). Invest Ophthal-mol Vis Sci. 2004;45:3683-3689.

53. Lines MA, Kozlowski K, Walter MA. Moleculargenetics of Axenfeld-Rieger malformations. HumMol Genet. 2002;11:1177-1184.

54. Gould DB, John SWM. Anterior segment dys-genesis and the developmental glaucomas arecomplex traits. Hum Mol Genet. 2002;11:1185-1193.

55. Trainor PA, Tam PP. Cranial paraxial meso-derm and neural crest cells of the mouse em-bryo: co-distribution in the craniofacial mesen-chyme but distinct segregation in branchialarches. Development. 1995;121:2569-2582.

56. Beebe DC, Coats JM. The lens organizes the an-terior segment: specification of neural crest celldifferentiation in the avian eye. Dev Biol. 2000;220:424-431.

57. Fuhrmann S, Levine EM, Reh TA. Extraocular mes-enchyme patterns the optic vesicle during early

eye development in the embryonic chick.Development. 2000;127:4599-4609.

58. Vincent AL, Billingsley G, Buys Y, et al. Digenicinheritance of early-onset glaucoma: CYP1B1, apotential modifier gene. Am J Hum Genet. 2002;70:448-460.

59. Kulkarni NH, Karavanich C, Atchley W, AnholtR. Characterization and differential expressionof a human gene family of olfactomedin-relatedproteins. Genet Res. 2000;76:41-50.

60. Lam DS, Leung YF, Chua JK, et al. Truncationsin the TIGR gene in individuals with and with-out primary open-angle glaucoma. Invest Oph-thalmol Vis Sci. 2000;41:1386-1391.

61. Wiggs JL, Vollrath D. Molecular and clinical evalu-ation of a patient hemizygous for TIGR/MYOC.Arch Ophthalmol. 2001;119:1674-1678.

62. Kim BS, Savinova OV, Reedy MV, et al. Tar-geted disruption of the myocilin gene (Myoc) sug-gests that human glaucoma-causing mutationsare gain of function. Mol Cell Biol. 2001;21:7707-7713.

63. Ueda J, Wentz-Hunter K, Yue BY. Distribution ofmyocilin and extracellular matrix components inthe juxtacanalicular tissue of human eyes. In-vest Ophthalmol Vis Sci. 2002;43:1068-1076.

64. Filla MS, Liu X, Nguyen TD, et al. In vitro local-ization of TIGR/MYOC in trabecular meshworkextracellular matrix and binding to fibronectin.Invest Ophthalmol Vis Sci. 2002;43:151-161.

65. Jacobson N, Andrews M, Shepard AR, et al.Non-secretion of mutant proteins of the glau-coma gene myocilin in cultured trabecular mesh-work cells and in aqueous humor. Hum MolGenet. 2001;10:117-125.

66. Caballero M, Rowlette LL, Borras T. Altered se-cretion of a TIGR/MYOC mutant lacking the ol-factomedin domain. Biochim Biophys Acta. 2000;1502:447-460.

67. Zillig M, Wurm A, Grehn F, Russell P, Tamm ER.Overexpression and properties of wild-type andTyr437His mutated myocilin in the eyes of trans-genic mice. Invest Ophthalmol Vis Sci. 2005;46:223-234.

68. Zhou Z, Vollrath D. A cellular assay distin-guishes normal and mutant TIGR/myocilinprotein. Hum Mol Genet. 1999;8:2221-2228.

69. Liu Y, Vollrath D. Reversal of mutant myocilin non-secretion and cell killing: implications for glaucoma.Hum Mol Genet. 2004;13:1193-1204.

70. Gobeil S, Rodrigue MA, Moisan S, et al. Intrac-ellular sequestration of hetero-oligomers formedby wild-type and glaucoma-causing myocilinmutants. Invest Ophthalmol Vis Sci. 2004;45:3560-3567.

71. Gobeil S, Letartre L, Raymond V. Functional analy-sis of the glaucoma-causing TIGR/myocilin pro-tein: integrity of amino-terminal coiled-coil re-gions and olfactomedin homology domain isessential for extracellular adhesion and secretion.Exp Eye Res. 2006;82:1017-1029.

