Association of matrix metalloproteinase gene polymorphisms with refractive error in Amish and Ashkenazi families.

Clear vision requires that images formed by incident light are focused at the eye's retinal plane. The maintenance of clear, focused, vision (i.e., emmetropia) through adulthood depends on a precise and complex regulation of eye shape during ocular development. This regulation ensures that the eye's focal and anatomic lengths are aligned. Any discrepancy between the position of the retina and the eye's focal point results in the spherical refractive errors myopia and hyperopia. In myopia, images of distant objects formed by the eye's optical system focus anterior to the retinal plane, causing blurred distance vision. In its functional opposite, hyperopia, these images focus behind the retina (in the unaccommodating eye). Hyperopia is associated with blurred near vision. Myopia and hyperopia are fundamentally qualitative definitions. However, the degree of departure from perfect focus can be quantified as the refractive error. Typically, refractive error represents the dioptric power of optical lenses necessary to achieve proper distance correction. By convention, negative values of refractive error (in diopters, D) represent myopia, whereas positive values represent hyperopia. Although there is a broad scientific consensus that environmental and behavioral factors influence refractive development and the genesis of myopia, genetic epidemiologic studies have consistently shown that the distribution of ocular refraction within populations is largely determined by genetics. Heritability estimates for refraction are usually very high across a wide spectrum of ethnic groups despite various intraethnic prevalences of myopia and myopigenic environmental influences. For example, we reported the heritability of refractive error in an adult Old Order Amish (AMISH) population to be 70%.1 High heritabilities are remarkably consistent across studies with estimates reported for Caucasian Americans,1–3 Europeans,4–7 and African Americans,3 ranging between 60% and 90%. Structurally, myopia is caused by an excessive axial length of the eye relative to its optical power.8 Hence, myopic eyes tend to be longer than nonmyopic eyes.8 The converse is true of hyperopia (i.e., hyperopic eyes are comparatively shorter than emmetropic and myopic eyes). Anatomically, these variations in axial length are due primarily to differences within the posterior (or vitreous) chamber, which occupies the bulk of the eye's volume. Although the molecular signal for blur-induced differential eye growth is thought to originate from within the retina, ocular elongation must occur via the growth of the outer tunic of the eye: the sclera. In mammals, the sclera is a fibrous connective tissue composed mainly of extracellular collagen, which accounts for up to 90% of the sclera's dry weight (Zorn N, et al. IOVS 1992;33:ARVO Abstract 1811). The majority (i.e., up to 99%) of scleral collagen is of the type I variety, although low levels of other collagen subtypes have also been found (Norton TT, et al. IOVS 1995;36:ARVO Abstract 3517). The structural organization of the scleral extracellular matrix (ECM) depends largely on the cellular activity of fibroblasts, the main ECM-producing cells in the sclera. The degradation of the ECM that occurs during scleral remodeling in eye growth and myopization (i.e., myopia development) is partially regulated through members of a major family of zinc- and calcium-dependent endopeptidases: the matrix metalloproteinases (MMPs) (see Rada et al.9 for a review). In humans, the MMP gene family comprises 23 distinct genes distributed across the genome; 9 MMP genes are located in a cluster at 11q22.2. The MMPs play numerous important roles in regulating cell–matrix composition in connective tissue and have been implicated in normal developmental processes and the pathogenesis of a variety of diseases.10,11 The expression of MMPs is generally low in tissues and is induced during active ECM remodeling.12 MMP regulation is mostly achieved at the transcriptional level but can occur at multiple stages. Activation of latent zymogens must occur for the MMPs to gain their proteolytic activity. Once activated, MMPs can be inactivated by multiple mechanisms, including direct interactions with one of four tissue inhibitors of matrix metalloproteinases (TIMPs).12 Given the important role of MMPs in ECM composition and remodeling, genetic variations in MMP genes are potential candidates for refractive error heritability and susceptibility to myopia. Indeed, a recent candidate gene study of older British adults reported statistically significant genetic associations between MMP3 and MMP9 polymorphisms and common myopia.13 We hypothesize that genetic polymorphisms in MMP and/or TIMP genes contribute to intrapopulation variations of refractive error measured as a quantitative trait. In the present study, we conducted family-based association analyses of genetic polymorphisms within MMP and TIMP candidate regions that included: MMP1, -2, -3, -7, -8, -9, -10, -12, -13, -14, -20, and -27, as well as TIMP1, -2, -3, and -4. These candidate regions were chosen to include genes whose homologs have shown differential expression in animal myopia models,14–17 as well as polymorphisms within a cluster of nine MMP genes situated at 11q22.2. Analyses were conducted on a subset of individuals from 63 Orthodox Ashkenazi Jewish (ASHK) and 55 Old Order Amish (AMISH) American families participating in the Myopia Family Study. We found statistically significant genetic associations between two single-nucleotide polymorphisms (SNPs), rs1939008 and rs9928731, and refractive error in the AMISH, but not the ASHK; rs1939008 is located between MMP1 and MMP10, and rs9928731 is located within MMP2.