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Relatinship between high mypia and primary
pen-angle glaucma
Ping Wang, De- Yong Jiang
!"#$%&$
!AIM: To review the relationship between high myopia
(HM) and primary open angle glaucoma (POAG) Irom the
aspects oI epidemiological Ieatures , clinic Ieatures , diag -
nosis , as well as genetic and molecular mechanism .
!METHODS: Twenty- eight original articles related to this
issue were selected . These articles were careIully re-
viewed to Iind out the possible mechanism oI the rela -
tionship between HM and POAG.
!RESULTS: HM is a genetically-associated disease and is
closely related with POAG. According to the TIGR gene
theory and the collagen gene theory , HM and POAG are
both associated with the mutations oI TIGR and collage -
nous lesions .
!CONCLUSIONS: HM and POAG are closely related to
each other in that their mechanisms are both related to
hyper tension gene and collagen gene .
!KEYWORDS: high myopia ; primary open-angle glauco -
ma ; TIGRgene
WangP,JiangDY.Relationshipbetweenhighmyopiaandprima-
ryopen-angleglaucoma.Int J Ophthalmol,2004;4(2):232-236
INTRODUCTION
H
ighmyopia(HM), alsocalledpathologicalmyopia
orprogressivemyopiaordegenerativemyopia, is
highlyprevalentandmayleadtoblindness. ItisoIten
characteristicoIdegenerativealterationin theposterior
Iundus. An epidemiologicalinvestigationshowedthat
theincidenceoIHMingeneralChinesepopulationwas
ashighas6.98
1|
. In the past two decades, many oph-
thalmologists have been engaged in the etiological stud-
ies oI HM, the purpose oI which is to clariIy the pro-
gressive mechanisms oI myopia Irom the environmental
and genetic viewpoints, but so Iar, no satisIactory con-
clusion is drawn. HM is generally recognized as a sort oI
genetics-associated disease closely related with POAG,
which is passed on as an autosomal-recessive trait as
well as a polygenic inheritance trait. With the rapid de-
velopment in molecular genetics, great achievements
have been made in the research oI glaucoma oI various
types. In particular, TIGR gene has been identiIied as a
causative gene oI glaucoma and candidate-gene oI
POAG
2-4|
. Mechanism oI POAG has been elucidated
Irom the points oI genetics and molecular biology. It is
pointed out that the deIects oI TIGR gene and the alter-
ation oI environmental Iactors may both lead to the oc-
currence oI TIGR-a speciIic protein in the trabecular
meshwork, which will cause IOP elevation.
These achievements can surely help reveal the etiologi-
cal mechanism oI HM in the near Iuture, and open a
path toward a better understanding oI HM and POAG
pathogenesis.
EPIDEMIOLOGY
The close relationship between HM and POAG has
been the interest oI many researchers. It is estimated
that IOP elevates in more than 27.8 oI HM population
and IOP elevation is a major causative Iactor oI HM and
contributes to its aggravation. Perkins also pointed out
that POAG, ocular hypertension and lower tension
glaucoma were oIten accompanied with HM while the
Department oI Ophthalmology, the Second Xiangya Hospital,
Central South University, Changsha 410011, Hunan Province,
China
Crrespndence t: Ping Wang. Department oI Ophthalmology,
the Second Xiangya Hospital, Central South University, Changsha
410011, Hunan Province, China. wangping22sina.com
Received: 2004-02-06
Original article
232
Internatonal Journal of Ophthalmology, Vol.4, No.2 Apr. 2004
Tel:029-82245172 Emal:IJO.2000@163.com
prevalece rateoIHM washigherithePOAG popula-
tio tha i geeral populatio. TheelevatiooIIOP
cotributestotheosetoIHM. Cliicaldataadepi-
demic ivestigatios show that icidece oI HM i
POAGpopulatiohasreached1.20
|5|
,whichissigiI-
icatlyhigherthathatigeeralpopulatio
|1|
. Partly
due tothe growigawareessoIHM-POAG, ad the
improveddiagosis, morepatiets ca be giveright
ad early diagosis, ad higher icidece oI HM-
POAGhasbeereportedirecetyears.
CLINIC FEATURES
ComparedtoPOAG,thecliicalIeaturesoIHM-POAG
areasIollows.!Itisusuallyoccult,especiallyiearly
stage;"IOPmustbecorrectediImeasuredwithSchi-
etz Toometrydue to the decrease oI coeIIiciecyoI
scleral rigidity (CSR). IOP measured with Goldma
Toometry teds to be higher. CoeIIiciet oI outIlow Ia-
cility (C value) isudermeavaluewhilethePo/Cis
icreased
|5|
; # Ateriorchamberisdeeperadcoreal
curvature is larger but the structure oI the aterior
chamberagleis otchaged; $ I the visualIield
somecharacteristicchagecabeoticed. Blidspot
appears earlier ad more oIte. However due to
choroidoretialatrophy irregularblidspotsmayoccur
adthusresultiatypicalvisualIieldloss
|6|
;%Abor-
mal cotrast sesitivity ca be detected i the early
stageadismoreremarkable;&Theopticdiscisoval
obliquelyisertedorpartlydeIected.Itispale.Theop-
ticcupisoIvariousIorms.Theratiobetweethemargi
areaad diameteroIthedisk is remarkablylowertha
that i POAG. Excavatio oIthe optic disc teds to
happeithecetraltoiIeriorarea. LocalatrophyoI
retialerveIiberlayer (RNFL) occursmostlyithe
lowretia whilediIIuseRNFLis closelyrelated tothe
visualIieldloss
|67|
.
