Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7

Yukihiro Shiga; Koji M Nishiguchi; Yosuke Kawai; Kaname Kojima; Kota Sato; Kosuke Fujita; Mai Takahashi; Kazuko Omodaka; Makoto Araie; Kenji Kashiwagi; Makoto Aihara; Takeshi Iwata; Fumihiko Mabuchi; Mitsuko Takamoto; Mineo Ozaki; Kazuhide Kawase; Nobuo Fuse; Masayuki Yamamoto; Jun Yasuda; Masao Nagasaki; Toru Nakazawa; Japan Glaucoma Society Omics Group (JGS-OG)

doi:10.1371/journal.pone.0186678

Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7

PLoS One. 2017 Dec 20;12(12):e0186678. doi: 10.1371/journal.pone.0186678. eCollection 2017.

Authors

Yukihiro Shiga¹, Koji M Nishiguchi², Yosuke Kawai^{3

4}, Kaname Kojima^{3

4

5}, Kota Sato^{1

6}, Kosuke Fujita^{1

7}, Mai Takahashi¹, Kazuko Omodaka^{1

6}, Makoto Araie⁸, Kenji Kashiwagi⁹, Makoto Aihara¹⁰, Takeshi Iwata¹¹, Fumihiko Mabuchi⁹, Mitsuko Takamoto¹⁰, Mineo Ozaki¹², Kazuhide Kawase¹³, Nobuo Fuse^{3

4}, Masayuki Yamamoto^{3

14}, Jun Yasuda^{3

4}, Masao Nagasaki^{3

4

5

15}, Toru Nakazawa^{1

2

7}; Japan Glaucoma Society Omics Group (JGS-OG)

Affiliations

¹ Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
² Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan.
³ Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan.
⁴ Graduate School of Medicine, Tohoku University, Miyagi, Japan.
⁵ Department of Cohort Genome Information Analysis, Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan.
⁶ Department of Ophthalmic imaging and information analytics, Tohoku University Graduate School of Medicine, Miyagi, Japan.
⁷ Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Miyagi, Japan.
⁸ Kanto Central Hospital of The Mutual Aid Association of Public School Teachers, Tokyo, Japan.
⁹ Department of Ophthalmology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
¹⁰ Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan.
¹¹ Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
¹² Ozaki Eye Hospital, Hyuga, Miyazaki, Japan.
¹³ Gifu University Hospital, Gifu, Japan.
¹⁴ Medical Biochemistry, Tohoku University Graduate School of Medicine, Miyagi, Japan.
¹⁵ Graduate School of Information Sciences, Tohoku University, Miyagi, Japan.

Abstract

Purpose: To test the genetic association between Japanese patients with primary open-angle glaucoma (POAG) and the previously reported POAG susceptibility loci and to perform genotype-phenotype analysis.

Methods: Genetic associations for 27 SNPs from 16 loci previously linked to POAG were assessed using genome-wide SNP data of the primary cohort (565 Japanese POAG patients and 1,104 controls). Reproducibility of the assessment was tested in 607 POAG cases and 455 controls (second cohort) with a targeted genotyping approach. For POAG-associated variants, a genotype-phenotype correlation study (additive, dominant, recessive model) was performed using the objective clinical data derived from 598 eyes of 598 POAG patients.

Results: Among 27 SNPs from 16 loci previously linked to POAG, genotypes for total of 20 SNPs in 13 loci were available for targeted association study. Among 8 SNPs in 3 loci that showed at least nominal association (P < 5.00E-02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected. For these SNPs the association was found significant in both the second cohort analysis and meta-analysis. The genotype-phenotype analysis revealed significant correlations between CDKN2B-AS1 (rs2157719) and decreased intraocular pressure (β = -6.89 mmHg, P = 1.70E-04; dominant model) after multiple corrections. In addition, nominal correlation was observed between CDKN2B-AS1 (rs2157719) and optic nerve head blood flow (β = -0.54 and -0.67 arbitrary units (AU), P = 2.00E-02 and 1.39E-02), between SIX6 (rs33912345) and decreased total peripapillary retinal nerve fiber layer thickness (β = -2.16 and -2.82 μm, P = 4.68E-02 and 2.40E-02, additive and recessive model, respectively) and increased optic nerve head blood flow (β = 0.44 AU, P = 2.20E-02; additive model) and between GAS7 (rs9913911) and increased cup volume (β = 0.03 mm3, P = 4.60E-02) and mean cup depth (β = 0.03 mm3, P = 4.11E-02; additive model) and decreased pattern standard deviation (β = -0.87 dB, P = 2.44E-02; dominant model).

Conclusion: The association between SNPs near GAS7 and POAG was found in Japanese patients for the first time. Clinical characterization of the risk variants is an important step toward understanding the pathology of the disease and optimizing treatment of patients with POAG.

MeSH terms

Adult
Alleles*
Cyclin-Dependent Kinase Inhibitor p15 / genetics*
Female
Genetic Predisposition to Disease*
Glaucoma, Open-Angle / genetics*
Homeodomain Proteins / genetics*
Humans
Japan
Male
Middle Aged
Polymorphism, Single Nucleotide
Trans-Activators / genetics*

Substances

CDKN2B protein, human
Cyclin-Dependent Kinase Inhibitor p15
Homeodomain Proteins
SIX6 protein, human
Trans-Activators

Grants and funding

This paper was supported in part by the Japan Society For The Promotion Of Science KAKENHI Grants-in-Aid for Scientific Research (B) (T.N. 26293372) and by an unrestricted grant from Senju Pharmaceutical Co. Ltd., Osaka, Japan. Part of SNP genotyping was supported by the Center of Innovation Program from Japan Science and Technology Agency, JST. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.