Abstract
BackgroundGlaucoma is a polygenic neurodegenerative disease and the second most common cause of blindness in Saudi Arabia. To test the hypothesis that genetic variants in the genes involved in the bone morphogenic protein (BMP) signaling pathway may be associated with glaucoma, we investigated the association between 3′ untranslated region variants, rs12997 in ACVR1 and rs1043784 in BMP6, and primary angle-closure glaucoma (PACG) and pseudoexfoliation glaucoma (PXG).MethodsIn a case-control study, TaqMan® real-time PCR-based genotyping was done in 444 subjects consisting of 250 controls, 101 PACG and 95 PXG cases, and tested for genetic association with glaucoma-types and other clinical phenotypes.ResultsRs12997[G] allele in ACVR1 exhibited significant 2-fold increased risk of PACG (p = 0.005) in women but not in men. Similarly, genotype analysis also showed that subjects carrying rs12997[G/G] genotype were at > 2-fold risk of PACG that remained significant after adjustment for age, sex, and Bonferroni correction in the recessive model. Furthermore, this effect was also significant in women only. In PXG, the rs12997[G/G] genotype showed a significant trend towards increased risk of the disease (OR = 2.04, 95% CI = 0.99–4.18, p = 0.049) but did not survive the Bonferroni correction. Regression analysis showed that rs12997[G/G] genotype was a significant predictor of PACG independent of age, sex, and rs1043784 genotypes. Likewise, age and rs12997[G/G] genotype showed significant effect on PXG outcome. The rs12997[A/G] genotype showed significant association with cup/disc ratio as compared to wild-type (p = 0.005) in PXG. Genotype and allele frequencies of rs1043784 in BMP6 did not show any significant association either with PACG or PXG.ConclusionsOur results suggest that the polymorphism rs12997 in the ACVR1 gene involved in the BMP signaling pathway is significantly associated with PACG and PXG in a Saudi cohort. This is the first study to associate this variant/gene with PACG and PXG. However, further studies would be needed to replicate these findings in a large population-based cohort.
Highlights
Glaucoma is a polygenic neurodegenerative disease and the second most common cause of blindness in Saudi Arabia
Our results suggest that the polymorphism rs12997 in the Activin A receptor type I (ACVR1) gene involved in the bone morphogenic protein (BMP) signaling pathway is significantly associated with primary angle-closure glaucoma (PACG) and pseudoexfoliation glaucoma (PXG) in a Saudi cohort
In the present study, we report a previously unreported association between variant rs12997 in the ACVR1 gene involved in BMP signaling and patients with PACG and PXG in a Saudi cohort
Summary
Obstruction in the outflow pathway of the aqueous humor due to structural changes in the trabecular meshwork (TM) and the resultant elevated intraocular pressure (IOP) are believed to be one of the major contributing factors leading to the damage of the optic nerve head (ONH), retinal ganglion cell (RGC) death and subsequent loss of vision in glaucoma [1]. Recent studies suggest an essential role of growth factors in maintaining ocular homeostasis in tissues related to glaucoma, and alterations in growth factor or their receptors may induce structural or functional changes in the TM or ONH and thereby play an important role in the pathogenesis of glaucoma [2, 3]. Members of the transforming growth factor-β (TGF-β) superfamily of growth factors have been implicated in glaucoma pathogenesis [4,5,6]. Besides TGF-β, the members of the TGF-β family include bone morphogenetic proteins (BMPs), activins and other signaling molecules [8]
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