DIAGNOSIS
ItisdiIIiculttodiagoseHM-POAGitheearlyphase
because its cliicalIeaturesare diIIeretIromthoseoI
classicPOAGitheIollowigways. !Itdevelopswith
o sigiIicatelevatiooIIOP; " Due to the mar-
crodisci HM the glaucomatousexcavatiooIoptic
erveheadcaotbeeasilyrecogized
|8|
; #Thee-
larged cous oIopticdisc prevets examiersIromi-
detiIyigpalloradatrophyoItheopticdisc;$Over-
lappigadtraspositiooIthetemporalretialvessels
dootoccurastheyareoItestraighteedasaresultoI
theover-tractioIromtheasalscleraadchoroid
|9|
; %
MaycasesoIearlyHM-POAGhaveIailedtobe rec-
ogized, due to the progressoImyopia. I the past
decade, however, diagosticskillsad techologyoI
HM-POAG have largely improved due to abudat
cliicaldataoHM-POAG
|6,9,10|
,especiallyothemor-
phologyoIoptic erve head ad the optic erve Iiber
deIects.
I diagosisoIpossibleHM-POAG, specialattetio
shouldbepaidtotheIollowig aspects. ! IOPmea-
suredwiththeimpressiotoometermustbecorrected.
Comparedwiththeimpressiotoometry, Goldmaap-
plaatiotoometryad toographyare recommeded;
"VisualIieldshouldbeexamiedaItercompletecor-
rectiooIreIractioaomalywithspectaclesorcotact
leses; # Morphologicalchages oIthe optic erve
head, such as deepexcavatiooIopticdisc, ad shal-
low,steepordeviateddiscedgeallsuggestthepossibil-
ityoIHM-POAG
|6,9|
; $EOGadDopplerareuseIul
adjuctsIordiagosis;%Corticosteroid provocative test
ad wavecurvaturegraphoIIOPvariatioca help us
IorecastthedegeeratioadprogressiooIHM.
MECHANISMS
ThereareseveralexplaatiosIorthecloserelatiobe-
tweeHMadPOAG. ! WiththesameIOP, more
tesioisaddedothescleraoImyopiceyesthathat
oIemmtropiceyes;"Imyopia,existeceoIglaucoma
predisposesIudus todamage; # IOPelevatiooIte
leads toextesiooIocularaxis; $ Iteractiosbe-
tweeHMadPOAGdevelopiaviciouscycle.
AttheedoIthe20
th
cetury, ewgeetictheories
collage ad hypertesiogee theorygavea better
explaatiototheHM-POAGrelatio.
Collagen Gene Theory
Myopc collagen gene PathologicalobservatiooI
myopicchickemodelsrevealedthatiHM, thecho-
dric lamiaoIsclera becamethicker, the umberoI
biuclear cells ad twicells icreased ad desityoI
233
2004 4 4 2
029-8224172 IJO.2000163.com
cells decreased. All these indicate that there is an in-
crease oI chondric cell proliIeration and secretion.
Electron microscopy revealed that in HM, sclera was
mainly arranged as lamellar, collagen Iiber bundle; the
diameter oI the Iibers decreased; a greater dispersion Ior
the range oI Iibers; an increase in star-shaped Iibers on
the cross section, as well as a greater prevalence oI Iiber
groups with uniIorm but extremelyIine diameter ad-
versely aIIected the development, organization, and
maturation oI the collagen Iramework. All these lead to
the ultramicroscopic changes Iound in pathologic my-
opia. Immunologists think that the auto-immunity reac-
tion may contribute to the antigenity damage and scleral
collagen variation
|11|
. So it is presumed that in HM, au-
to-immunity reaction to collagen and the accumulation
oI immune complex in interstitial cause scleral damage,
cut oII the inter-molecular relationship, produce varia-
tion in the immunological collagen gene, and conse-
quently result in the progress oI myopia. Wang Iound
out that pathological myopia had a negative correlation
with the HLA antigen B
1
, and a positive correlation
with HLAB
8
and the collagen gene Coll
11
A
2
may be the
causative gene oI high myopia
|11|
.
