Abstract
This study investigated the genetic association of three single nucleotide polymorphisms (SNPs; rs10483727, rs33912345, and rs146737847) at the SIX1-SIX6 locus with primary open angle glaucoma (POAG) in the Chinese population. A total of 866 subjects with POAG (685 high-tension glaucoma (HTG) and 181 normal-tension glaucoma (NTG)) and 266 control individuals were included. Significant genetic association was identified for rs10483727 in HTG (P=0.02; odds ratio (OR)=1.31), NTG (P=7.41×10-6; OR=2.71), and POAG (i.e., HTG and NTG combined; P=0.001; OR=1.44). rs33912345 was also significantly associated with HTG (P=0.008; OR=1.36), NTG(P=2.72×10-6; OR=2.27), and POAG (P=3.84×10-4; OR=1.49). The rare SIX6 mutation, rs146737847, was not found in the subjects enrolled in this study. Stratification by patient age identified that both rs10483727 and rs33912345 were significantly associated with NTG in patients aged above 40 years (P=2.08×10-5; OR=2.28), whereas in patients aged between 20–40 years, rs33912345 was significantly associated with NTG (P=0.017; OR=2.06). In HTG, the genetic associations for both rs10483727 and rs33912345 were significant in patients aged between 20–40 years (P=0.006; OR=1.56) but not in those aged above 40 years (P=0.118, OR=1.21 and P=0.042, OR=1.29, respectively). This study replicated the association of POAG with two SNPs at the SIX1-SIX6 locus and demonstrated that SNPs, rs10483727 and rs33912345, are significantly associated with POAG, especially with NTG in patients aged above 40 years.
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Anderson, D.R., Drance, S.M., and Schulzer, M. (2001). Natural history of normal-tension glaucoma. Ophthalmology 108, 247–253.
Burdon, K.P., Mitchell, P., Lee, A., Healey, P.R., White, A.J., Rochtchina, E., Thomas, P.B., Wang, J.J., and Craig, J.E. (2015). Association of open-angle glaucoma loci with incident glaucoma in the Blue Mountains Eye Study. Am J Ophthalmol 159, 31–36.e1.
Carnes, M.U., Liu, Y.P., Allingham, R.R., Whigham, B.T., Havens, S., Garrett, M.E., Qiao, C., Katsanis, N., Wiggs, J.L., Pasquale, L.R., Ashley- Koch, A., Oh, E.C., and Hauser, M.A. (2014). Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma. PLoS Genet 10, e1004372.
Chen, L.J., Tam, P.O., Leung, D.Y., Fan, A.H., Zhang, M., Tham, C.C., Chiang, S.W., Fan, B.J., Wang, N., and Pang, C.P. (2012). SNP rs1533428 at 2p16.3 as a marker for late-onset primary open-angle glaucoma. Mol Vis 18, 1629–1639.
Chen, Y., Hughes, G., Chen, X., Qian, S., Cao, W., Wang, L., Wang, M., and Sun, X. (2015). Genetic variants associated with different risks for high tension glaucoma and normal tension glaucoma in a Chinese population. Invest Ophthalmol Vis Sci 56, 2595–2600.
Cheng, C.Y., Allingham, R.R., Aung, T., Tham, Y.C., Hauser, M.A., Vithana, E.N., Khor, C.C., and Wong, T.Y. (2015). Association of common SIX6 polymorphisms with peripapillary retinal nerve fiber layer thickness: the Singapore Chinese Eye Study. Invest Ophthalmol Vis Sci 56, 478–483.
Fan, B.J., Wang, D.Y., Pasquale, L.R., Haines, J.L., and Wiggs, J.L. (2011). Genetic variants associated with optic nerve vertical cup-to-disc ratio are riskfactors for primary open angle glaucoma in a US Caucasian population. Invest Ophthalmol Vis Sci 52, 1788–1792.
