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N. R. Kollu, I. Kaur, R. S. Parikh, A. K. Mandal, R. Thomas, S. Chakrabarti; Evaluation of NTF4, VAV2 and VAV3 Genes in Primary Open Angle and Primary Angle Closure Glaucomas in an Indian Population. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6436.
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© ARVO (1962-2015); The Authors (2016-present)
Primary open angle glaucoma (POAG), is a clinically and genetically heterogeneous optic neuropathy, which is attributed to multiple genes with varying magnitudes of effect. Among the several loci mapped in POAG, only three genes, namely, MYOC, OPTN and WDR36 have been characterized that exhibit high levels of allelic heterogeneity worldwide. Recently, heterozygous mutations in novel genes, viz. neurotrophin-4 (NTF4; 19q13.3) in Europeans and SNPs in VAV2 (9q34.1) and VAV3 (1p13.3) in Japanese have been associated with POAG. We generated comparable data to understand their involvement in an ethnically different population (Indian) with POAG and primary angle closure glaucoma (PACG).
The NTF4 gene along with the associated and flanking SNPs in VAV2 and VAV3 were screened in a clinically well characterized cohort of 537 subjects that included cases of POAG (n=141), PACG (n=111) and ethnically matched normal controls (n=285). Screening was accomplished by bi-directional sequencing on an automated DNA sequencer using the BigDye chemistry (Applied Biosystems, Foster City, CA). The mutation and association data were analyzed using standard statistical softwares.
Resequencing of NTF4 did not reveal any disease-associated mutations in POAG and PACG. Five variations were observed that included a non-synonymous change (A88V), a silent change (P151P), two changes in the 3’UTR region and a known polymorphism (rs11669977) in cases of POAG; the PACG cases exhibited only the A88V variation. Interestingly, the A88V mutation amongst Europeans was more prevalent in our normal controls (4.91%, 95%CI, 2.95-8.07) compared to the POAG (2.14%, 95%CI, 0.73-6.11; p=0.126) and PACG (2.85%, 95%CI, 0.97-8.06; p=0.258) cases. There were no clinical differences at presentation among the POAG and PACG cases harboring the A88V variation with respect to IOP, cup to disc ratio and visual field defects. The risk alleles of VAV2 and VAV3, were not associated with either POAG (p=0.533 and p=0.133) or PACG (p=0.223 and p=0.394), respectively. Similarly, the genotypes and haplotypes generated with the flanking SNPs at these loci did not exhibit any association to POAG and PACG.
The present data indicated a lack of involvement of NTF4, VAV2 and VAV3 in our cohort suggesting that these genes are unlikely to be major candidates in glaucoma pathogenesis.
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