Association of SIX1/SIX6 locus polymorphisms with regional circumpapillary retinal nerve fibre layer thickness: The Nagahama study

Yoshikawa, Munemitsu; Yamashiro, Kenji; Nakanishi, Hideo; Miyata, Manabu; Miyake, Masahiro; Hosoda, Yasuhiro; Tabara, Yasuharu; Matsuda, Fumihiko; Yoshimura, Nagahisa

doi:10.1038/s41598-017-02299-7

Cited by 9 publications

(14 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SNP rs10483727 was the first SIX1-SIX6 SNP identified with POAG association, 14,31 and rs33912345 was more frequently investigated in recent studies. 23,37,39 SNP rs10483727 is located in the intergenic region between SIX1 and SIX6, whereas rs33912345 is a missense variant (p.His141Asn) in SIX6. The two SNPs are in strong linkage disequilibrium (LD) (R 2 > 0.96; 1000 Genomes Project Phase 3 v5, provided in the public domain and accessed from http://www.internationalgenome.…”

Section: Discussionmentioning

confidence: 99%

Association of Polymorphisms at theSIX1-SIX6Locus With Primary Open-Angle Glaucoma

et al. 2019

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PURPOSE. To evaluate the association of single-nucleotide polymorphisms (SNPs) in the SIX1-SIX6 locus with primary open-angle glaucoma (POAG) through a systematic review and metaanalysis from 22 studies. METHODS. To our knowledge, all case-control association studies on SNPs in the SIX1-SIX6 locus and POAG reported up to August 30, 2018, in PubMed, Embase, and Web of Science were retrieved. Unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for each SNP were calculated using a fixed-or random-effect model according to interstudy heterogeneity. RESULTS. This meta-analysis involved 12 SNPs in SIX1-SIX6 reported in 22 studies. The association of rs10483727 with POAG has been presented in 16 studies involving 14,402 patients and 27,425 controls, whereas rs33912345 has been investigated in 12 studies involving 10,563 patients and 16,740 controls. Meta-analyses revealed significant associations of these two SNPs with POAG in the pooled populations under all genetic models. Stratified analyses by population detected significant association of both SNPs in the East Asian and Caucasian subgroups, but not in South Asian or African subgroups. Among the other SNPs that were reported by up to four cohorts of East Asian and African ancestries, only rs12436579 showed a significant association in the meta-analysis (OR ¼ 0.79, P ¼ 1.08 3 10 À4). CONCLUSIONS. This meta-analysis confirmed the association of rs10483727 and rs33912345 in SIX1-SIX6 with POAG. The associations of both SNPs were specifically detected in East Asian and Caucasian cohorts, rather than in South Asian and African cohorts, suggesting an ethnic difference. SNP rs12436579 is a candidate variant for the disease that awaits validation in other populations.

show abstract

Section: Discussionmentioning

confidence: 99%

Association of Polymorphisms at theSIX1-SIX6Locus With Primary Open-Angle Glaucoma

et al. 2019

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

show abstract

“…However, in the case of POAG and SIX1/SIX6, it is not known when these genetic variants start exerting their effects 24 . Studies have reported that individuals with risk allele in SIX1/SIX6 are more susceptible to glaucoma 1,3,25 and have thinner RNFL [20][21][22][23] . Note that these RNFL studies were conducted in older individuals, hence it is not clear whether thinner RNFL found in the older individuals with SIX1/SIX6 variants is due to these individuals being born with thinner RNFLs or due to a faster rate of RNFL degeneration as they age.…”

Section: Discussionmentioning

confidence: 99%

“…www.nature.com/scientificreports/ in the Japanese study 22 . In rs10483727, an European cohort study reported significant global RNFL thinning with each copy of the risk allele as well as the inferior and superior sectors 23 but the study cohort contained a large portion of glaucoma cases and suspects (~ 80%).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Age-dependent regional retinal nerve fibre changes in SIX1/SIX6 polymorphism