72. Vollrath D, Liu Y. Temperature sensitive secre-tion of mutant myocilins. Exp Eye Res. 2006;82:1030-1036.

73. Aroca-Aguilar JD, Sanchez-Sanchez F, Ghosh S,Coca-Prados M, Escribano J. Myocilin mutationscausingglaucomainhibit the intracellularendopro-telytic cleavage of myocilin between animo acidsArg 226 and Ile 227. J Biol Chem. 2005;280:21043-21051.

74. Finzi S, Pinto CF, Wiggs JL. Molecular and clini-cal characterization of a patient with a chromo-some 4p deletion, Wolf-Hirschhorn syndrome,and congenital glaucoma. Ophthalmic Genet.2001;22:35-41.




75. Ferguson JG Jr, Hicks EL. Rieger’s anomaly andglaucoma associated with partial trisomy 16q:case report. Arch Ophthalmol. 1987;105:323.

76. Kogame K, Fukuhara T, Maeda A, Kudo Y. A par-tial short arm deletion of chromosome 20:46, XY,del(20)(p11). Jinrui Idengaku Zasshi. 1978;23:153-160.

77. Furuta Y, Hogan BL. BMP4 is essential for lensinduction in the mouse embryo. Genes Dev. 1998;12:3764-3775.

78. Chang B, Smith RS, Peters M, et al. Haploinsuf-ficient Bmp4 ocular phenotypes include ante-rior segment dysgenesis with elevated intraocu-lar pressure. BMC Genet. 2001;2:18.

79. Blixt A, Mahlapuu M, Aitola M, Pelto-Huikko M,Enerback S, Carlsson P. A forkhead gene, FoxE3is essential for lens epithelial proliferation andclosure of the lens vesicle. Genes Dev. 2000;14:245-254.

80. Saika S, Liu CY, Azhar M, et al. TGFbeta2 in cor-neal morphogenesis during mouse embryonicdevelopment. Dev Biol. 2001;240:419-432.

81. John SW, Smith RS, Savinova OV, et al. Essen-tial iris atrophy, pigment dispersion, and glau-coma in DBA/2J mice. Invest Ophthalmol Vis Sci.1998;39:951-962.

82. Chang B, Smith RS, Hawes NL, et al. Interact-ing loci cause severe iris atrophy and glaucomain DBA/2J mice. Nat Genet. 1999;21:405-409.

83. Anderson MG, Smith RS, Hawes NL, et al. Mu-tations in genes encoding melanosomal pro-teins cause pigmentary glaucoma in DBA/2Jmice. Nat Genet. 2002;30:81-85.

84. Sundin OH, Leppert GS, Silva ED, et al. Extremehyperopia is the result of null mutations in MFRP,which encodes a Frizzled-related protein. ProcNatl Acad Sci U S A. 2005;102:9553-9558.

85. Bruttini M, Longo I, Frezzotti P, et al. Mutationsin the myocilin gene in families with primaryopen-angle glaucoma and juvenile open-angleglaucoma. Arch Ophthalmol. 2003;121:1034-1038.

86. Wiggs JL, Lynch S, Ynagi G, et al. A genome-wide scan identifies novel early-onset primaryopen-angle glaucoma loci on 9q22 and 20p12.Am J Hum Genet. 2004;74:1314-1320.

87. Pang CP, Fan BJ, Canlas O, et al. A genome-wide scan maps a novel juvenile-onset primaryopen angle glaucoma locus to chromosome 5q.Mol Vis. 2006;12:85-92.

88. Budde WM, Jonas JB. Family history of glau-coma in the primary and secondary open-angleglaucomas. Graefes Arch Clin Exp Ophthalmol.1999;237:554-557.

89. Damji KF, Bains HS, Amjadi K, et al. Familial oc-currence of pseudoexfoliation in Canada. Can JOphthalmol. 1999;34:257-265.