Gallardo, M.E., Lopez-Rios, J., Fernaud-Espinosa, I., Granadino, B., Sanz, R., Ramos, C., Ayuso, C., Seller, M.J., Brunner, H.G., Bovolenta, P., and Rodriguez, D.C.S. (1999). Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies. Genomics 61, 82–91.
Iglesias, A.I., Springelkamp, H., van der Linde, H., Severijnen, L.A., Amin, N., Oostra, B., Kockx, C.E., van den Hout, M.C., van Ijcken, W.F., Hofman, A., Uitterlinden, A.G., Verdijk, R.M., Klaver, C.C., Willemsen, R., and van Duijn, C.M. (2014). Exome sequencing and functional analyses suggest that SIX6 is a gene involved in an altered proliferation-differentiation balance early in life and optic nerve degeneration at old age. Hum Mol Genet 23, 1320–1332.
Iwase, A., Suzuki, Y., Araie, M., Yamamoto, T., Abe, H., Shirato, S., Kuwayama, Y., Mishima, H.K., Shimizu, H., Tomita, G., Inoue, Y., and Kitazawa, Y. (2004). The prevalence of primary open-angle glaucoma in Japanese: the Tajimi Study. Ophthalmology 111, 1641–1648.
Kawakami, K., Sato, S., Ozaki, H., and Ikeda, K. (2000). Six family genes–structure and function as transcription factors and their roles in development. Bioessays 22, 616–626.
Kuo, J.Z., Zangwill, L.M., Medeiros, F.A., Liebmann, J.M., Girkin, C.A., Hammel, N., Rotter, J.I., and Weinreb, R.N. (2015). Quantitative trait locus analysis of SIX1-SIX6 with retinal nerve fiber layer thickness in individuals of European descent. Am J Ophthalmol 160, 123–130.e1.
Li, X., Perissi, V., Liu, F., Rose, D.W., and Rosenfeld, M.G. (2002). Tissue- specific regulation of retinal and pituitary precursor cell proliferation. Science 297, 1180–1183.
Liang, Y.B., Friedman, D.S., Zhou, Q., Yang, X., Sun, L.P., Guo, L.X., Tao, Q.S., Chang, D.S., and Wang, N.L. (2011). Prevalence of primary open angle glaucoma in a rural adult Chinese population: the Handan eye study. Invest Ophthalmol Vis Sci 52, 8250–8257.
Liu, Y., Hauser, M.A., Akafo, S.K., Qin, X., Miura, S., Gibson, J.R., Wheeler, J., Gaasterland, D.E., Challa, P., Herndon, L.W., Ritch, R., Moroi, S.E., Pasquale, L.R., Girkin, C.A., Budenz, D.L., Wiggs, J.L., Richards, J.E., Ashley-Koch, A.E., and Allingham, R.R. (2013). Investigation of known genetic risk factors for primary open angle glaucoma in two populations of African ancestry. Invest Ophthalmol Vis Sci 54, 6248–6254.
Mabuchi, F., Sakurada, Y., Kashiwagi, K., Yamagata, Z., Iijima, H., and Tsukahara, S. (2015). Involvement of genetic variants associated with primary open-angle glaucoma in pathogenic mechanisms and family history of glaucoma. Am J Ophthalmol 159, 437–444.e2.
Macgregor, S., Hewitt, A.W., Hysi, P.G., Ruddle, J.B., Medland, S.E., Henders, A.K., Gordon, S.D., Andrew, T., McEvoy, B., Sanfilippo, P.G., Carbonaro, F., Tah, V., Li, Y.J., Bennett, S.L., Craig, J.E., Montgomery, G.W., Tran-Viet, K.N., Brown, N.L., Spector, T.D., Martin, N.G., Young, T.L., Hammond, C.J., and Mackey, D.A. (2010). Genome- wide association identifies ATOH7 as a major gene determining human optic disc size. Hum Mol Genet 19, 2716–2724.
Miller, S.A., Dykes, D.D., and Polesky, H.F. (1988). A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16, 1215.
