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Background: The CAV1‐CAV2 locus has been associated with primary open‐angle glaucoma (POAG) and intraocular pressure. However, its association with normal‐tension glaucoma (NTG) was inconclusive. Therefore, we evaluated this association in Chinese and Japanese. Methods: Two single‐nucleotide polymorphisms (SNPs, rs4236601 and rs1052990) from previous genome‐wide association studies of POAG were genotyped in a total of 2220 study subjects: a Hong Kong Chinese cohort of 537 NTG patients and 490 controls, a Shantou Chinese cohort of 102 NTG and 731 controls and an Osaka Japanese cohort of 153 NTG and 207 controls. Subgroup analysis by gender was conducted. Outcomes from different cohorts were combined using meta‐analysis. Results: SNP rs4236601 was significantly associated with NTG in the two Chinese cohorts (Pmeta =.0019, OR = 4.55, I2 = 0). In contrast, rs4236601 was monomorphic in the Osaka cohort. The association of rs1052990 was insignificant in a meta‐analysis combining Chinese and Japanese cohorts (Pmeta =.81, OR = 1.05; I2 = 64%), and the OR tended towards opposite directions between Chinese (OR = 1.26) and Japanese (OR = 0.69). Gender‐specific effects of the SNPs were not statistically significant in the logistic regression or Breslow‐day tests of ORs (P >.05), although rs4236601 was significant in males (P =.0068; OR = 10.30) but not in females (P =.14; OR = 2.65) in the meta‐analysis of Chinese subjects. Conclusions: In this study, we confirmed the association of rs4236601 at the CAV1‐CAV2 locus with NTG in Chinese. SNP rs4236601 is monomorphic, and rs1052990 tends towards a different direction in the Japanese cohort. Further studies are warranted to verify the ethnic difference and gender‐specific effects of this locus. [ABSTRACT FROM AUTHOR]

Abstract The purpose of the study was to evaluate the association profiles of the SIX6 locus with primary open-angle glaucoma (POAG) in southern Chinese and Japanese. In this study, we tested single marker and haplotype-based associations of 11 tagging single nucleotide polymorphisms (SNPs) covering the SIX6 locus with POAG in a Hong Kong Chinese cohort (N = 1402). A novel SNP (i.e., rs12436579) and two SNPs (i.e., rs33912345 and rs10483727) from previous genome-wide association studies were further tested in a Chinese cohort from Shantou (N = 888) and a Japanese cohort from Osaka (N = 463). Results from the three cohorts were meta-analysed using a random-effect model. We found rs12436579, which has not been previously reported, was associated with POAG in Hong Kong and Shantou Chinese (P combined = 4.3 × 10−5, OR = 0.72, I2 = 0). Additionally, we replicated the association of one known SNP, rs33912345 (P combined = 0.0061, OR = 0.69, I2 = 45%), with POAG in the Chinese cohorts but not in the Japanese cohort (P > 0.6). Another known SNP, rs10483727, was nominally associated with POAG in the two Chinese cohorts (P combined = 0.017, OR = 0.70, I2 = 53%). All these three SNPs were significantly associated with POAG when the three cohorts were combined in meta-analysis (P combined <0.005). Furthermore, two haplotypes, C-C (P combined = 1.13 × 10−5, OR = 1.41, I2 = 0) and A-A (P combined = 0.045, OR = 0.68, I2 = 70%), defined by rs33912345-rs12436579 were associated with POAG in Chinese but not in Japanese. In conclusion, this study confirmed the association between two GWAS SNPs in SIX6 (rs33912345 and rs10483727) and POAG. Also, a SNP, rs12436579, not associated with POAG before, was found to be associated with POAG in Chinese. Further studies are warranted to elucidate the role of this novel SNP in POAG. Highlights • Validation of reported association between the SIX6 SNPs and POAG. • Identification of a novel SNP rs12436579 associated with POAG in Southern Chinese. • Haplotype rs33912345-rs12436579 had a stronger association than single SNP. • Different association patterns of SIX6 with POAG between Chinese and Japanese. [ABSTRACT FROM AUTHOR]