Krumbiegel Mandy, Pasutto Francesca, Mardin Christian Y, Weisschuh Nicole, Paoli Daniela, Gramer Eugen, Zenkel Matthias, Weber Bernhard H F, Kruse Friedrich E, Schlötzer-Schrehardt Ursula, Reis André
Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.
Invest Ophthalmol Vis Sci. 2009 Jun;50(6):2796-801. doi: 10.1167/iovs.08-2339. Epub 2009 Jan 31.
Pseudoexfoliation (PEX) syndrome is a generalized elastic microfibrillopathy characterized by fibrillar deposits in intra- and extraocular tissues. Genetic and nongenetic factors are known to be involved in its etiopathogenesis. This study was focused on six functional candidate genes involved in PEX material deposition and the analysis of their potential association with PEX syndrome and PEX glaucoma (PEXG).
Fifty single-nucleotide polymorphisms (SNPs) capturing >95% of overall genetic variance observed in Europeans at loci for FBN1, LTBP2, MFAP2, TGM2, TGF-b1, and CLU were genotyped in 333 unrelated PEX-affected and 342 healthy individuals of German origin, and a genetic association study was performed. To replicate the findings, two SNPs of the CLU gene were genotyped in a further 328 unrelated German patients with PEX as well as in 209 Italian patients with PEX and 190 Italian control subjects.
Association with PEX was observed only for the SNP rs2279590 in intron 8 of the CLU gene coding for clusterin (corrected P = 0.0347, OR = 1.34) in our first German cohort. Likewise, a frequent haplotype encompassing the associated risk allele showed nominally significant association. None of remaining SNPs or SNP haplotypes were associated with PEX. The association found was confirmed in a second German cohort (P = 0.0244) but not in the Italian cohort (P = 0.7173). In addition, the association with CLU SNP rs2279590 was more significant in German patients with PEX syndrome than in those with PEXG.
Genetic variants in the gene encoding clusterin may represent a risk factor for PEX in German patients but not in Italian patients. Variants in FBN1, LTBP2, MFAP2, TGF-b1, and TGM2 do not play a major role in the etiology of PEX syndrome, at least in German patients.
假性剥脱（PEX）综合征是一种全身性弹性微原纤维病，其特征为眼内和眼外组织中有纤维状沉积物。已知遗传和非遗传因素均参与其发病机制。本研究聚焦于六个参与PEX物质沉积的功能性候选基因，并分析它们与PEX综合征和PEX青光眼（PEXG）的潜在关联。
在333名患有PEX的无关德国人和342名健康德国人中，对50个单核苷酸多态性（SNP）进行基因分型，这些SNP涵盖了欧洲人在FBN1、LTBP2、MFAP2、TGM2、TGF-β1和CLU基因座上观察到的>95%的总体遗传变异，并进行了遗传关联研究。为了重复研究结果，在另外328名患有PEX的无关德国患者、209名患有PEX的意大利患者和190名意大利对照受试者中，对CLU基因的两个SNP进行了基因分型。
在我们的第一个德国队列中，仅观察到编码簇集蛋白的CLU基因第8内含子中的SNP rs2279590与PEX相关（校正P = 0.0347，OR = 1.34）。同样，包含相关风险等位基因的常见单倍型显示出名义上的显著关联。其余SNP或SNP单倍型均与PEX无关。在第二个德国队列中证实了所发现的关联（P = 0.0244），但在意大利队列中未得到证实（P = 0.7173）。此外，与CLU SNP rs2279590的关联在患有PEX综合征的德国患者中比在患有PEXG的患者中更显著。
编码簇集蛋白的基因中的遗传变异可能是德国患者患PEX的危险因素，但不是意大利患者的危险因素。FBN1、LTBP2、MFAP2、TGF-β1和TGM2的变异在PEX综合征的病因中至少在德国患者中不发挥主要作用。
