Eye color is one of the defining features of the human animal. It is the subject of song and verse and at the same time features prominently on your driver’s license and passport. It can even be used as a biometric identifier, akin to fingerprinting or voice recognition. Despite this prominence, iris pigmentation rarely enters into any significant clinical consideration even though the color of a patient’s iris can impact his ocular health, and it can be a factor in drug efficacy and in the susceptibility to adverse drug effects. This month we delve into ocular pigmentation biology, pharmacology and genetics and ask the question: How does the color of patients’ eyes affect the way we treat their ocular disorders?

Ocular Pigments

There are two major pigmented structures in the eye, the iris and the retinal pigment epithelium. While RPE cells are central to overall retinal function, here we will focus on the pigments found in the iris. The iris is composed of two layers: a stromal, anterior layer and a posterior pigmented epithelial layer.1,2 The two layers both contain pigmented cells but are embryologically distinct. The stromal layer cells are derived from the neural crest, while posterior epithelial cells are ectodermal in origin. The melanocytes of both layers contain melanosomes, specialized organs that synthesize and store various melanins. There is no compelling evidence suggesting any of these pigmented structures are ever secreted from the melanocytes in the eye, although this is common in other tissues. What we refer to as eye color derives from a combination of factors, including the types of melanins synthesized, the pigments of the anterior iris and the light scattering properties of the anterior stroma.

The two major pigments synthesized in all melanocytes are the eumelanin (black/brown) and pheomelanin (red/yellow).3,4
Despite its striking appearance, the most profound effects of the OCA1 type of oculocutaneous albinism are the spectrum of visual defects: poor acuity; foveal hypoplasia; nystagmus and strabismus. ( Image courtesy Ora Inc.)
Melanocytes throughout the body can synthesize either or both of these pigments, and the ratio of the two is a significant factor in determining the color of the tissue. The posterior epithelial layer of the iris, as well as the RPE, produce eumelanin only, while the stromal melanocytes typically contain both pigments. Individuals with defects in melanin synthesis, whether partial or complete, display some level of albinism, either ocular or oculocutaneous. More critical for eye color than the ratio of the two pigments is the density of melanosomes in the stromal melanocytes. A continuum of iris color, from blue to gray, and then to green and brown, can be correlated with a corresponding graded increase in melanosome density. More subtle differences in grays, hazels and greens result from individual differences in pigment ratios.

The mechanics of pigment production rely on a family of related enzymes, the tyrosinases.5 Two major family members, tyrosinase and tyrosinase-related protein 1, catalyze oxidations including the key conversion of tyrosine to dihydroxyphenylalanine. Several additional oxidation steps follow to ultimately generate both eumelanin and pheomelanin. The difference between the two pigments is that pheomelanin also includes cysteine as one of its building-block components, and so the availability of this precursor can also impact iris color. Expression levels of TYR and TYRP are critical to pigment synthesis, and genetic defects in their expression result in two types of oculocutaneous albinism, OCA1 and OCA3.

Genetics of Eye Color

The presentations of some forms of pigment disorders are striking, and so they may seem more common conditions than they really are; in the United States about 1:16,000, or 20,000 individuals, have some form of albinism.6 The specific genotypes dictate the spectrum of disease and impact on visual function. Genes implicated in the four major types of oculocutaneous albinism, OCA1 to -4, have been identified, and an understanding of their function has provided important clues to the role of pigmented cells in the eye.7

The most common form of the disease, OCA1, is caused by mutations in the TYR gene, and it results in either a partial or complete loss of melanin biosynthesis.6,7 These patients have pinkish skin, blue-grey irides and a prominent photophobia. They typically have poor acuity, foveal hypoplasia, nystagmus and strabismus. Melanocytes are known to play extensive roles in development, and this may underlie both foveal defects and less common instances of chiasmic misrouting of nerve fiber tracts. Recent work has focused on correlating foveal organization and BCVA to try and understand the role iris pigmentation plays in ocular development.

