Purpose: To evaluate the association of myocilin (MYOC), optineurin (OPTN), and apolipoprotein E (APOE) genes and their interactions in primary open angle glaucoma (POAG).
Methods: A cohort of 400 unrelated POAG patients (294 high tension glaucoma, HTG, and 106 normal tension glaucoma, NTG) and 281 unrelated control subjects were recruited. All coding exons and splicing junctions in MYOC and OPTN were screened for sequence alterations. Common polymorphisms in APOE were genotyped. Single genes were investigated by univariate and haplotype analysis, and gene-gene interactions by logistic regression and stratified analysis. Multiple comparisons were corrected by the Bonferroni method. Bioinformatics analysis was performed to assess the conservation of mutation sites across species and to predict putative motifs and secondary structures in mutated proteins.
Results: Disease-causing mutations in MYOC and OPTN were identified in 1.75% and 1% of POAG patients, respectively. Most of these mutations were highly conserved across species, many predicted to create new motifs or change protein secondary structures. No individual MYOC polymorphisms significantly contributed to HTG or NTG. A haplotype containing the minor allele of the MYOC IVS2+35A>G increased NTG risk (p=0.0001). Three OPTN polymorphisms, T34T, IVS5+38T>G, and IVS8-53T>C increased NTG risk (p<0.0008), while IVS5+38T>G increased HTG risk (p=0.0006). One haplotype that contains the minor alleles of 3 OPTN polymorphisms, T34T, IVS5+38T>G, and IVS7+24G>A, increased NTG risk (p=0.0002). APOE epsilon4 carriers had a decreased NTG risk (p=0.007). Possible gene-gene interactions were found between MYOC, OPTN, and APOE.
Conclusions: Disease-causing mutations in MYOC and OPTN accounted for only a small proportion of Chinese POAG patients. Common polymorphisms in MYOC, OPTN, and APOE might interactively contribute to POAG, indicating a polygenic etiology.