I recently opened my e-mail to find an unexpected question from a patient, “Doc, I have the risky phenotype for the CFH SNP. Does this mean I will get macular degeneration?” At first I was confused, until I realized the patient had recently purchased a DNA analysis kit from an online company and needed help understanding the results.

I had to do a little research to find the answers.

‘Consumer’ Genetic Testing
On June 25, 2000, President Clinton hailed the completion of the first draft of the human genome at a cost of over $3 billion. Ten years later, genetic testing is a commodity sold on the Internet and in drug stores for less than $500. Every day, consumers submit DNA for analysis and, like my patient, confront primary health care providers with questions about how to interpret the results.

Ongoing advances in genetic research along with the direct to consumer availability of genetic testing have widened the gap between physician knowledge and patient expectations. As primary caregivers, we need to be aware of the current state of genetic testing to better inform and provide care for our patients.

Direct to consumer (DTC) genetic testing allows a consumer to learn their genetic risk of developing health conditions, carrier status of inheritable diseases and how genetics may alter their response to certain medications, all without the involvement of a health care professional or insurance company.

In the recent past, DTC genetic testing cost upwards of $1,000. Today, with the costs substantially lower, testing is becoming more affordable and widespread; local convenience stores are now advertising the sale of off-the-shelf paternity testing kits and Walgreens has announced its intention to offer the Pathway Genomics “Insight Kit” for $20 to $30, with reports costing from $79 for Drug Response, Health Conditions or Pre-Pregnancy Planning at $179, or all three for $279.

To submit a DNA sample for testing, an individual can either swab the inside of a cheek or spit into a collection tube. The sample is mailed back to the laboratory for replication and analysis. Results are provided online, by mail or by telephone. For an additional fee, genetic counselors are available to explain results and answer questions.

Genotyping vs. Sequencing
The Human Genome Project took more than 10 years to sequence the more than three billion base pairs in the DNA of a few subjects.¹ While advances in sequencing technology have significantly reduced the time it takes to decode an entire genome to a few weeks, technology has not yet reached the point where it is possible to map an entire genome quickly and inexpensively.

So, instead of sequencing, most DTC genetic testing companies employ a type of genotyping involving only the 0.05% of human DNA that is variable. They use single nucleotide polymorphisms (SNPs, pronounced snips) to analyze upwards of 580,000 locations on a person’s genome to find DNA sequence differences.^2-4 While these variations are a small fraction of the human genome, they are responsible for all of the differing traits in humans.

Using this method, researchers have identified more than 100 regions of the genome with gene variants linked to a higher risk of diseases—such as diabetes, coronary artery disease, breast and prostate cancer, rheumatoid arthritis and macular degeneration.

The locations analyzed by DTC genetic testing companies are chosen via review of scientific literature and classified as either established research (research backed up by multiple studies) or preliminary research (significant findings not yet reproduced by multiple studies). As scientific consensus changes, often so do these distinctions. The locations tested are also chosen based on traits of broad interest to consumers.

Genetics and Your Eyes
In addition to testing for the many systemic diseases that may affect your vision, several companies are testing for SNPs related to specific ocular traits and conditions.

• Exfoliative glaucoma. In Northern European populations, more than 99% of cases of exfoliative glaucoma are associated with variations in one gene, LOXL 1.^5-9 With one copy of the riskier LOXL 1 SNP, the risk of exfoliation syndrome is increased 3.7 times. Two copies increase the odds 14 times. Approximately 35% of people with European ancestry have one copy of the riskier SNP, while 22% have two copies.^7,8 There is no proven association, however, between these genetic variants and any other type of glaucoma.

• Eye color. Your eye color is a result of the interaction of multiple genes and variations of these genes. A SNP in the HERC2 location can be either an A version or a G version.^10-12 Two copies of the A version results in brown eyes. One A and one G produce either brown or green eyes, with the color depending on other variations in other genes. Two copies of the G version usually produce blue eyes, or green, depending on the other SNPs.

