Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
PLoS One. 2012;7(10):e46742. doi: 10.1371/journal.pone.0046742. Epub 2012 Oct 23.
Fuchs endothelial corneal dystrophy (FECD) is the most common late-onset, vision-threatening corneal dystrophy in the United States, affecting about 4% of the population. Advanced FECD involves a thickening of the cornea from stromal edema and changes in Descemet membrane. To understand the relationship between FECD and central corneal thickness (CCT), we characterized common genetic variation in COL8A2 and TCF4, genes previously implicated in CCT and/or FECD. Other genes previously associated with FECD (PITX2, ZEB1, SLC4A11), and genes only known to affect CCT (COL5A1, FOXO1, AVGR8, ZNF469) were also interrogated. FECD probands, relatives and controls were recruited from 32 clinical sites; a total of 532 cases and 204 controls were genotyped and tested for association of FECD case/control status, a 7-step FECD severity scale and CCT, adjusting for age and sex. Association of FECD grade with TCF4 was highly significant (OR= 6.01 at rs613872; p = 4.8×10(-25)), and remained significant when adjusted for changes in CCT (OR= 4.84; p = 2.2×10(-16)). Association of CCT with TCF4 was also significant (p = 6.1×10(-7)), but was abolished with adjustment for FECD grade (p = 0.92). After adjusting for FECD grade, markers in other genes examined were modestly associated (p ∼ 0.001) with FECD and/or CCT. Thus, common variants in TCF4 appear to influence FECD directly, and CCT secondarily via FECD. Additionally, changes in corneal thickness due to the effect of other loci may modify disease severity, age-at-onset, or other biomechanical characteristics.
福克司内皮角膜营养不良（FECD）是美国最常见的迟发性、威胁视力的角膜营养不良，影响约 4%的人口。晚期 FECD 涉及基质水肿和 Descemet 膜改变导致的角膜增厚。为了了解 FECD 与中央角膜厚度（CCT）之间的关系，我们对 COL8A2 和 TCF4 中的常见遗传变异进行了特征描述，这两个基因先前与 CCT 和/或 FECD 有关。还研究了与 FECD 相关的其他基因（PITX2、ZEB1、SLC4A11）以及仅已知会影响 CCT 的基因（COL5A1、FOXO1、AVGR8、ZNF469）。FECD 先证者、亲属和对照者从 32 个临床站点招募；对 532 例病例和 204 例对照者进行基因分型，并检测 FECD 病例/对照状态、7 级 FECD 严重程度量表和 CCT 的关联，同时调整年龄和性别。TCF4 与 FECD 分级的关联具有高度显著性（rs613872 的 OR=6.01；p=4.8×10(-25)），并且在调整 CCT 变化时仍然显著（OR=4.84；p=2.2×10(-16)）。CCT 与 TCF4 的关联也具有显著性（p=6.1×10(-7)），但在调整 FECD 分级后则被消除（p=0.92）。在调整 FECD 分级后，所研究的其他基因中的标记物与 FECD 和/或 CCT 具有适度的关联（p ∼ 0.001）。因此，TCF4 中的常见变体似乎直接影响 FECD，并通过 FECD 间接影响 CCT。此外，由于其他位点的影响导致的角膜厚度变化可能会改变疾病严重程度、发病年龄或其他生物力学特征。
