Genetic association study on corticosteroid-induced elevation of the intraocular pressure

Glaucoma is one of the most prevalent eye diseases and the second most common
cause of blindness worldwide. The most common form is primary open angle
glaucoma (POAG). Glaucoma is a slowly progressing neuropathy of the optic nerve
that causes loss of visual field and eventually blindness. Elevated
intra-ocular pressure (IOP) is the most important risk factor.

Corticosteroids, which are often used for the treatment of many diseases in
ophthalmology and other specialities, may cause an elevation of the IOP. The
chance of an elevation of the IOP is highest with topical, subtenon,
subconjunctival and intravitreal administration. However, also dermal, nasal,
inhalant and systemic use of corticosteroids may cause an elevation of the IOP.
When this happens, it is called a steroid response. It is estimated that
corticosteroids induce ocular hypertension in approximately 18%-36% of the
general population and in patients with POAG this percentage can be as high as
92%. The elevated IOP is mostly reversible when the use is terminated, but it
may take some time to normalize. However, when the treatment is sustained, this
can cause a glaucomatous neuropathy of the optic nerve. The latter is called
corticosteroid-induced glaucoma and may lead to visual field loss and
eventually blindness.

The IOP is determined by the outflow resistance across the trabecular meshwork
and the Schlem-canal system, the aqaeous humour production and the level of
episcleral venous pressure. Corticosteroid-induced glaucoma is caused by an
increase in outflow resistance. However, the precise mechanism isn*t clear yet.
Genetic factors are likely to affect the susceptibility to a corticosteroid
response. Therefore, an overview of the genetic and molecular mechanisms of
corticosteroid-induced glaucoma can give more insight in the pathogenesis.
Genetic association studies give us the opportunity to discover genes that are
associated with the disease by searching for variances in alleles or genotypes
(SNPs or single nucleotide polymorphisms) in the genomes between patients with
and without IOP response on corticosteroids.

In this study we will investigate the occurrence of SNPs in around 125 cases
with corticosteroid-induced ocular hypertension in comparison with around 235
controls without a corticosteroid response. In order to find SNPs related to
the corticosteroid response, it is important that both groups are comparable by
means of underlying disease. Therefore, patients will be matched on the
indication for the use of corticosteroids, the duration of exposure, route of
administration, and type and dosage of the corticosteroid.

To our knowledge one small genome-wide association study (GWAS) has been
conducted comparing 32 patients with and without corticosteroid-induced ocular
hypertension after treatment with intravitreal triamcinolone. They identified
two SNPs proximal of the transcriptional start site (near the 5*) of HCG22 on
chromosome 6, suggesting that the molecular mechanisms for association of the
variants with IOP could be through the regulation of the HCG22 gene expression.
However, this is a rather small sample population and the investigators didn*t
match for the underlying disease. Further, Hogewind et al. performed SNP
analysis in multiple genes (SFRS3, FKBP4, FKBP5, and NR3C1) in
corticosteroid-induced ocular hypertension.

This study enables us to identify patients at risk for developing
corticosteroid-induced glaucoma and to gain a better insight in the
pathogenesis of corticosteroid-induced glaucoma. This may also lead to the
discovery of biomarkers that indicate an increased risk of developing
steroid-induced glaucoma and new prevention and treatment strategies, which are
necessary as the treatment of corticosteroid induced glaucoma now only focuses
at lowering the IOP and can still be challenging.

The objective is to investigate the differences in SNPs in patients with
corticosteroid-induced ocular hypertension in comparison with patients exposed
to corticosteroids who do not respond with an IOP increase. Based on the SNPs,
genes involved in corticosteroid-induced glaucoma can be identified.

This study is an observational cohort study (matched case-referent) and will be
conducted at the University Eye Clinic Maastricht of the Maastricht University
Medical Centre+ (MUMC+), the Netherlands. Patients will be included from the
outpatient clinic. The study population will consist of patients that are using
or have recently used topical, subconjunctival or intravitreal corticosteroids.
The participants will be divided in two groups: cases of corticosteroid
responders and controls without a corticosteroid response. A corticosteroid
response will be defined as an increase of the IOP * 6 mmHg from baseline and
in comparison to the other eye (in case of unilateral treatment). Patients who
have shown an increase in IOP after exposure to corticosteroids will be
identified as reported by the treating ophthalmologist or resident in the
medical record. Referents will be identified as those who have been exposed to
corticosteroids but didn*t have an increase in IOP.

As previously described, patients will be matched based on their indication for
the use of corticosteroids, the duration of exposure, route of administration,
and type and dosage of the corticosteroid. In order to perform the matching,
the inclusion of the patients will be checked weekly and we will make sure that
for every patient with a corticosteroid response, two patients without a
response will be found.
Previous studies showed that on average, one out of three patients develop an
increase in intraocular pressure after using topical corticosteroids and two
out of three don*t. The matching will be ensured as all patients that are
exposed to corticosteroids will be included.

The clinicians will identify their patients who, based on their data in the
clinical patient system (SAP), may qualify for participation in this study.
This identification will take place over a retrospective period of six years
(to 2010). After identification, the treating clinicians will send their
patients a noncommittal letter in which they inform the patient about this
study. The patient information and informed consent will hereby be attached. If
patients are willing to participate they are asked to contact the researcher
before the start of their appointment and are asked to bring the informed
consent with them. During the appointment, the clinician will also ask whether
the patient has received the letter and if he/she wants to be approached by the
researcher. During the consultation hours, the researcher will be available to
provide further details about this study, to include patients if they wish to
participate and to sign the informed consent.
Further, the treating clinicians will identify new corticosteroid responders
and patients that are newly exposed to corticosteroids (in the context of the
matching) during their regular consultation hours. These patients will be
informed about this study by their own treating clinician and they will receive
the patient information letter. Patients will also be asked if they, free of
any obligation, want to be approached by the researcher. In case of agreement,
the researcher will contact the patient after one week. If patients are willing
to participate, an appointment will be planned (if possible adjacent to another
planned appointment). The patients will also be asked to bring the informed
consent letter they have received to the scheduled appointment. The informed
consent will be signed together with the researcher.

The duration of inclusion is estimated at one to one and a half years and the
duration of the study at two years.

The risks associated with participation are negligible and the burden can be
considered minimal. The blood collection may cause some pain and a bruise. The
blood sample will provide three tubes of 10 ml blood within one venous
bloodpunction (in total 30 ml) and is unlikely to cause other complaints.