title: Association of common SIX6 polymorphisms with peripapillary retinal nerve fiber layer thickness: the Singapore Chinese Eye Study.
abstract: OBJECTIVE
  Recently the common SIX6 missense variant rs33912345 was found to be highly associated with glaucoma. The aim of this study was to investigate the association between this SIX6 variant and peripapillary retinal nerve fiber layer (RNFL) thickness measured by spectral-domain optical coherence tomography (SD-OCT) in a population setting.
  
  
  METHODS
  Study subjects were enrolled from the Singapore Chinese Eye Study (SCES), a population-based survey of Singaporean Chinese aged 40 years or older. Subjects underwent a comprehensive ocular examination. Spectral-domain OCT was used to measure RNFL thicknesses. Genotyping of SIX6 rs33912345 (Asn141His) was performed using HumanExome BeadChip.
  
  
  RESULTS
  A total of 2129 eyes from 1243 SCES subjects (mean age: 55.0 ± 7.4 years) with rs33912345 genotype data and SD-OCT images were included for the analysis. Of these, 26 eyes of 21 subjects had glaucoma. The frequency of rs33912345 risk variant C (His141) was 80% in the study subjects. Each rs33912345 C allele was associated with a decrease of 1.44 μm in RNFL thickness after adjusting for age, sex, genetic principal components, and axial length (P = 0.001). These associations remained similar in 2096 nonglaucoma eyes in which each C allele was associated with a decrease of 1.39 μm in RNFL thickness (P = 0.001). The strongest association was observed in the superior RNFL sector (a decrease of 2.83 μm per risk allele, P < 0.001) followed by the inferior RNFL sector (a decrease of 2.24 μm per risk allele, P = 0.003), while the association did not reach significance in the nasal and temporal sectors.
  
  
  CONCLUSIONS
  Nonglaucomatous individuals with the SIX6 missense variant have reduced RNFL thickness in regions known to be particularly affected in those with glaucoma. This may be the primary mechanism for increased risk of POAG in individuals who carry the SIX6 His141 risk variant.
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.
authors.forename: R Rand
authors.initials: RR
authors.lastname: Allingham
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore.
authors.forename: Tin
authors.initials: T
authors.lastname: Aung
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore.
authors.forename: Yih-Chung
authors.initials: YC
authors.lastname: Tham
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hauser
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore Duke-NUS Graduate Medical School, Singapore.
authors.forename: Eranga N
authors.initials: EN
authors.lastname: Vithana
authors.affiliation: Division of Human Genetics, Genome Institute of Singapore, Singapore.
authors.forename: Chiea Chuen
authors.initials: CC
authors.lastname: Khor
authors.affiliation: Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
authors.forename: Tien Yin
authors.initials: TY
authors.lastname: Wong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003430:Cross-Sectional Studies; D004247:DNA / Q000235:genetics*; D005136:Eye Proteins; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D005902:Glaucoma, Open-Angle / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology*; D011110:Polymorphism, Genetic; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*; D012189:Retrospective Studies; D012846:Singapore / Q000453:epidemiology; D041623:Tomography, Optical Coherence / Q000379:methods; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; C491945:SIX6 protein, human; D015534:Trans-Activators; D004247:DNA
keywords: SIX6; genetic association; glaucoma; retinal nerve fiver layer thickness