• AMD. Research shows that genetic factors contribute at least as much as environmental factors to the risk of AMD.^13-27 One genetic factor involves the expression of the Complement Factor H (CFH) gene, which encodes a protein that regulates the complement system and chronic inflammation.^15-23 The CFH protein inhibits complement triggered in response to elevated levels of C-reactive protein (CRP). People who have the riskier version of this SNP make an altered version of the CFH protein with a reduced ability to bind CRP. While the exact mechanism is currently unknown, excess levels of CRP may lead to an overactive complement system and persistent inflammation that damages eye tissue and leads to AMD.

There is also evidence of synergy between environmental and genetic risk factors for AMD.^24-27 Smoking is an environmental risk factor that more than doubles the risk of AMD.²⁷ Research shows that a SNP in the CFH gene interacts with smoking, making the risk of smoking even higher for people with one or more copies of the riskier version.²⁷

Ethical and Privacy Considerations
The growing availability and use of genetic testing outside of the clinical setting raises several safety, ethical and privacy concerns.

The sale of genetic analysis directly to consumers may result in situations where clinically significant test results are disclosed without the benefit of interpretation or counseling by a health care professional. Genetic testing provides only partial information about a person’s health. Other genetic factors, lifestyle choices and environmental factors also affect a person’s risk of developing many disorders. In many cases, these aspects of disease risk are not addressed by at-home genetic tests and counseling may only be available for an additional fee.

Recently there have been congressional hearings on the safety and consequences of making these tests directly available to consumers, as well as investigations by the Government Accountability Office and the FDA.  

DTC genetic testing companies strongly caution that results are not diagnostic, and instead indicate the likelihood of someone with your particular genotype having an increased chance of developing a particular condition. Even with the disclaimer, there is still a substantial risk for consumers to misunderstand results and make misinformed decisions about disease treatment or prevention.

These tests also raise the specter of privacy concerns and insurance discrimination, including fears of genetic pre-selection and misuse of personal genetic information. To this end, consumers are encouraged to carefully read the privacy policies of any DTC company.

The Genetic Information Nondiscrimination Act (GINA) was signed into law on May 21, 2008 to protect Americans from discrimination in health insurance and employment decisions on the basis of genetic information.²⁸

Genetic Tests in Practice
Most diseases result from the interaction of our genetics, lifestyle and environment. When the patient in my chair is overweight, the presence of a genetic tendency toward diabetes would not change the nutrition and obesity counseling I provide. It would, however, give me one more tool to emphasize the risk of doing nothing. In contrast, I would routinely perform gonioscopy on a patient who has two copies of the risky exfoliative glaucoma protein.

For my patient who e-mailed me with his AMD concerns, I emphasized smoking cessation, the importance of nutrition and UV protection. I assured him that although his genetic risk was slightly higher for AMD, it did not mean that he was, or ever would be, diagnosed with the condition.

As research advances the estimates of a patient’s disease risk based on their genetic profiles will change, and the use of genetic risk factors to guide screening and preventive measures will become more commonplace. Other tests will become available to predict optimal prevention, treatment and drug therapy. As scientists elicit more and more associations between disease and disease associated alleles, the number of available genetic tests continues to rise in both clinical and commercial settings.

Personalized medicine has the potential to help us diagnose earlier, avoid unwanted drug side effects and provide more effective disease treatment and prevention. The market for direct to consumer genetic testing is growing, allowing consumers to be better informed about the genetic aspects of disease and allowing them to take a more active role in their own health.

However, DTC genetic tests have significant limitations and as optometrists, we play an important role in helping consumers make informed healthcare decisions.

Dr. Falcon is the owner of Falcon Family Eye Care in Chandler, Ariz. She and her husband have submitted DNA samples to 23andme and are eagerly awaiting the results.

