Abstract
Purpose: :
Matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) are involved in extracellular matrix remodeling and eye growth. Animal studies have shown differential expression of MMP and TIMP genes in experimental myopia. We investigated the association of refractive error and polymorphisms in MMP and TIMP genes in Old Order Amish (AMISH) and Ashkenazi Jewish (ASHK) individuals from the Myopia Family Study.
Methods: :
Individuals from 57 AMISH and 63 ASHK families were recruited to participate in the Myopia Family Study. Ascertainment was designed to enrich the sample for multiplex myopic families; the average mean spherical equivalent (MSE) refractive error was -1.73D(±2.79) in AMISH, and -3.51D (±3.30) in ASHK. 148 common (MAF>0.1) haplotype tagging SNPs covering 14 MMP and 4 TIMP genes were genotyped in 359 AMISH and 535 ASHK participants. Quantitative-trait family-based association analyses of MSE and the mean spherical component of refraction (SPH) were performed separately for AMISH and ASHK subgroups using the ASSOC method implemented in the program MERLIN. Bonferroni-corrected significance thresholds were defined to account for correlations within 109 haplotype blocks in our samples: a p-value<.00046 (.05/109) or a local false-discovery rate (q-value) <0.05 were considered statistically significant.
Results: :
After quality-control filtering, 131 SNPs were included in the analyses. No MMP or TIMP polymorphisms in ASHK families showed statistically significant evidence of association to refraction (min p=.0132, q=0.94 at rs11225314). In AMISH families, two SNPs showed significant association with refractive phenotypes: rs1939008 (p=0.00016, q=0.046 for SPH) located ~4 Kb downstream of MMP1; and intronic SNP rs9928731 located between exons 6 and 7 of MMP2 (p=0.00026, q=0.046 for SPH).
Conclusions: :
We found statistically significant associations of ocular refraction to polymorphisms near MMP1 and within MMP2 in Old Order Amish families, but not among Ashkenazi Jews. Our results suggest that MMP genes are involved in the modulation of ocular refraction in defined human populations. Furthermore, genetic and/or environmental heterogeneity likely contribute differences in association results between ethnic groups.
Keywords: myopia • genetics