Wojciechowski Robert, Bailey-Wilson Joan E, Stambolian Dwight
Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland 21224, USA.
Invest Ophthalmol Vis Sci. 2010 Oct;51(10):4989-95. doi: 10.1167/iovs.10-5474. Epub 2010 May 19.
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in scleral extracellular matrix remodeling and have shown differential expression in experimental myopia. The genetic association of refractive error and polymorphisms in MMP and TIMP genes in Old Order Amish (AMISH) and Ashkenazi Jewish (ASHK) families was investigated.
Individuals from 55 AMISH and 63 ASHK families participated in the study. Ascertainment was designed to enrich the families for myopia; the mean spherical equivalent (MSE) refractive error (SD) was -1.61 (2.72) D in the AMISH, and -3.56 (3.32) D in the ASHK. One hundred forty-six common haplotype tagging SNPs covering 14 MMP and 4 TIMP genes were genotyped in 358 AMISH and 535 ASHK participants. Association analyses of MSE and the spherical component of refraction (SPH) were performed separately for the AMISH and the ASHK. Bonferroni-corrected significance thresholds and local false discovery rates were used to account for multiple testing.
After they were filtered for quality-control, 127 SNPs were included in the analyses. No polymorphisms showed statistically significant association to refraction in the ASHK (minimum P = 0.0132). In AMISH, two SNPs showed evidence of association with refractive phenotypes: rs1939008 (P = 0.00016 for SPH); and rs9928731 (P = 0.00026 for SPH). These markers were each estimated to explain <5% of the variance of SPH in the AMISH sample.
Statistically significant genetic associations of ocular refraction to polymorphisms near MMP1 and within MMP2 were identified in the AMISH but not among the ASHK families. The results suggest that the MMP1 and MMP2 genes are involved in refractive variation in the AMISH. Genetic and/or environmental heterogeneity most likely contribute to differences in association results between ethnic groups.
基质金属蛋白酶（MMPs）和金属蛋白酶组织抑制剂（TIMPs）参与巩膜细胞外基质重塑，并在实验性近视中表现出差异表达。本研究调查了老派阿米什人（AMISH）和德系犹太人（ASHK）家族中屈光不正与MMP和TIMP基因多态性的遗传关联。
来自55个AMISH家族和63个ASHK家族的个体参与了本研究。研究设计旨在富集近视家族；AMISH家族的平均球镜等效（MSE）屈光不正（标准差）为-1.61（2.72）D，ASHK家族为-3.56（3.32）D。在358名AMISH参与者和535名ASHK参与者中，对覆盖14个MMP基因和4个TIMP基因的146个常见单倍型标签SNP进行了基因分型。分别对AMISH和ASHK进行MSE和球镜屈光成分（SPH）的关联分析。采用Bonferroni校正的显著性阈值和局部错误发现率来处理多重检验。
经过质量控制筛选后，127个SNP纳入分析。在ASHK中，没有多态性与屈光有统计学显著关联（最小P = 0.0132）。在AMISH中，两个SNP显示出与屈光表型相关的证据：rs1939008（SPH的P = 0.00016）；以及rs9928731（SPH的P = 0.00026）。这些标记在AMISH样本中各自估计解释SPH变异的<5%。
在AMISH家族中发现了眼屈光与MMP1附近和MMP2内多态性的统计学显著遗传关联，但在ASHK家族中未发现。结果表明MMP1和MMP2基因参与了AMISH家族的屈光变异。遗传和/或环境异质性很可能导致不同种族之间关联结果的差异。
