Toward Novel Diagnostics for Primary Open-Angle Glaucoma? An Association Study of Polymorphic Variation in Ras Homolog Family Member (A, B, C, D) Genes RHOA, RHOB, RHOC, and RHOD

Abstract

The annual economic burden of visual disorders in the United States was estimated as $139 billion. The World Health Organization has listed glaucoma in the top 10 priority eye diseases. Primary open-angle glaucoma (POAG) is a common subtype, with a lack of clinical tools for early diagnosis. The Rho GTPases belong to the Ras superfamily of proteins; the RhoA immunostaining in the optic nerve head in human glaucoma is reportedly increased. We investigated the association of polymorphisms in the Ras Homolog Family Member A, B, C, and D genes (RHOA, RHOB, RHOC, and RHOD, respectively). In a total sample of 361 unrelated subjects (179 patients with POAG and 182 age- and sex-matched healthy controls), RHOA (rs6784820, rs974495), RHOB (rs62121967), RHOC (rs11102522), and RHOD (rs61891303, rs2282502) polymorphisms were characterized by the BioMark HD dynamic array system with real-time polymerarse chain reaction. Among these candidate genetic markers and considering the Bonferroni correction, RHOA rs974495 polymorphism was significantly associated with POAG (p = 0.0011), with the TT genotype increasing the disease risk 4.9 times (95% CI 1.630-15.023). The allele and haplotype distributions of the above RHO candidate polymorphisms did not diplay a significant association. This is the first study, to the best of our knowledge, to identify a significant genotypic association between POAG and RHOA gene rs974495 polymorphism. These observations warrant replication in independent samples in the pursuit of precision medicine for rapid and early glaucoma diagnosis, and molecular targets for innovation in therapeutics of this common eye disease.

RHO Gene Polymorphisms in Patients with Pterygium

“…Genomic DNA was extracted from whole peripheral blood samples with salting-out method and stored at −20 °C until analysis [7]. Genomic DNAs were analyzed in all patients and controls using the dynamic array system (Fluidigm, South San Francisco, CA, USA) as previously described [8]. A 96.96 dynamic array on the BioMark HD system (Fluidigm, South San Francisco, CA, USA) was used for detection of polymorphism.…”

Insights into the regulatory molecules involved in glaucoma pathogenesis

“…There exists ample data that evidence the importance of RHOA and RHO signaling in TM functions and glaucoma pathogenesis (Goldhagen, Proia, Epstein, & Rao, 2012;Q. Liu et al, 2012;Moazzeni et al, 2019;Saracaloglu et al, 2016;M. Zhang, Maddala, & Rao, 2008).…”

“…The feedback mechanism also includes RHOA. There exists ample data that evidence the importance of RHOA and RHO signaling in TM functions and glaucoma pathogenesis (Goldhagen, Proia, Epstein, & Rao, 2012; Q. Liu et al, 2012; Moazzeni et al, 2019; Saracaloglu et al, 2016; M. Zhang, Maddala, & Rao, 2008). The data include effects on aqueous humor fluid outflow through TM cells and increased IOP (Iyer et al, 2012; Shubham & Mishra, 2012; M. Zhang et al, 2008).…”