高度近視與鞏膜基質成份基因單核苷酸多型性及其單倍型之相關性

Abstract

近視鞏膜薄化與眼球增長的主要導因正是鞏膜基質的重塑現象。人類鞏膜中small leucine-rich proteoglycans (SLRPs) 扮演調節膠原微纖維(collagen fibrils)聚集與互動的重要角色，進而影響鞏膜的機械特性及眼軸增長。與家族性高度近視有連鎖關係的染色體12q21-23 (MYP 3)區段正是三個SLRP genes所在，它們是decorin、lumican、及dermatan sulfate proteoglycan 3 (DSPG-3) genes。 藉由高度近視實驗組120人及對照組137人，吾人評估decorin、lumican、及 DSPG3 genes的單核苷酸多型性(single nucleotide polymorphism，SNP)及單倍型(haplotype)與台灣人高度近視易感性的相關性。吾人分別在此三基因選出四個、八個、及四個單核苷酸多型性以定序(direct DNA sequencing)方式進行基因定型。其中，lumican gene SNP rs3759223: T>C 與高度近視有相當顯著的相關性 (p=2.83×10-4)。四個lumican SNPs 具有顯著連鎖不平衡(linkage disequilibrium，LD)，並且形成haplotype block。吾人以Sliding-window單倍型分析(haplotype analysis)方式發現，rs3759223 與 rs3741834 組成的haplotype profile 與高度近視有顯著的相關性 (global p = 1.0725 ×10-6)。特定單倍型測試(Haplotype-specific tests) 則顯示 C-C 與T-C haplotypes與高度近視有顯著的相關性，風險比odds ratios (95%信賴區間 confidence interval，CI) 分別為19.32 (2.55-146.54) 及 0.69(0.46-1.04)。 高度近視患者中帶有C-C haplotype者，傾向有較長的眼軸長與較深的近視度數。rs3759223 與 rs3741834 皆位於lumican gene 的調控區段，因此得以影響鞏膜膠原微纖維生成(collagen fibrillogenesis)及近視形成。Multifactor dimensionality reduction (MDR) 分析的結果，同樣再度證實此單區域相關性(single-locus association)，並且推算lumican gene rs2300588 與rs3741834 間具有明顯的雙區域互動模式(two-locus interaction model)存在。 Lumican gene 調控區段的基因變異，也就是rs3759223 與 rs3741834之所在，可能與台灣華人的高度近視易感性(high myopia susceptibility)有相關性，因此，本區段相當值得進ㄧ步探討與研究！

Scleral thinning and eyeball elongation in myopic eyes are related to the remodeling of scleral extracellular matrices. Small Leucine-Rich Proteoglycans (SLRPs) in human sclera play an important role in regulating the assembly and interaction of collagen fibrils, which influence scleral mechanical properties and axial elongation. Mutations in SLRP genes have been reported in common high myopia. Chromosome 12q21-23 (MYP 3), linked with certain familial high myopia, includes three SLRP genes, which are decorin, lumican, and dermatan sulfate proteoglycan 3 (DSPG-3). By 120 cases and 137 controls, we evaluated the association of SNPs and haplotypes at the decorin, lumican, and DSPG3 genes with high myopia susceptibility in Taiwanese patients. We genotyped 4, 8, and 4 SNPs, respectively, within these three genes by using direct DNA sequencing. The lumican gene SNP rs3759223: T>C showed significant associations with high myopia (p=2.83×10-4). Four lumican SNPs showed significant linkage disequilibrium and formed a haplotype block. Sliding-window haplotype analyses revealed that the block consisting of rs3759223 and rs3741834 showed significant goodness of fit (global p = 1.0725 ×10-6). Haplotype-specific tests showed that the C-C and T-C haplotypes were significantly associated with high myopia, with odds ratios (95% confidence interval) of 19.32 (2.55-146.54) and 0.69(0.46-1.04), respectively. In high myopia cases, those with C-C haplotype tend to have more severe myopia and longer axial length. rs3759223 and rs3741834 are in putative regulatory element of lumican gene which influences fibrillogenesis of scleral collagen fibers and the myopia development. The results of a multifactor dimensionality reduction (MDR) analysis corroborated the single-locus association and suggested a significant two-locus interaction model composed of SNPs rs2300588 and rs3741834 in the lumican gene. Genetic variation in regulatory domains of the lumican gene, where both rs3759223 and rs3741834 locate, in Han Chinese may be associated with high myopia susceptibility, making this region worthy of further investigation！