Less profound types of albinism, including OCA2 and OCA4, are caused by defects in melanosome function that result in low amounts of eumelanin.6,7 This shift in the ratios of pigments has subtle effects, both in terms of the affected individual’s appearance, and in the extent of visual function impairment. Some pigments are visible at birth, and any color in skin and eyes increases with age. Ocular issues such as nystagmus and photophobia are present but less severe than in OCA1. The mutations associated with the OCA4 gene are most common in patients with a Japanese heritage. Mutations in the TYRP gene are classified as OCA3, and are most common in those of African ancestry. Affected individuals display reduced pigmentation and lighter-colored eyes, and have the mildest forms of nystagmus and strabismus.

Melanosome Control

One of the features of the melanosome that distinguishes it from other intracellular structures is an enzyme complex that includes TYR, TYRP and the melanocyte-stimulating hormone receptor.2,4 This complex responds to MSH and other signaling molecules by increasing functional expression of TYR, leading to an increase in melanin synthesis. Melanins have several roles, but key among these is protection from the harmful effects of UV radiation, and both UVA and UVB wavelengths are readily absorbed by both pigments.

Iris hyperchromia and increased lash length and density occur in some patients being treated with prostaglandins. At the time of this photo, the patient had been using Xalatan in the left eye for a year. ( Image courtesy Joel Schuman, MD. )
In addition, exposure to excess UV light can trigger an inflammatory response (in the skin and in the eye) activating inflammatory responses including cyclooxygenase-dependent prostaglandin E2 biosynthesis. A consequence of increased expression of pleiotropic signaling molecules such as PGE2 is a feedback stimulation of TYR expression.8,9 This normal physiological response to sunlight is hijacked in the PG-induced iris hyperpigmentation seen in some cosmetic use of PGs. Small amounts of these formulations reach the ocular surface, where they can readily penetrate to the stromal melanocytes, activate increased TYR expression, and stimulate increases in melanosomes that result in a darkening of the iris that is only slowly reversible.

Patients using PGE2-containing formulations to enhance growth of eyelashes may also experience changes in the color and shape of the upper eyelids. This is due to the stimulation of skin pigment expression, and a reduction in the volume of fat deposits, an effect also stimulated by PGE2.10 The resulting sunken ocular sulcus, particularly on the upper lids, is an effect that most patients will not be happy with. While some might make the aesthetic choice between longer lashes or sunken sockets, for those using PG agonists to treat ocular hypertension, it may be possible to mitigate this effect by switching to a different product.10

Disease Risk/Drug Interactions

Our discussion of eye color goes beyond genetics and aesthetics. There have been many studies published with the goal of correlating eye color with the risk of various ocular disorders, from melanomas to age-related macular degeneration.11-13 There is no shortage of such risk assessments, and they do provide some information on the relationship between eye color and relative risks. For example, several studies have shown positive correlation between iris pigment and the risk of geographic atrophy or glaucoma. Similarly, the increased risk of ocular melanoma in those with lighter eye color is similar to other melanomas for which those with lighter skin are at greater risk of developing the disease. Despite these findings, focusing on epidemiological trends may overlook the greater potential impact of ocular pigmentation on drug pharmacokinetics.

Patients using PGE2-containing formulations to enhance growth of eyelashes may also experience changes in the color and shape of the upper eyelids.
Underlying the progression from baby blue eyes to black lies the potential for a confounding impact on any therapeutic agent, from artificial tears to the newest biologicals. A patient with deep brown irides has two to four times more ocular melanin than one with light blue eyes,5 and the ability of melanins to bind and alter the pharmacokinetics of a drug may be the single biggest impact eye color has on therapy. This potential for altering the pharmacokinetics of drugs is particularly important because so many ophthalmic medications are delivered topically, where local drug binding can exert a greater relative effect. Many classes of drugs used in the eye, including alpha- and beta-adrenergics, antibiotics14 and corticosteroids15 have been shown to bind to melanin-containing tissues with high affinity.

This binding activity is seen across multiple classes of drugs, yet is predominantly drug-specific: For example, triamcinolone binds with high affinity, while dexamethasone does not. The importance of melanin binding is demonstrated by its inclusion as one of the required tests in the toxicological profiling of topically applied drugs.

Eye color is a trait we share with other higher vertebrates, yet it seems a very human attribute. While we can classify a person according to a predominant coloration, the patterns and intricacy of the iris help to remind us of our individuality. They can also serve as a reminder of each of our patient’s unique (and not always predictable) response to their therapeutic regimes.  REVIEW

Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School. Dr. McLaughlin is a medical writer at Ora Inc.

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