Association and Familial Segregation of CTG18.1 Trinucleotide Repeat Expansion of TCF4 Gene in Fuchs' Endothelial Corneal Dystrophy
Association and Familial Segregation of CTG18.1 Trinucleotide Repeat Expansion of TCF4 Gene in Fuchs' Endothelial Corneal Dystrophy
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DOI：
10.1167/iovs.13-12611
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发表时间：
2014-01-01
影响因子：
4.4
通讯作者：
Xing, Chao
中科院分区：
文献类型：
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作者：
Mootha, V. Vinod;Gong, Xin;Xing, Chao
目的。我们检测了TCF4基因的两个内含子多态(CTG18.1和rs613872)与Fuchs内皮性角膜营养不良(FECD)的关系，并分析了它们在家族中的分离模式。招募了先证者的现有家庭成员。单核苷酸多态(SNP)rs613872的基因分型采用Sanger测序或实时等位基因鉴别分析。三核苷酸重复序列多态性CTG18.1采用短串联重复序列分析和三重重复序列扩增相结合的方法进行基因分型。~gt；=40的胞嘧啶核苷-鸟氨酸(CTG)重复长度为扩展的CTG18.1等位基因。评估这两个基因座与FECD的关联性。结果两个基因处于连锁不平衡状态，病例组r(2)=0.65，对照组r(2)=0.31。FECD与rs613872(P=3.1×10(-17))、CTG18.1扩展等位基因(P=6.5×10(-25))及它们的单倍型(P=5.9×10(-19))显著相关。FECD的rs613872G等位基因每个拷贝的优势比(OR)估计为9.5(95%可信区间[CI]，5.1~17.5)。CTG18.1扩展等位基因每一拷贝的OR值为32.3(95%CI，13.4~77.6)。在52%(15/29)的完全外显性家系和10%(3/29)不完全外显性家系中，扩增的CTG 18.1等位基因与该性状共分离。结论：据我们所知，首次独立复制扩增的CTG 18.1等位基因可显著增加FECD的风险(增加30倍)。在大多数家系中，扩展的等位基因与完全外显的特征是共分离的，但我们也记录了不完全外显的情况。
PURPOSE. We tested the association between two intronic polymorphisms (CTG18.1 and rs613872) in TCF4 and Fuchs' endothelial corneal dystrophy (FECD), and analyzed their segregation patterns in families.METHODS. We recruited 120 unrelated Caucasian subjects with FECD and 100 controls. Available family members of probands were recruited. Genotyping of the single nucleotide polymorphism (SNP) rs613872 was performed using Sanger sequencing or real-time allelic discrimination assay. The trinucleotide repeat polymorphism, CTG18.1, was genotyped using a combination of short tandem repeat assay and triplet repeat primed PCR assay. The cytosinethymine- guanine (CTG) repeat length of >= 40 was classified as an expanded CTG18.1 allele. Association of the two loci with FECD was evaluated. Segregation in 29 families was examined.RESULTS. The two polymorphisms are in linkage disequilibrium (r(2) = 0.65 in cases and 0.31 in controls). Significant associations were found between FECD and rs613872 (P = 3.1 x 10(-17)), expanded CTG18.1 allele (P = 6.5 x 10(-25)), and their haplotypes (P = 5.9 x 10(-19)). The odds ratio (OR) of each copy of the rs613872 G allele for FECD was estimated to be 9.5 (95% confidence interval [CI], 5.1-17.5). The OR of each copy of the CTG18.1 expanded allele was estimated to be 32.3 (95% CI, 13.4-77.6). The expanded CTG 18.1 allele cosegregated with the trait in 52% (15/29) of families with complete penetrance and 10% (3/29) with incomplete penetrance.CONCLUSIONS. We report, to our knowledge, the first independent replication of the expanded CTG 18.1 allele conferring significant risk for FECD (> 30-fold increase). The expanded allele cosegregates with the trait with complete penetrance in a majority of families, but we also document cases of incomplete penetrance.