Upload
rahma-sha-dyah
View
215
Download
0
Embed Size (px)
Citation preview
7/28/2019 korneal distropi
1/4
Th e n e w e n g l a n d j o u r n a l o f medicine
n engl j med 363;11 nejm.org september 9, 20101072
Major Progress in Fuchss Corneal DystrophyAlan F. Wright, M.B., Ch.B., Ph.D, and Baljean Dhillon, B.M., B.S.
The expected outcomes of the almost 800 genome-
wide association studies of common biomedical
traits that have been reported so far1 have rarely
been made explicit but might include the identi-fication of statistically robust genetic associations,
the elucidation of the heritable nature of the traits,
and some utility to biology or medicine, such as
mechanistic dissection or clinical prediction of
disease. So far, the results have met the first goal
but have generally disappointed on the second
and third ones,2 although it could be argued that
the jury is still out.
There are several problems. First, the great ma-
jority of genetic effects that have been identif ied
have been so small (odds ratios, 1.1 to 1.3) that
they generally do not explain more than a few per-cent of the heritability of disease. Second, an un-
expectedly large number of variants have been as-
sociated with most analyzed traits, suggesting that
many of these variants have only peripheral effects
on the trait. Other observers who see the glass as
being half full3 point to the identification of new
physiological mechanisms, such as urate transport
in the kidney,4 or disease pathways, such as in
Crohns disease (autophagy)5 and age-related mac-
ular degeneration (complement activation).6
In this issue of the Journal, Baratz et al.7 de-
scribe associations between DNA sequence vari-
ants and a common eye condition, Fuchss cor-
neal dystrophy (FCD). These variants generate
hypotheses regarding the pathological mecha-
nism, confer high odds ratios, and imply poten-
tially useful clinical tests.
Corneal transparency is critically dependent on
a monolayer of endothelial cells to maintain the
dehydration and hence the clarity of its collage-
nous stroma, which makes up 90% of corneal
thickness. FCD is a bilateral disorder of the cor-
neal endothelium, most commonly occurring inpersons in their 40s or 50s. It affects 5% of Amer-
icans over the age of 40 years and can lead to pro-
gressive loss of endothelial cells, corneal clouding,
and loss of sight.8 The cornea shows extracellu-
lar deposits, usually called guttae (Latin gutta,
a droplet), which confer a beaten-metal ap-
pearance to the innermost endothelial layer and
can be observed on slit-lamp biomicroscopy. The
endothelium comes to resemble a lunar landscape,
with irregular craters and holes resulting from cell
loss, and there is reduced water movement out ofthe cornea, causing stromal hydration. This pro-
cess impairs corneal transparency, giving rise to
glare and blurred vision, most noticeably on wak-
ing in the morning. Cataract surgery in patients
with FCD can accelerate endothelial-cel l loss,
resulting in edema of all corneal layers, loss of
vision, and a blind, painful eye.9 The only perma-
nent solution is corneal transplantation. FCD-
associated corneal clouding after cataract surgery
is now a major cause of the 42,000 corneal trans-
plantations performed in the United States ev-
ery year.FCD is a genetically complex disorder, but the
familial risk is relatively high, with a sibling risk
ratio of 10, suggesting the suitability of this con-
dition for genomewide association studies.10 Bar-
atz et al. performed a relatively small-scale asso-
ciation study, using 130 FCD case subjects and
260 control subjects, a sample size that would be
considered underpowered by most grants commit-
tees, given the small effects usually observed in
genomewide association studies. The results, how-
ever, showed a strong association (P = 1.011012)
between FCD and common (noncoding) sequence
variants in the gene encoding transcription fac-
tor 4 (TCF4). The result was replicated in an in-
dependent series (P = 1.791013), but the most
striking finding was the unusually high odds ra-
tios of 5.5 for those carrying a single risk allele
and 30 for those carrying two risk alleles. (About
2% of subjects from the control population car-
ried two risk alleles.)
There are two interesting aspects of this asso-
ciation. The first is the insight into corneal biol-
ogy. TCF4 encodes E2-2, a member of the E-proteinfamily of class I basic helixloophelix (bHLH)
transcription factors, which is expressed in the
cornea. These proteins form homodimers or het-
erodimers with other bHLH proteins, which acti-
vate or repress specific target genes.11 The func-
tions of E2-2 seem to vary with tissue context but
include the regulation of cell-adhesion proteins,
The New England Journal of Medicine
Downloaded from nejm.org on May 26, 2013. For personal use only. No other uses without permission.
Copyright 2010 Massachusetts Medical Society. All rights reserved.
