Association betweenSRBD1andELOVL5Gene Polymorphisms and Primary Open-Angle Glaucoma

Abstract

PURPOSE. The S1 RNA binding domain 1 (SRBD1) and elongation of long-chain fatty acids family member 5 (ELOVL5) have been reported to be susceptibility genes for early-onset normaltension glaucoma (NTG). The present study we conducted to assess whether these genes were associated with primary open-angle glaucoma (POAG), including late-onset NTG and high-tension glaucoma (HTG). METHODS. Three hundred seventy Japanese patients with POAG, including 158 NTG and 212 HTG patients and 191 control subjects were analyzed for SRBD1 (rs3213787) and ELOVL5 (rs735860) gene polymorphisms. RESULTS. The A allele frequencies of rs3213787 were significantly higher in NTG (98.4%, P ϭ 0.0003) and HTG (97.6%, P ϭ 0.0013) patients than in the control subjects (92.7%). The A allele frequency was significantly higher (P ϭ 0.014), even though the NTG patients were limited to those diagnosed at ages older than 60 years. The POAG patients with the CC or CT risk genotypes of rs735860 were significantly older (P ϭ 0.032, analysis of variance, P ϭ 0.043 and P ϭ 0.015, respectively) than were the POAG patients with the TT genotype, and the frequency of a family history of glaucoma in POAG patients with the CC risk genotype was significantly higher (P ϭ 0.015) than that in POAG patients with the TT genotype. CONCLUSIONS. SRBD1 gene polymorphism is associated with the development of HTG as well as NTG, including late-onset NTG. Typical POAG associated with ELOVL5 gene polymorphism may have a late rather than an early onset. (Invest Ophthalmol Vis Sci. 2011;52:4626 -4629) G laucoma includes a group of eye disorders characterized by visual field defects, apoptosis of the retinal ganglion cells, and progressive degeneration of the optic nerve. Primary open-angle glaucoma (POAG) represents the most prevalent form of glaucoma and is clinically classified as high-tension glaucoma (HTG), in which elevated intraocular pressure (IOP) is a major feature, and normal-tension glaucoma (NTG), in which IOP is consistently within the statistically normal population range. It is recognized that POAG is a multifactorial disorder involving the role of multiple genes. 1 To date, mutations in three genes (myocilin, 2 optineurin, 3 and WD repeat domain 36 4 ) and several susceptibility gene polymorphisms, such as optic atrophy 1 5 and estrogen receptor beta, 6 have been reported to contribute to the development of POAG. However, these mutations and polymorphisms do not account for all POAG cases, and other unknown genetic factors are considered to contribute to the development of POAG. In the Japanese population, the prevalence of NTG is higher than in other ethnic populations (92% of Japanese patients with POAG have NTG), 7 and it is important to elucidate the genetic factors that are responsible for the development of NTG.To identify susceptibility genes for early-onset NTG, we previously performed a genome-wide association study with more than 500,000 single-nucleotide polymorphisms (SNPs; GeneChip Human Mapping 500K Array Set; Affymetrix Inc., Santa Clara, CA), ...

Involvement of Genetic Variants Associated With Primary Open-Angle Glaucoma in Pathogenic Mechanisms and Family History of Glaucoma

“…Moreover, in the present study, the prevalence of non-IOP-related genetic variants in patients with HTG as well as NTG was significantly higher than that observed in the control subjects, indicating that the vulnerability of the RGC/optic nerve owing to non-IOP-related genetic variants also plays an important role in the pathogenesis of HTG, in addition to IOP elevation induced by IOPrelated genetic variants, such as genetic variants near transmembrane and coiled-coiled domains 1 (TMCO1), 18 growth arrest-specific 7 (GAS7), 23 glucocorticoidinduced transcript 1/islet cell autoantigen 1 (GLCCI1/ ICA1), 24 and family with sequence similarity 125, member B (FAM125B). 25 Furthermore, it has been reported that some non-IOP-related genetic variants, such as optic atrophy 1 (OPA1), 26 SRBD1, 21 and CDKN2B/CDKN2B-AS1 22,27,28 genetic variants, contribute to the pathogenesis of HTG as well as NTG; the present results support these findings. Ramdas and associates 12 reported that the VCDR increases as the number of SNPs included in the genetic risk scores associated with VCDR increases and that these genetic risk scores are significantly associated with POAG.…”

“…17 The rs3213787, rs735860, and rs1063192 was genotyped using an allele-specific primer real-time polymerase chain reaction (PCR) method as previously described. 21,22 The following primers were used for amplification, and the predicted amplicon lengths for rs3213787, rs735860, and rs1063192 were 105, 212, and 365 base pairs, respectively: rs3213787: A allele-specific forward primer: AATGTATAAACC CATAGACGTTCCCTA G allele-specific forward primer: AATGTATAAACC CATAGACGTTCCCTG Common reverse primer: TCACAGAATCTTGAG TTTAACTGGC rs735860: C allele-specific forward primer: CCTTGGTCCTG CTCCGTCC T allele-specific forward primer: CCTTGGTCCTGC TCCGTCT Common reverse primer: GACCCAGAGTGCCAG AACA rs1063192: T allele-specific forward primer: TGTGGAATCTTT CCTAATGACGACT C allele-specific forward primer: TGTGGAATCTT TCCTAATGACGACC Common reverse primer: TTTCTGTATTCCACA ATGGAGC Allelic discrimination for these genetic variants was achieved using PCR amplification of specific alleles. Briefly, the first nucleotide difference (A or G) between sense primers used to discriminate between the major and minor alleles for rs3213787 is located on the 3' end.…”

Advances in glaucoma genetics

“…Meguro et al (Writing Committee for the Normal Tension Glaucoma Genetic Study Group of Japan Glaucoma Society et al, 2010) performed a GWAS for NTG in a Japanese population and identified two loci associated with NTG: rs3213787 on the SRBD1 gene and rs735860 on the ELOVL5 gene. Subsequent studies reported the positive association of POAG with these genetic variants (Gibson et al, 2012;Mabuchi et al, 2011). Ramdas et al (2010) performed a GWAS of the optic disc area and vertical cupto-disc ratio (VCDR) using the data from Caucasian participants in the Rotterdam Study and identified the association between the three loci and the optic disc area (the CDC7/TGFBR3 region, ATOH7, and SALL1) and six with VCDR (CDKN2B, SIX1, SCYL1, CHEK2, ATOH7, and DCLK1).…”

Genome-wide association studies: applications and insights gained in Ophthalmology

“…44 Although SRBD1 and ELOVL5 are thought to be non-IOP-related genetic factors, both SNPs (rs3213787 and rs735860) were found to be associated with NTG and HTG. There was no difference in the maximum IOP between the HTG patients with the at-risk alleles, leading to the suggestion that these SNPs act independent of IOP.…”