90. Allingham RR, Loftsdottir M, Gottfredsdottir MS,et al. Pseudoexfoliation syndrome in Icelandicfamilies. Br J Ophthalmol. 2001;85:702-707.

91. Anderson DR, Drance SM, Schulzer M; Collabo-rative Normal-Tension Glaucoma Study Group.Factors that predict the benefit of lowering in-traocular pressure in normal tension glaucoma.Am J Ophthalmol. 2003;136:820-829.

92. Aung T, Ocaka L, Ebenezer ND, et al. A majormarker for normal tension glaucoma: associa-tion with polymorphisms in the OPA1 gene. HumGenet. 2002;110:52-56.

93. Yan X, Tezel G, Wax MB, Edward DP. Matrix met-alloproteinases and tumor necrosis factor al-

pha in glaucomatous optic nerve head. ArchOphthalmol. 2000;118:666-673.

94. Yuan L, Neufeld AH. Tumor necrosis factor-alpha: a potentially neurodestructive cytokine pro-duced by glia in the human glaucomatous opticnerve head. Glia. 2000;32:42-50.

95. Alward WL, Kwon YH, Kawase K, et al. Evalua-tion of optineurin sequence variations in 1,048patients with open-angle glaucoma. Am JOphthalmol. 2003;136:904-910.

96. Tang S, Toda Y, Kashiwagi K, et al. The asso-ciation between Japanese primary open-angleglaucoma and normal tension glaucoma pa-tients and the optineurin gene. Hum Genet. 2003;113:276-279.

97. Aung T, Rezaie T, Okada K, et al. Clinical fea-tures and course of patients with glaucoma withthe E50K mutation in the optineurin gene. In-vest Ophthalmol Vis Sci. 2005;46:2816-2822.

98. Hauser MA, Figueiredo Sena D, Flor JD, et al.Distribution of optineurin sequence variations inan ethnically diverse population of low tensionglaucoma patients from the United States.J Glaucoma. 2006;15:358-363.

99. Ariani F, Longo I, Frezzotti P, et al. Optineuringene is not involved in the common high-tension form of primary open-angle glaucoma.Graefes Arch Clin Exp Ophthalmol. 2006;244:1077-1082.

100. Golubnitschaja-Labudova O, Liu R, Decker C, ZhuP, Haefliger IO, Flammer J. Altered gene expres-sion in lymphocytes of patients with normal-tension glaucoma. Curr Eye Res. 2000;21:867-876.

101. Alward WL, Fingert JH, Coote MA, et al. Clinicalfeatures associated with mutations in the chro-mosome 1 open-angle glaucoma gene (GLC1A).N Engl J Med. 1998;338:1022-1027.

102. Angius A, Spinelli P, Ghilotti G, et al. MyocilinGln368stop mutation and advanced age as risk fac-tors for late-onset primary open-angle glaucoma.Arch Ophthalmol. 2000;118:674-679.

103. Baird PN, Richardson AJ, Mackey DA, Craig JE,Faucher M, Raymond V. A common disease hap-lotype for the Q368STOP mutation of the myo-cilin gene in Australian and Canadian glaucomafamilies. Am J Ophthalmol. 2005;140:760-762.

104. Monemi S, Spaeth G, DaSilva A, et al. Identifi-cation of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1. HumMol Genet. 2005;14:725-733.

105. Hewitt AW, Dimasi DP, Mackey DA, Craig JE.A glaucoma case-control study of the WDR36gene D658G sequence variant. Am J Ophthalmol.2006;142:324-325.

106. Mao M, Biery MC, Kobayashi SV, et al. T lym-phocyte activation gene identification by coregu-lated expression on DNA microarrays. Genomics.2004;83:989-999.

107. Yang J, Patil RV, Yu H, Gordon M, Wax MB.T cell subsets and sIL-2R/IL-2 levels in patientswith glaucoma. Am J Ophthalmol. 2001;131:421-426.

108. Hauser MA, Allingham RR, Linkroum K, et al.Distribution of WDR36 DNA sequence variantsin patients with primary open-angle glaucoma.Invest Ophthalmol Vis Sci. 2006;47:2542-2546.