7/28/2019 korneal distropi
2/4
editorials
n engl j med 363;11 nejm.org september 9, 2010 1073
such as E-cadherin, which can be associated with
epithelial-to-mesenchymal transition (EMT)12 with
loss of cell polarity and cellcell adhesion. E2-2 is
known to up-regulate the ZEB1 gene, which en-
codes the zinc finger E-box binding homeobox 1
protein. ZEB1 binds the same class of DNA se-
quences as E2-2 and represses E-cadherin during
EMT13,14 (Fig. 1). Little is known about EMT inthe cornea. An intriguing possibility is that cor-
neal stem cells that are located in a niche at the
corneal endothelial periphery require EMT in or-
der to migrate toward and replace damaged en-
dothelium (Fig. 2).14,15 Mutations in ZEB1 are also
a rare cause of early-onset FCD.16
Other mechanistic possibilities exist, includ-
ing a gradual loss of functional endothelium re-
sulting from premature senescence (as seen in
mice deficient in Zeb1), an increased production of
extracellular matrix associated with EMT (which
could explain the extracellular deposits), and en-doplasmic reticulum stress caused by the pres-
ence of abnormal E2-2 protein (proteinopathy).
Baratz et al. uncovered genetic risk variants of
relatively large effect size, suggesting that once
the true causal variants have been identified (those
described by Baratz et al. are probably indirectly
associated), a clinically useful predictive test may
be on the horizon. Currently, patients who re-
quire cataract or laser-assisted in situ keratomile-
usis (LASIK) refractive surgery are screened by
slit-lamp biomicroscopy for the presence of gut-
tae, but the large number of corneal transplan-
tations that are associated with FCD indicate that
such screening is ineffective. New surgical tech-
niques offer hope in FCD but are technically high-
ly demanding like putting a ship in a bottle.
However, prevention is better than a cure, and a
simple genetic test might highlight patients who
are at highest risk for complications after either
cataract8 or refractive17 surgery.
The study by Baratz et al. requires further rep-
lication before a predictive test can even be con-
sidered; identification of the causal DNA sequencevariants would be a further advance. Moreover,
the associated variants require evaluation in co-
hort studies to give an unbiased estimate of their
predictive value. If these hurdles are overcome,
piloting the introduction of such tests into a clin-
ical setting and health economic evaluation will
be needed. A more distant goal will be to develop
a means of disease prevention in those at highest
risk for corneal complications among the 10 mil-
lion patients undergoing cataract or refractive
surgery globally each year.18 Genomewide asso-
ciation studies have not yet led to many clinically
useful tests (partly because few can be coupled to
Wnt/TCF pathway
E2-2
ZEB1
E-cadherin
Epithelial-to-mesenchymal transition
Mesenchyma(migration, proliferation, stem-cell properties)
Progenitor cells
New corneal endothelium
?
?
Figure 1. Possible Role of the E2-2 Transcription Factorin Fuchss Corneal Dystrophy (FCD).
The expression of E2-2 may normally promote epitheli-al-to-mesenchymal transition (EMT) as part of the
physiological response to injury. Activation of the Wnt/
TCF pathway, perhaps associated with age-related cor-neal damage or stress, can induce E2-2 expression,
causing down-regulation of E-cadherin and promotingEMT, probably by increasing the expression of ZEB1,
which directly represses the E-cadherin promoter. Theprecise sequence of events in FCD is unknown, but a
speculative possibility is that dysregulation of E2-2 re-duces both ZEB1 expression and EMT (or the closely
related endothelial-to-mesenchymal transition) in pe-ripheral corneal stem cells,14 reducing migration and
proliferation of progenitor cells and the replacement ofdamaged or lost corneal endothelial cells. Mutations in
ZEB1 cause epithelial transition of the corneal endo-
thelium and are another cause of FCD.
The New England Journal of Medicine
Downloaded from nejm.org on May 26, 2013. For personal use only. No other uses without permission.
Copyright 2010 Massachusetts Medical Society. All rights reserved.
7/28/2019 korneal distropi
3/4
Th e n e w e n g l a n d j o u r n a l o f medicine
n engl j med 363;11 nejm.org september 9, 20101074
a clinically useful intervention), which makes itall the more interesting to see whether predic-
tive genetic testing in FCD proves to be clini-
cally robust.
Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.
From the Medical Research Council Human Genetics Unit, In-stitute of Genetics and Molecular Medicine, Western GeneralHospital (A.F.W.), and the Department of Ophthalmology, Prin-
cess Alexandra Eye Pavilion and College of Medicine and Veteri-nary Medicine of the University of Edinburgh (B.D.) all inEdinburgh.
This article (10.1056/NEJMe1007495) was published on August25, 2010, at NEJM.org.
