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Introduction
A. Clinical optometry as currently practiced is undergoing a fundamental, revolutionary transformation.
This transformation will change the way optometrists understand, classify, diagnose, treat and manage
disease.
B. The Human Genome Project and other revolutionary advances have started to increase and broaden
the importance of genetics/genomics in all health care. This revolution will alter eye care forever, and
it involves a tremendous change from the “old genetics” to the “new genetics.” Genetics is no longer
an esoteric academic specialty that involves rare diseases.
Basic concepts
A. The human genome consists of all the DNA in each human cell.
1. DNA is made up of a variable sequence of 4 nucleotide bases (A, T, C, & G).
2. DNA makes up genes that make up chromosomes.
B. The flow of genetic information is from DNA to RNA to protein. A set of three nucleotide bases in the
DNA sequence specify an amino acid in the protein sequence. Thus the “blueprint for life” consists of
a 4-letter alphabet and 3-letter words.
Human Genome Project (HGP)
A. This was a 15-year worldwide research effort (1990-2005).
B. It was considered so important that the National Human Genome Research Institute was formed at
NIH.
C. The HGP involved the sequencing of human DNA (3 billion base pairs).
D. The HGP was completed ahead of schedule and under-budget in April of 2003.
E. It identified the 20,000 to 25,000 genes in human DNA.
Paradigm shift
A. The “old genetics”.
1. The old genetics dealt with conditions caused by a mutation in a single gene or by an extra or
missing chromosome or part of a chromosome.
2. These conditions are relatively rare. Most patients are not directly affected by them. Thus, these
conditions play a relatively small role in health care.
3. The conditions are rare enough that genetics care could be provided by medical geneticists and
genetic counselors, with occasional involvement of primary care providers.
B. The “new genetics”.
1. The new genetics emerged due to knowledge derived from the HGP.
2. Essentially all medical conditions have a genetic component and can be viewed through a
“genetic lens.”
3. The new genetics deals with multifactorial conditions that are partly caused by mutation(s) in
gene(s).
a. Multifactorial systemic conditions include diabetes, atherosclerosis, colon cancer, breast
cancer, etc.
b. Multifactorial ocular conditions include the glaucomas, AMD, diabetic retinopathy, etc.
4. These conditions are common enough that genetics care will be supplied primarily by primary
care providers from many health disciplines with occasional involvement of medical geneticists
and genetic counselors.
5. The new genetics will provide a better understanding of the non-genetic (environmental) factors in
health & disease.
6. There will be a shift from an emphasis on disease treatment to health maintenance.
Molecular optometry.
A. Clinical optometry is undergoing a fundamental, revolutionary transformation.
B. This will change the way optometrists:
1. Classify diseases
2. Understand disease
3. Diagnose diseases
4. Treat & manage diseases.
C. Look at the patient through a “genetic lens” (i.e., incorporate genetic thinking & principles).
Improved classification of diseases.
A. The present system is based on clinical description (phenotype).
B. Knowledge from the HGP & other advances will allow a more rational classification based on genetic
causes (genotype) and influences.
C. Ex. Retinitis pigmentosa
1. is a group of retinal dystrophies
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includes autosomal dominant (AD), autosomal recessive (AR), X-linked recessive (XR), and
mitochondrial forms of inheritance
3. results from mutations on at least 10 chromosomes
D. Ex. Corneal dystrophies (14 genes have been identified on 12 chromosomes)
Improved understanding of pathogenesis/pathophysiology.
A. We are moving toward a molecular level of understanding of diseases.
B. Ex. Identification of genes for specific types of glaucomas:
1. Myocilin (MYOC) – accounts for 10-20% of JOAG and about 3-5% of POAG
2. Optineurin (OPTN) – accounts for about 17% of familial POAG (normal-tension)
3. WDR36 – accounts for more than 5% of POAG
4. Cytochrome P4501B1 enzyme (CYP1B1) – mutated in primary congenital glaucoma
5. 9 other glaucoma genes have been identified and at least 22 chromosomal loci have been found.
C. Ex. Age-related cataracts – genetics accounts for about 48% of nuclear cataract variability and about
58% of cortical cataract variability.
D. Ex. Age-related macular degeneration
1. CFH gene.
a. A polymorphism in the complement factor H gene (CFH) on chromosome 1q31 accounts for
20-50% of the overall risk of developing AMD.
b. Individuals who carry a single copy of this variant have a two- to four-fold increased risk of
AMD. Individuals who carry two copies of the variant have a five- to seven-fold increased
risk.
c. Atrophic tissue damage and neovascularization are potential results of chronic inflammation
mediated by the complement system.
2. LOC387715 gene.
a. A polymorphism in the LOC387715 gene on chromosome 10 accounts for as high as 57% of
the overall risk of developing AMD.
b. Individuals who carry a single copy of this variant have a three-fold increased risk of AMD.