1. Abdellah Z, Ahmidi A, Ahmed S, et al. Finishing the euchromatic sequence of the human genome. Nature. 2004 Oct; 431(7011):931-45.
2. Abravaya K, Huff J, Marshall R, et al. Molecular beacons as diagnostic tools: technology and applications. Clin Chem Lab Med. 2003 April; 41(4):468-474.
3. Gunderson KL, Steemers FJ, Ren H, et al. Whole-genome genotyping. Methods Enzymol. 2006; 410:359-76.
4. Syvanen AC. Accessing genetic variation: genotyping single nucleotide polymorphisms. Nat Rev Genet. 2001 Dec; 2(12):930-42.
5. Bergeron-Sawitzke J, Gold B, Olsh A, et al. Multilocus analysis of age-related macular degeneration. Eur J Hum Genet. 2009 Sep;17(9):1190-9.
6. Scholl HP, Fleckenstein M, Charbel Issa P, et al. An update on the genetics of age-related macular degeneration. Mol Vis. 2007 Feb;13:196-205.
7. Francis PJ, Hamon SC, Ott J, et al. Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss. J Med Genet. 2009 May;46(5):300-7.
8. Robman L, Baird PN, Dimitrov PN, et al. C-Reactive Protein Levels and Complement Factor H Polymorphism Interaction in Age-related Macular Degeneration and Its Progression. Ophthalmology. 2010 Oct; 17(10):1982-8.
9. Despriet DD, Klaver CC, Witteman JC, et al. Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. JAMA. 2006 Jul;296(3):301-9.
10. Klein R, Knudtson MD, Klein BE, et al. Inflammation, complement factor H, and age-related macular degeneration: the multi-ethnic Study of atherosclerosis. Ophthalmology. 2008 Oct;115(10):1742-9.
11. Conley YP, Jakobsdottir J, Mah T, et al. CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. Hum Mol Genet. 2006 Nov; 15(21):3206-18.
12. Johnson PT, Betts KE, Radeke MJ, et al. Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid. Proc Natl Acad Sci U S A. 2006 Nov;103(46):17456-61.
13. Laine M, Jarva H, Seitsonen S, et al. Y402H polymorphism of complement factor H affects binding affinity to C-reactive protein. J Immunol. 2007 Mar;178(6):3831-6.
14. Maller J, George S, Purcell S, et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet. 2006 Sep;38(9):1055-9
15. Skerka C, Lauer N, Weinberger AA, et al. Complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration. Mol Immunol 2007 Jul;44(13):3398-406.
16. Gibson J, Cree A, Collins A, et al. Determination of a gene and environment risk model for age-related macular degeneration. Br J Ophthalmol. 2010 Oct; 94(10):1382-7.
17. Klein R, Cruickshanks KJ, Nash SD, et al. The prevalence of age-related macular degeneration and associated risk factors. Arch Ophthalmol. 2010 Jun;128(6):750-8.
18. Liutkeviciene R, Lesauskaite V, Asmoniene V, et al. Factors determining age-related macular degeneration: a current view. Medicina (Kaunas). 2010;46(2):89-94.
19. Dhubhghaill SS, Cahill MT, Campbell M, et al. The pathophysiology of cigarette smoking and age-related macular degeneration. Adv Exp Med Biol. 2010;664:437-46.
20. Ritch R. The management of exfoliative glaucoma. Prog Brain Res. 2008;173;211-24.
21. Thorleifsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science. 2007 Sep;317(5843):1397-400.
22. Aragon-Martin JA, Ritch R, Liebmann J, et al. Evaluation of LOXL1 gene polymorphisms in exfoliation syndrome and exfoliation glaucoma. Mol Vis. 2008 Mar;14:533-41.
23. Challa P, Schmidt S, Liu Y, et al. Analysis of LOXL1 polymorphisms in a United States population with pseudoexfoliation glaucoma. Mol Vis. 2008 Jan;14:146-9.
24. Ringvold A. Epidemiology of the pseudo-exfoliation syndrome. Acta Ophthalmol Scand. 1999 Aug; 77(4):371-5.
25. Sturm RA, Duffy DL, Zhao ZZ, et al. A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color. Am J Hum Genet. 2008 Feb;82(2):424-31.
26. Eiberg H, Troelsen J, Nielsen M, et al. Blue eye color in humans may be caused by a perfectly associated founder mutation in a regulatory element located within the HERC2 gene inhibiting OCA2 expression. Hum Genet. 2008 Mar;123(2):177-87.
27. Kayser M, Liu F, Janssens AC, et al. Three genome-wide association studies and a linkage analysis identify HERC2 as a human iris color gene. Am J Hum Genet. 2008 Feb;82(2):411-23.
28. Clifton JM, VanBeuge SS, Mladenka C, et al. The Genetic Information Nondiscrimination Act 2008: What clinicians should understand. J Am Acad Nurse Pract. 2010 May;22(5):246-9.