Osman, W., Low, S.K., Takahashi, A., Kubo, M., and Nakamura, Y. (2012). A genome-wide association study in the Japanese population confirms 9p21 and 14q23 as susceptibility loci for primary open angle glaucoma. Hum Mol Genet 21, 2836–2842.
Philomenadin, F.S., Asokan, R.,N,V., George, R., Lingam, V., and Sarangapani, S. (2015). Genetic association of SNPs near ATOH7, CARD10, CDKN2B, CDC7 and SIX1/SIX6 with the endophenotypes of primary open angle glaucoma in Indian population. PLoS One 10, e0119703.
Quigley, H.A., and Broman, A.T. (2006). The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90, 262–267.
Ramdas, W.D., van Koolwijk, L.M., Ikram, M.K., Jansonius, N.M., de Jong, P.T., Bergen, A.A., Isaacs, A., Amin, N., Aulchenko, Y.S., Wolfs, R.C., Hofman, A., Rivadeneira, F., Oostra, B.A., Uitterlinden, A.G., Hysi, P., Hammond, C.J., Lemij, H.G., Vingerling, J.R., Klaver, C.C., and van Duijn, C.M. (2010). A genome-wide association study of optic disc parameters. PLoS Genet 6, e1000978.
Ramdas, W.D., van Koolwijk, L.M., Lemij, H.G., Pasutto, F., Cree, A.J., Thorleifsson, G., Janssen, S.F., Jacoline, T.B., Amin, N., Rivadeneira, F., Wolfs, R.C., Walters, G.B., Jonasson, F., Weisschuh, N., Mardin, C.Y., Gibson, J., Zegers, R.H., Hofman, A., de Jong, P.T., Uitterlinden, A.G., Oostra, B.A., Thorsteinsdottir, U., Gramer, E., Welgen-Lussen, U.C., Kirwan, J.F., Bergen, A.A., Reis, A., Stefansson, K., Lotery, A.J., Vingerling, J.R., Jansonius, N.M., Klaver, C.C., and van Duijn, C.M. (2011). Common genetic variants associated with open-angle glaucoma. Hum Mol Genet 20, 2464–2471.
Weinreb, R.N., and Khaw, P.T. (2004). Primary open-angle glaucoma. Lancet 363, 1711–1720.
Wiggs, J.L., Yaspan, B.L., Hauser, M.A., Kang, J.H., Allingham, R.R., Olson, L.M., Abdrabou, W., Fan, B.J., Wang, D.Y., Brodeur, W., Budenz, D.L., Caprioli, J., Crenshaw, A., Crooks, K., Delbono, E., Doheny, K.F., Friedman, D.S., Gaasterland, D., Gaasterland, T., Laurie, C., Lee, R.K., Lichter, P.R., Loomis, S., Liu, Y., Medeiros, F.A., McCarty, C., Mirel, D., Moroi, S.E., Musch, D.C., Realini, A., Rozsa, F.W., Schuman, J.S., Scott, K., Singh, K., Stein, J.D., Trager, E.H., Vanveldhuisen, P., Vollrath, D., Wollstein, G., Yoneyama, S., Zhang, K., Weinreb, R.N., Ernst, J., Kellis, M., Masuda, T., Zack, D., Richards, J.E., Pericak-Vance, M., Pasquale, L.R., and Haines, J.L. (2012). Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet 8, e1002654.
Williams, S.E., Carmichael, T.R., Allingham, R.R., Hauser, M., and Ramsay, M. (2015). The genetics of POAG in black South Africans: a candidate gene association study. Sci Rep 5, 8378.
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Sang, J., Jia, L., Zhao, B. et al. Association of three single nucleotide polymorphisms at the SIX1-SIX6 locus with primary open angle glaucoma in the Chinese population. Sci. China Life Sci. 59, 694–699 (2016). https://doi.org/10.1007/s11427-016-5073-y
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DOI: https://doi.org/10.1007/s11427-016-5073-y