Individuals who carry two copies of the variant have a five- to eight-fold increased risk.
c. If a patient were homozygous for risk alleles at both CFH and LOC387715, the disease odds
ratio (OR) would be about 58.
Improved diagnostic testing.
A. Microarrays (DNA chips, RNA chips, Protein chips)
B. “Lab-on-a-chip” microfluidics
C. Point-of-care testing
D. Tests will become available in the next 10 years to determine risk for common diseases.
E. Thinking will shift to probabilities (statistical risks) instead of definitive answers.
F. Goal of $1000 genome sequencing. The cost of sequencing the first genome (HGP) was about
$3,000,000. Two National Institutes of Health funding programs have challenged scientists to achieve
a $100,000 human genome by 2009 and a $1,000 genome by 2014. Recent approaches in
development for reading genomes suggest that a $20,000 human genome may come as soon as
2010.
G. Some currently available tests for ocular diseases:
1. OcuGene test (InSite Vision). This tests for one mutation in the controversial promoter
region of the myocilin gene. Should optometrists be using this test?
2. ABCR (ABCA4) gene mutation detection assay (Asper Ophthalmics) for mutations causing
Stargardt disease
3. LCA microarray test for Leber congenital amaurosis (Asper Ophthalmics)
4. More than 1000 genetic tests available from commercial labs (including tests for various
glaucomas, corneal dystrophies, retinal dystrophies, cataracts, ARMD, & various pathogens)
H. Reasons for genetic testing
1. Predictive testing
a. Presymptomatic testing for predicting adult-onset disorders
b. Predispositional testing for estimating risk of developing adult-onset disorders
2. Confirmational diagnosis of a symptomatic individual
3. Carrier testing
4. Prenatal diagnostic testing
5. Newborn screening
6. Preimplantation genetic diagnosis
Improved management and treatment.
A. Identification of patients with susceptibility genes will allow determination of:
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XII.
1. Risk level
2. Types of testing
3. Timing of surveillance visits
4. Appropriate lifestyle changes
B. Antisense drugs.
1. These drugs are complementary strands of portions of messenger RNA (mRNA).
2. The drugs bind to mRNA and inhibit transcription of protein.
3. Fomivirsen was the first antisense drug marketed. It is used for treating CMV retinitis.
C. Gene therapy.
1. Proof-of-principle provided for RPE65 gene
a. Visual function recovery has been shown in a canine model of Leber congenital amaurosis.
b. Clinical trials on humans are likely within 1-2 years.
2. Two ocular angiogenesis human trials are now ongoing.
a. They involve intravitreal injection of a viral vector with a gene for pigment epithelium-derived
factor (PEDF) in patients with severe AMD. PEDF is an antiangiogenic factor.
b. One clinical trial is still in Phase 1 and the other trial is in Phase 2 already.
3. RP and other retinal dystrophies are active targets.
4. China has approved the world’s first commercially-licensed gene therapy (for head-and-neck
squamous cell carcinoma).
D. RNA interference (RNAi).
1. Small double-stranded interfering RNAs (siRNAs) can silence messenger RNAs carrying a
complementary sequence.
2. RNAi is used to selectively inhibit gene expression in various diseases.
3. Two clinical trials for wet AMD have been launched (Acuity Pharmaceuticals; Sirna Therapeutics).
One trial is still in Phase 1 (Sirna Therapeutics), and the other trial is already in Phase 2 (Acuity
Pharmaceuticals). The Acuity Pharmaceuticals drug silences the Vascular Endothelial Growth
Factor (VEGF) gene, and the Sirna Therapeutics drug silences the VEGF Receptor-1 gene.
4. Off-target effects are under investigation.
E. Genetic counseling – new role for primary care clinicians (including optometrists)
1. Genetic counseling will become more and more a primary care responsibility.
2. There are not enough genetics counselors or medical geneticists to handle the increase in
demand.
3. Every health care provider will become a genetic counselor in the next 10 years.
Pharmacogenetics / Pharmacogenomics.
A. Each year, 100,000 people die from adverse reactions to drugs & over 2 million have serious
reactions.
B. Some drugs work well in some patients & not as well in other patients.
C. DNA variations (polymorphisms) in genes responsible for drug metabolism affect a patient’s response
to drugs.
D. Single nucleotide polymorphisms (SNPs; pronounced like “snips”) in genes that are involved in
drug metabolism can account for much of the ability of some drugs to cause adverse reactions and/or
to be ineffective.
E. The Amplichip CYP450 Microarray (Roche/Affymetrix) is now commercially available for testing two
of the genes involved in drug metabolism.
F. ODs will prescribe medications and determine drug doses based on the patient’s genotype and SNP
pattern:
1. Improving efficacy & safety of drugs
2. Decreasing morbidity & mortality
3. Decreasing overall cost of health care.
G. “Personalized medicine” will evolve for many drugs and diseases by the year 2020.
Ethical, legal, social implications (ELSI).