Hindorff LA, Junkins HA, Hall PN, Mehta JP, Manolio TA.1.A catalog of published genome-wide association studies. Bethes-
da, MD: National Human Genome Research Institute. (AccessedAugust 16, 2010, at ht tp://www.genome.gov/gwastudies.)
Figure 2. Anatomy of the Corneal Epithelium, Stroma, and Endothelium.
Shown is the corneal and conjunctival junction, or limbus, where corneal stem cells are thought to reside. The ante-
rior limbus is widely proposed to provide a niche for stem cells that give rise to corneal epithelium, but there is also
evidence of endothelial stem cells in the corneal periphery, perhaps in a distinct niche at the posterior limbus. 14,15These limbal cells are normally quiescent in adults but proliferate and become migratory in response to tissue injury.
The New England Journal of Medicine
Downloaded from nejm.org on May 26, 2013. For personal use only. No other uses without permission.
Copyright 2010 Massachusetts Medical Society. All rights reserved.
7/28/2019 korneal distropi
4/4
editorials
n engl j med 363;11 nejm.org september 9, 2010 1075
Goldstein DB. Common genetic variation and human traits.2.N Engl J Med 2009;360:1696-8.
Manolio TA. Genomewide association studies and assess-3.ment of the risk of disease. N Engl J Med 2010;363:166-76.
Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identi-4.
fied urate transporter influencing serum urate concentration,urate excretion and gout. Nat Genet 2008;40:437-42.
Budarf ML, Labb C, David G, Rioux JD. GWA studies: re-5.writing the story of IBD. Trends Genet 2009;25:137-46.
Donoso LA, Vrabec T, Kuivaniemi H. The role of comple-6.ment Factor H in age-related macular degeneration: a review.Surv Ophthalmol 2010;55:227-46.
Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and7.Fuchss corneal dystrophy. N Engl J Med 2010;363:1016-24.
Hogan MJ, Wood I, Fine M. Fuchs endothelial dystrophy of8.
the cornea: 29th Sanford Gifford Memorial lecture. Am J Oph-thalmol 1974;78:363-83.
Adamis AP, Filatov V, Tripathi BJ, Tripathi RC. Fuchs endo-9.thelial dystrophy of the cornea. Surv Ophthalmol 1993;38:149-68.
Krachmer JH, Purcell JJ Jr, Young CW, Bucher KD. Corneal10.endothelial dystrophy: a study of 64 families. Arch Ophthalmol
1978;96:2036-9.
Flora A, Garcia J J, Thaller C, Zoghbi HY. The E-protein Tcf411.interacts with Math1 to regulate differentiation of a specific
subset of neuronal progenitors. Proc Natl Acad Sci U S A 2007;
104:15382-7.
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithel ial-mes-12.enchymal transitions in development and disease. Cell 2009;
139:871-90.Eger A, Aigner K, Sonderegger S, et al. DeltaEF1 is a tran-13.
scriptional repressor of E-cadherin and regulates epithelial plas-
ticity in breast cancer cells. Oncogene 2005;24:2375-85.McGowan SL, Edelhauser HF, Pfister RR, Whikehart DR.14.
Stem cell markers in the human posterior limbus and cornealendothelium of unwounded and wounded corneas. Mol Vis
2007;13:1984-2000.Takacs L, Toth E, Berta A, Vereb G. Stem cells of the adult15.cornea: from cytometric markers to therapeutic applications.
Cytometry A 2009;75:54-66.Riazuddin SA, Zaghloul NA, Al-Saif A, et al. Missense muta-16.
tions in TCF8 cause late-onset Fuchs corneal dystrophy and in-
teract with FCD4 on chromosome 9p. Am J Hum Genet 2010;86:45-53.
Moshirfar M, Feiz V, Feilmeier MR, Kang PC. Laser in situ17.keratomileusis in patients with corneal guttata and family his-
tory of Fuchs endothelial dystrophy. J Cataract Refract Surg2005;31:2281-6.
Vision 2020: the cataract challenge. Community Eye Health18.
2000;13:17-9.
Copyright 2010 Massachusetts Medical Society.
applyforjobselectronicallyatthenejmcareercenter
Physicians registered at the NEJM CareerCenter can apply for jobs electronicallyusing their own cover letters and CVs. You can keep track of your job-application
history with a personal account that is created when you register
with the CareerCenter and apply for jobs seen online at our Web site.VisitNEJMjobs.orgfor more information.
The New England Journal of Medicine
Downloaded from nejm.org on May 26, 2013. For personal use only. No other uses without permission.
Copyright 2010 Massachusetts Medical Society. All rights reserved.