PURPOSE. To evaluate the noelin 2 gene as a disease-causing factor for open-angle glaucoma (OAG) and the interactions between the noelin 2 (OLFM2), optineurin (OPTN), and myocilin (MYOC) genes. METHODS. OLFM2 was analyzed in 770 Japanese subjects including 215 patients with elevated intraocular pressure (IOP), 277 with normal IOP, 38 with juvenile open-angle glaucoma, and 240 control subjects. Two single-nucleotide polymorphisms (SNPs) in OPTN (c.412G3 A and c.603T3 A) and one SNP in MYOC (c.227G3 A) were examined. Single genes were investigated by univariate analysis and the gene-gene interactions by logistic regression analysis. Associations between genotypes and clinical characteristics at the time of diagnosis were examined. RESULTS. In OLFM2, 12 sequence variants were identified in 770 Japanese subjects. Arg144Gln (exon 4) was identified in two (0.3%) of the patients and in none of the control subjects. Combinations of OLFM2/317A and OPTN/412A or OLFM2/ 1281T and OPTN/412A were associated with patients with elevated IOP (P ϭ 0.018 or P ϭ 0.012, respectively). The combination of OLFM2/317G and OPTN/603A was significantly associated with elevated IOP (P ϭ 0.018). No significant association was detected between SNPs in OLFM2 and in MYOC. Patients with normal IOP and with OLFM2/ 678AϩOPTN/412G or OLFM2/1281CϩOPTN/412G had significantly worse visual field scores (P ϭ 0.022 or 0.030, respectively). CONCLUSIONS. The Arg144Gln mutation in OLFM2 is a possible disease-causing mutation in Japanese patients with OAG. Common polymorphisms in OLFM2 and OPTN may interactively contribute to the development of OAG, indicating a polygenic etiology. (Invest Ophthalmol Vis Sci. 2006;47:5368 -5375) DOI:10.1167/iovs.06-0196 G laucoma is the second leading cause of blindness worldwide, and is estimated to affect more than 60 million people. Open-angle glaucoma (OAG), the most common form, is present in almost 2% of the world's population older than 40 years. 1 Glaucoma includes a group of conditions that is characterized by progressive optic neuropathy with visual field changes corresponding to the damage of the retinal nerve fibers. These changes are usually associated with an elevation of intraocular pressure (IOP). Elevated IOP is generally accepted to be a major risk factor for glaucomatous changes. Genetic factors also play a major role in the etiology of OAG. 3 The first gene to be characterized was the trabecular meshwork-inducible glucocorticoid response (TIGR) gene on 1q. 14 Most of the mutations in MYOC are located in the olfactomedin domain. Olfactomedin is a secreted polymeric glycoprotein of unknown function with an evolutionarily conserved C-terminal motif. 5 Mukhopadhyay et al. 19 identified myocilin-related human proteins having a conserved olfactomedin domain using bioinformatics approaches and examined the expression patterns in the eye. Myocilin-related proteins with homology to human myocilin were selected by BLASTp