Change of collagen fiber in POAG Observa-
tions oI aqueous outIlow system showed that more col-
lagenous Iibers existed in the trabecular meshwork and
in this region, the basement membrane also became
thicker
|12|
. Furthermore it is recognized that atrophy oI
the optic nerve Iibers in POAG originates Irom lamina
cribrosa, where collagenous Iiber is one oI the main ex-
tra-interstitial macromolecules. Recently it was Iound
that the number and density oI TypeIVcollagenprotein
increasedinPOAG
|13|
. MorrisonIoundabnormaldepo-
sitionsoITypeI, III, IVcollageninlaminacrobrosain
monkeyeyeswithelevatedIOP
|14|
.
Investigations also demonstrated that under certain
pressure, synthesisoIcollagenproteinwasassociated
withthecorrespondinggeneticexpression
|1|
. Buttill
nowmanykeypointsremainunknown. Scientistsgen-
erallyagreethat it is the collagenIiberdeIectscaused
byIOPelevationthatdamageandthinlaminacribrosa,
and eventually, result in atrophyoIthe opticalnerve
Iiber.
Tosumup, bothHMandPOAGareconsideredasdis-
easescharacteristicoIcollagenlesion.
Hypertenion Gene
Steroid hypertenion tet BothHMandPOAGhave
hypersensitive response to corticosteroids. Only 4
- oI the general population have hypersensitive re-
sponse while 90 oI the POAG patients have it. Steven
M Iound that IOP increased in about 88 oI the HM
patients aIter corticosteroid administration, oI whom
more than 29 had IOP higher than 31mmHg. These
suggest that both HM and POAG carry certain
gene-regulating steroid receptors.
In 1997, Johnson et al
|16|
noticed under light microscope
and electron microscope that some FBM materials were
deposited in the trabecular meshwork aIter long-term
steroid administration. A Iew years ago, Weinreb et al
|17|
Iound that in cultured human trabecular meshwork cells,
there were glucortisteroid receptors with strong aIIinity,
through which glucortisteroid can aIIect gene/protein
expression, produce extracellular deposits and conse-
quently increase the obstruction oI the trabecular mesh-
work to aqueous outIlow.
Lots oI investigations
|18-22|
suggest that steroids can in-
Iluence the cells in the trabecular meshwork Irom as-
pects oI biochemistry, cellular biochemistry and molec-
ular biology. In particular, aIter dexamethasone was ad-
ministered Ior some time, the trabecular cells expressed
the ku protein (TIGR protein). In Polansky's experi-
ment, the trabecular meshwork cells Irom diIIerent
donors expressed ku protein at diIIerent levels under
the eIIect oI steroids
|23|
, which indicates that there is an
individual diIIerence in the protein expression oI tra-
becular meshwork cells induced by steroids. So corti-
costeroids-induced IOP elevation can be explained in
the Iollowing way. TIGR exist more widely and densely
in trabecular meshwork oI POAG than in that oI normal
people; and genetic deIects and environmental Iactors
can aIIect the TIGR gene promoters and consequently
aIIect the valuable number oI the TIGR protein and gly-
coprotein products; these products in the trabecular
meshwork result in the IOP elevation.
234
Internatonal Journal of Ophthalmology, Vol.4, No.2 Apr. 2004
Tel:029-82245172 Emal:IJO.2000@163.com
TIGR Gene In 1997 guyenandPolansky
|23|
Iirst i-
dentiIied this protein/glycoproteininducing pattern in
humancultured trabecular meshworkcells havingex-
posedtoglucocorticoidsIorlongtime. Onthis basis,
theymappedTIGRgeneand clonedit to1q23-q25 at
thegenelocusGLC1A
|2,24|
. More than 25 mutations en-
coded by TIGR gene have been Iound and all oI them
are located in the third exon which encodes a
250-amino aciddomainwithhomology toolIactomedin.
It suggeststhatmutationswithinthisregionmayinter-
Ierewithnormalabsorptionand metabolismoIprotein
byaIIectingcombinationoITIGRproteinwithcells,and
consequently result in the abnormal accumulation oI
TIGRprotein, the increase in obstructionoIaqueous
outIlow throughthetrabecularmeshwork, andtheele-
vationoIIOP. The incidence oITIGRmutationshas
suggestedthat many POAGpatients may carry TIGR
mutations.owitisconIirmedthattheTIGRgeneisthe
candidategeneoIPOAG, andexistsextensivelyinthe
trabecular meshworkand ciliary body, both oIthem
participateinproductionoIaqueousIluidandregulation
oIitsoutIlow
|23|
.SoTIGRgeneisregardedasoneoIIOP
controllinggenes.
ThepatternoITIGRgenemutations-55ku proteinex-
pression--IOP elevationcan be used to elucidate the
mechanismoIsteroid-induced hypertension(OHT). In-
duced by DXM, the gene oI HM and POAG are most
likely to express speciIic protein
|23|
. Although the un-
derlying mechanism oI corticosteroids-induced IOP or
glaucoma in HM remains unknown, it is presumed to be
associated with the TIGR gene. However, till now, only
Iour possible HM gene loci have been mapped up
|25-.28|