Charng

Simcoe

Sanfilippo

et al. 2020

Sci Rep

View full text Add to dashboard Cite

SIX1/SIX6 polymorphism has been shown to be associated with glaucoma. Studies have also found that, in older adults, retinal nerve fibre layer (RNFL) thickness is significantly thinned with each copy of the risk allele in SIX1/SIX6. However, it is not known whether these genetic variants exert their effects in younger individuals. Comparing a healthy young adult with an older adult cohort (mean age 20 vs 63 years), both of Northern European descent, we found that there was no significant RNFL thinning in each copy of the risk alleles in SIX1/SIX6 in the eyes of younger individuals. The older cohort showed an unexpectedly thicker RNFL in the nasal sector with each copy of the risk allele for both the SIX1 (rs10483727) and SIX6 (rs33912345) variants. In the temporal sector, thinner RNFL was found with each copy of the risk allele in rs33912345 with a decrease trend observed in rs10483727. Our results suggest that SIX1/SIX6 gene variants exert their influence later in adult life. Genome-wide association (GWA) studies have identified multiple genetic variants that increase susceptibility to Primary Open-Angle Glaucoma (POAG) 1-3. Among these, the rs10483727 variant in the SIX1 region was significantly associated with POAG diagnosis and progression in a quantitative trait GWA study 4 and with risk of POAG in a later case-control GWA study 3. More importantly, the rs10483727 variant was associated with POAG across different ethnicities 2,5-8. However, to date, no causal variants driving its association with POAG have been identified. Similarly, the effect of rs10483727 on protein function remains unknown. The missense variant rs33912345 (Asn141His), found in the SIX6 locus 9 , is in strong linkage disequilibrium with rs10483727. It is also associated with POAG and has been shown to alter the function of the SIX6 protein 10. SIX6 is involved in the differentiation and survival of retinal ganglion cells 11,12 , which are the primary cells affected in POAG. Both SIX1 and SIX6 belong to the family of sine oculis (SIX) transcription factors with six members in mammals (SIX1 to SIX6). All members of the family are characterized by the presence of two highly conserved domains: a homeobox domain and a SIX domain 13,14. SIX1 is expressed in several tissues, including the optic vesicles and the limb mesenchyme, but it is poorly expressed in the eye. In contrast, studies in different species, including humans, have shown that SIX6 is highly expressed in the developing retina, especially in the retinal ganglion and the amacrine cells 11,15,16. Genetic inactivation of SIX6 has been shown to result in hypoplasia of the mice retina, which subsequently lead to absence of the optic nerves 16. It is well established that POAG results in thinning of the retinal nerve fibre layer (RNFL) 17,18 , thus RNFL assessment has become indispensable in POAG management 19. Polymorphisms in SIX6 and SIX1 have been reported to result in significant RNFL thinning but the region of RNFL thinning has varied depending on the study. More specifically, each...

show abstract

“…Although these polymorphisms have never been studied before in relation to congenital cataract and microphthalmia, they have been studied/associated with other disease phenotypes such as BMP4 -V152A with tooth agenesis,[ 30 31 ] cleft lip,[ 32 33 ] and cutaneous melanoma,[ 34 ] and SIX6 - H141N with primary-open angle glaucoma. [ 35 36 37 ]…”

Section: Discussionmentioning

confidence: 99%

Evaluating the association of bone morphogenetic protein 4-V152A and SIX homeobox 6-H141N polymorphisms with congenital cataract and microphthalmia in Western Indian population

Vidya

Sankaranarayanan³

2018

Journal of Postgraduate Medicine

View full text Add to dashboard Cite

Background:Congenital cataract and microphthalmia are highly heterogeneous congenital eye disorders that affect normal vision. Although mutation in several genes has been shown to cause congenital cataract and microphthalmia, genetic studies associating single-nucleotide polymorphisms with these conditions is scarce. Hence, the present study aims to investigate the association of bone morphogenetic protein 4 (BMP4)-V152A (rs17563), and SIX homeobox 6 (SIX6)-H141N (rs33912345) polymorphisms with congenital cataract and microphthalmia in Western Indian cohorts.Materials and Methods:BMP4-V152A and SIX6-H141N were genotyped in 561 participants comprising of 242 congenital cataracts, 52 microphthalmia, and 267 controls using polymerase chain reaction (PCR) and allele specific oligonucleotide (ASO)-PCR method, respectively.Results:The frequency of BMP4- 152A was found to be significantly different between the cases and controls (Odds ratio (OR) 95% confidence interval [CI] = 1.4 [1.03–1.76], P = 0.0275). The frequency of BMP4- 152AA genotype was found to be significantly higher in congenital cataract cases as compared to controls (OR [95% CI] = 2.1 [1.14–3.67], P = 0.0154. The V-N haplotype of BMP4-V152A and SIX6-H141N was found to have a protective effect toward congenital cataract (OR [95% CI] = 0.72 [0.56–0.94], P = 0.0163) and microphthalmia (OR [95% CI] = 0.63 [0.40–1.01, P = 0.0541).Conclusions:The BMP4- 152AA genotype might play role in the causation of congenital cataract, whereas BMP4-SIX6 V-N haplotype might play a protective role toward the development of congenital cataract and microphthalmia.

show abstract

Association of SIX1/SIX6 locus polymorphisms with regional circumpapillary retinal nerve fibre layer thickness: The Nagahama study

Cited by 9 publications

References 41 publications

Association of Polymorphisms at theSIX1-SIX6Locus With Primary Open-Angle Glaucoma

Association of Polymorphisms at theSIX1-SIX6Locus With Primary Open-Angle Glaucoma

Age-dependent regional retinal nerve fibre changes in SIX1/SIX6 polymorphism

Evaluating the association of bone morphogenetic protein 4-V152A and SIX homeobox 6-H141N polymorphisms with congenital cataract and microphthalmia in Western Indian population

Contact Info

Product

Resources

About