A. Informed consent
B. Confidentiality/privacy
C. Discrimination (e.g., employers, insurers)
D. Psychological impact
E. Fairness in access to genetic services
F. Conceptual/philosophical/religious implications
G. Clinical issues including education of clinicians, patients, & the general public
Why the genomics revolution is important for optometric practice.
A. Virtually all diseases have a genetic component. This means optometric physicians will need to:
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raise genetic hypotheses with every patient (i.e., look at each patient through a “genetic lens”)
realize when genetic factors play a role in a patient. Thus, we will have to be aware of genetic
contributions to the common diseases seen in practice
3. improve family history taking skills and, in selective cases, draw a three-generation pedigree
4. be able to identify patients who need genetic services and/or referral
5. know how, when, and where to obtain advice and refer patients
6. know how to access new knowledge on medical genetics and use it in patient care
B. Everyone has 5-50 significant genetic flaws.
C. There is an exponential rise in genetic knowledge.
D. New diagnostic/prognostic/treatment options are increasing. This means optometric physicians will
need to:
1. learn the indications for genetic testing and the availability of genetic tests for specific ocular
conditions.
2. deal with “risk” and genetic predisposition
3. manage low and moderate risk patients
4. use genetics to individualize patient care and preserve health
5. be able to read the increasing number of ophthalmic journal articles on genetic/genomic issues,
and thus to keep current
6. be able to identify, understand, and address the ethical, legal, social, and financial issues
associated with genetic conditions as they arise in primary and specialty (e.g., pediatric optometry
and low vision) practice
E. There are not enough genetic specialists to handle the increase in demand.
F. There is a growing demand for genetic information and services by patients. Thus, optometrists will
need to be able to:
1. address the increasing number of patient’s questions and concerns about new genetic
technologies and information related to eye care
2. explain genetic concepts
G. Direct marketing of genetic tests to health care professionals & potential customers is occurring.
H. Ophthalmic journals are publishing more & more articles on ocular genetics & new disease genes.
I.
Enhanced genetic literacy & competency of ODs is necessary.
Selected References.
A. Books
1. Black GCM. Genetics for ophthalmologists. The molecular genetic basis of ophthalmic disorders.
Remedica Publishing: Chicago, 2002.
2. Samples JR (ed.). Ophthalmic genetics: diagnosis and therapy. Ophthalmology Clinics of North
America (vol. 16, no. 4), Philadelphia: W. B. Saunders Co., December 2003.
3. Wissinger B, Kohl S, Langenbeck U (eds.). Genetics in ophthalmology (Developments in
ophthalmology, v. 37). Karger: New York, 2003.
B. Journal articles
1. Aldave AJ, Yellore VS, Self CA, Holsclaw D, Small K. The usefulness of buccal swabs for
mutation screening in patients with suspected corneal dystrophies. Ophthalmology
2004;111:1407-9.
2. Challa P. Glaucoma genetics: advancing new understandings of glaucoma pathogenesis. Int
Ophthalmol Clin 2004;44:167-85.
3. Cohen CS, Allingham RR. The dawn of genetic testing for glaucoma. Curr Opin Ophthalmol
2004;15:75-9.
4. Daiger SP. Identifying retinal disease genes: how far have we come, how far do we have to go?
Novartis Found Symp 2004;255:17-27; discussion 27,36, 177-8.
5. Fan BJ, et al. Molecular diagnostics of genetic eye diseases. Clin Biochem 2006 Jan 9: [Epub
ahead of print].
6. Hejtmancik JF, Smaoui N. Molecular genetics of age-related cataract. Exp Eye Res 2004;79:3-9.
7. Klein RJ, et al. Complement factor H polymorphism in age-related macular degeneration. Science
2005;308:385-9.
8. Klintworth GK. The molecular genetics of the corneal dystrophies – current status. Front Biosci
2003 May 01;8:d687-713.
9. MacDonald IM, Tran M, Musarella MA. Ocular genetics: current understanding. Surv Ophthalmol
2004;49:159-96.
10. Tuo J, Bojanowski CM, Chan C-C. Genetic factors of age-related macular degeneration. Prog
Retin Eye Res 2004;23:229-49.
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2.
XIII.
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11. Rivera A, et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related
macular degeneration, contributing independently of complement factor H to disease risk. Hum
Mol Genet 2005;14:3227-36.
12. Wormington CM. Genetic frontiers: The era of molecular optometry. Rev Optom 2003;140(8):7683.
13. Wormington CM. How to put genetics into your practice now. Rev Optom 2004;141(11).
14. Wormington CM. The genomics revolution and molecular optometry: educational implications.
Optom Ed 2004;29:43-48.
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