109. Stoilova D, Child A, Trifan O, Crick R, Coakes R,Sarfarazi M. Localization of a locus (GLC1B) foradult-onset primary open angle glaucoma to the

2cen-q13 region. Genomics. 1996;36:142-150.

110. Wirtz MK, Samples J, Kramer P, et al. Mappinga gene for adult-onset primary open-angle glau-coma to chromosome 3q. Am J Hum Genet.1997;60:296-304.

111. Trifan OC, Traboulsi E, Stoilova D, et al. A thirdlocus (GLC1D) for adult-onsest primary open-angle glaucoma maps to the 8q23 region. Am JOphthalmol. 1998;126:17-28.

112. Sarfarazi M, Child A, Stoilova D, et al. Localiza-tion of the fourth locus (GLC1E) for adult-onsetprimary open-angle glaucoma to the 10p15-p14 region. Am J Hum Genet. 1998;62:641-652.

113. Wirtz MK, Samples J, Rust K, et al. GLC1F, a newprimary open-angle glaucoma locus, maps to7q35-q36. Arch Ophthalmol. 1999;117:237-241.

114. Allingham RR, Wiggs JL, Hauser E, et al. Earlyadult-onset POAG linked to 15q11-13 using or-dered subsets analysis. Invest Ophthalmol VisSci. 2005;46:2002-2005.

115. Woodroffe A, Krafchak CM, Fuse N, et al. Or-dered subset analysis supports a glaucoma lo-cus at GLC1I on chromosome 15 in families withearlier adult age at diagnosis. Exp Eye Res. 2006;82:1068-1074.

116. Nemesure B, Jiao X, He Q, et al; Barbados Fam-ily Study Group. A genome-wide scan for pri-mary open-angle glaucoma (POAG): the Barba-dos Family Study of Open-Angle Glaucoma. HumGenet. 2003;112:600-609.

117. Rotimi CN, Chen G, Adeyemo AA, et al. Genome-wide scan and fine mapping of quantitative traitloci for intraocular pressure on 5q and 14q inWest Africans. Invest Ophthalmol Vis Sci. 2006;47:3262-3267.

118. Leibovitch I, Kurtz S, Shemesh G, et al. Hyper-homocystinemia in pseudoexfoliation glaucoma.J Glaucoma. 2003;12:36-39.

119. Bleich S, Roedl J, Von Ahsen N, et al. Elevatedhomocysteine levels in aqueous humor of pa-tients with pseudoexfoliation glaucoma. Am JOphthalmol. 2004;138:162-164.

120. Altintas O, Maral H, Yuksel N, Karabas VL, Dillio-glugil MO, Caglar Y. Homocysteine and nitric ox-ide levels in plasma of patients with pseudoexfo-liation syndrome, pseudoexfoliation glaucoma, andprimary open-angle glaucoma. Graefes Arch ClinExp Ophthalmol. 2005;243:677-683.

121. Newman NJ. Hereditary optic neuropathies: fromthe mitochondria to the optic nerve. Am JOphthalmol. 2005;140:517-523.

122. Valentino ML, Barboni P, Ghelli A, et al. The ND1gene of complex I is a mutational hot spot forLeber’s hereditary optic neuropathy. Ann Neurol.2004;56:631-641.

123. Olichon A, Guillou E, Delettre C, et al. Mitochon-drial dynamics and disease, OPA1. Biochim Bio-phys Acta. 2006;1763:500-509.

124. Pasquale LR, Kang JH, Manson JE, Willett WC,Rosner BA, Hankinson SE. Prospective study oftype 2 diabetes mellitus and risk of primary open-angle glaucoma in women. Ophthalmology. 2006;113:1081-1086.

125. Zhang X, Clark AF, Yorio T. Regulation of glu-cocorticoid responsiveness in glaucomatous tra-becular meshwork cells by glucocorticoidreceptor-beta. Invest Ophthalmol Vis Sci. 2005;46:4607-4616.




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