Interactive effects of ATOH7 and RFTN1 in association with adult-onset primary open-angle glaucoma.

PURPOSE Genome-wide association studies have shown association of the atonal homolog 7 (ATOH7) and raftlin lipid raft linker 1 (RFTN1) genes with glaucoma-related optic disc parameters. ATOH7 and RFTN1 sequence variations were investigated in patients with primary open-angle glaucoma (POAG) and their relationships with vertical cup-to-disc ratio (VCDR) and central corneal thickness (CCT) were determined. METHODS In 289 unrelated controls and 142 patients with adult-onset POAG, including 117 with high-tension glaucoma (HTG) and 25 with normal-tension glaucoma (NTG), the single exon of ATOH7 was sequenced by direct sequencing. Additional single-nucleotide polymorphisms (SNP) at upstream ATOH7 (rs1900004 and rs3858145) and an RFTN1 SNP (rs690037) were genotyped. Quantitative trait and disease associations were analyzed by linear and logistic regression respectively, controlling for sex and age. RESULTS ATOH7 rs61854782 was associated with VCDR (P = 0.004) in controls and RFTN1 rs690037 was associated with CCT in combined POAG (HTG+NTG; P = 0.026). No coding mutation was detected in POAG, and no SNP was associated with POAG (P between 0.441 and 0.996). However, ATOH7 rs3858145 showed significant interaction with RFTN1 rs690037 in NTG and combined POAG (P = 0.026 and 0.013 respectively). ATOH7 rs3858145 GG combined with RFTN1 rs690037 TT conferred risk for glaucoma in HTG, NTG, and combined POAG (odds ratio = 2.11, 8.44, and 2.69, respectively). CONCLUSIONS Coding mutations of ATOH7 were unlikely to be involved in POAG. But combination of ATOH7 and RFTN1 SNPs increased risk to POAG, indicating their diversified effects in the complex genetics of glaucoma.

[1]  A. Uitterlinden,et al.  Genome-wide association studies in Asians confirm the involvement of ATOH7 and TGFBR3, and further identify CARD10 as a novel locus influencing optic disc area. , 2011, Human molecular genetics.

[2]  Louis R Pasquale,et al.  Genetic variants associated with optic nerve vertical cup-to-disc ratio are risk factors for primary open angle glaucoma in a US Caucasian population. , 2011, Investigative ophthalmology & visual science.

[3]  T. Glaser,et al.  Deletion of a remote enhancer near ATOH7 disrupts retinal neurogenesis, causing NCRNA disease , 2011, Nature Neuroscience.

[4]  A. Hofman,et al.  A Genome-Wide Association Study of Optic Disc Parameters , 2010, PLoS genetics.

[5]  T. Spector,et al.  Genome-wide association identifies ATOH7 as a major gene determining human optic disc size , 2010, Human molecular genetics.

[6]  F. Guillemot,et al.  Conserved regulatory sequences in Atoh7 mediate non-conserved regulatory responses in retina ontogenesis , 2009, Development.

[7]  A. Yoshimura,et al.  A Major Lipid Raft Protein Raftlin Modulates T Cell Receptor Signaling and Enhances Th17-Mediated Autoimmune Responses1 , 2009, The Journal of Immunology.

[8]  M. Loda,et al.  Caveolin-1 interacts with a lipid raft-associated population of fatty acid synthase , 2008 .

[9]  Yingfeng Zheng,et al.  Heritability of optic disc and cup measured by the Heidelberg Retinal Tomography in Chinese: the Guangzhou twin eye study. , 2008, Investigative ophthalmology & visual science.

[10]  Frank Dudbridge,et al.  Likelihood-Based Association Analysis for Nuclear Families and Unrelated Subjects with Missing Genotype Data , 2008, Human Heredity.

[11]  P. Deyn,et al.  Association study of cholesterol-related genes in Alzheimer’s disease , 2007, Neurogenetics.

[12]  C. Leung,et al.  A genome-wide scan maps a novel juvenile-onset primary open-angle glaucoma locus to 15q. , 2006, Investigative ophthalmology & visual science.

[13]  Mingguang He,et al.  Prevalence and clinical characteristics of glaucoma in adult Chinese: a population-based study in Liwan District, Guangzhou. , 2006, Investigative ophthalmology & visual science.

[14]  H. Quigley,et al.  The number of people with glaucoma worldwide in 2010 and 2020 , 2006, British Journal of Ophthalmology.

[15]  R. Ritch,et al.  A genome-wide scan maps a novel juvenile-onset primary open angle glaucoma locus to chromosome 5q. , 2006, Molecular vision.

[16]  C. Kee,et al.  Identification of flotillin-1 as a protein interacting with myocilin: implications for the pathogenesis of primary open-angle glaucoma. , 2005, Biochemical and biophysical research communications.

[17]  J. L. Poulsen,et al.  Central corneal thickness is highly heritable: the twin eye studies. , 2005, Investigative ophthalmology & visual science.

[18]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[19]  Liang Xu,et al.  [The prevalence and its screening methods of primary open angle glaucoma in defined population-based study of rural and urban in Beijing]. , 2004, [Zhonghua yan ke za zhi] Chinese journal of ophthalmology.

[20]  S. Resnikoff,et al.  Global data on visual impairment in the year 2002. , 2004, Bulletin of the World Health Organization.

[21]  Owen J. Marshall.  PerlPrimer: cross-platform, graphical primer design for standard, bisulphite and real-time PCR , 2004, Bioinform..

[22]  Y. Jan,et al.  Conserved and divergent functions of Drosophila atonal, amphibian, and mammalian Ath5 genes , 2003, Evolution & development.

[23]  A. Yoshimura,et al.  The B cell‐specific major raft protein, Raftlin, is necessary for the integrity of lipid raft and BCR signal transduction , 2003, The EMBO journal.

[24]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[25]  T. Glaser,et al.  Molecular characterization and mapping of ATOH7, a human atonal homolog with a predicted role in retinal ganglion cell development , 2002, Mammalian Genome.

[26]  L. Dandona,et al.  Open-angle glaucoma in an urban population in southern India: the Andhra Pradesh eye disease study. , 2000, Ophthalmology.

[27]  R. Cumming,et al.  Inhaled corticosteroids, family history, and risk of glaucoma. , 1999, Ophthalmology.

[28]  M. C. Leske,et al.  Analyses of reported family history of glaucoma: a preliminary investigation. The Barbados Eye Study Group. , 1996, Ophthalmic epidemiology.

[29]  J Katz,et al.  Risk factors for the development of glaucomatous visual field loss in ocular hypertension. , 1994, Archives of ophthalmology.

[30]  V. Sheffield,et al.  Genetic linkage of familial open angle glaucoma to chromosome 1q21–q31 , 1993, Nature Genetics.

[31]  H. A. Quigley,et al.  Open-angle glaucoma. , 1993, The New England journal of medicine.

[32]  J. Teikari.  Genetic factors in open‐angle (simple and capsular) glaucoma , 1987, Acta ophthalmologica.

[33]  B. Bengtsson.  THE INHERITANCE AND DEVELOPMENT OF CUP AND DISC DIAMETERS , 1980, Acta ophthalmologica.

[34]  M Feinleib,et al.  Size of the physiologic cup of the optic nerve head. hereditary and environmental factors. , 1975, Archives of ophthalmology.

[35]  H. Xue,et al.  GABRB2 in schizophrenia and bipolar disorder: disease association, gene expression and clinical correlations. , 2009, Biochemical Society transactions.