Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations

Abstract

Glaucoma, the world’s leading cause of irreversible blindness, is a complex disease, with differential presentation as well as ethnic and geographic disparities. The multifactorial nature of glaucoma complicates the study of genetics and genetic involvement in the disease process. This review synthesizes the current literature on glaucoma and genetics, as stratified by glaucoma subtype and ethnicity. Primary open-angle glaucoma (POAG) is the most common cause of glaucoma worldwide, with the only treatable risk factor (RF) being the reduction of intraocular pressure (IOP). Genes associated with elevated IOP or POAG risk include: ABCA1, AFAP1, ARHGEF12, ATXN2, CAV1, CDKN2B-AS1, FOXC1, GAS7, GMDS, SIX1/SIX6, TMCO1, and TXNRD2. However, there are variations in RF and genetic factors based on ethnic and geographic differences; it is clear that unified molecular pathways accounting for POAG pathogenesis remain uncertain, although inflammation and senescence likely play an important role. There are similar ethnic and geographic complexities in primary angle closure glaucoma (PACG), but several genes have been associated with this disorder, including MMP9, HGF, HSP70, MFRP, and eNOS. In exfoliation glaucoma (XFG), genes implicated include LOXL1, CACNA1A, POMP, TMEM136, AGPAT1, RBMS3, and SEMA6A. Despite tremendous progress, major gaps remain in resolving the genetic architecture for the various glaucoma subtypes across ancestries. Large scale carefully designed studies are required to advance understanding of genetic loci as RF in glaucoma pathophysiology and to improve diagnosis and treatment options.

The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease

“…Several lines of evidence including GWAS, animal models and in vitro studies suggest ABCA1 plays an important role in the pathophysiology of glaucoma, mainly POAG. Although glaucoma is not a characteristic of Tangier disease, GWAS for IOP and POAG have identified common variants in or near ABCA1 (rs2472493 and rs2487032) among more than 50 loci in Asian and European Caucasian populations [292][293][294][295]. However, while ABCA1 and other genes involved in lipid metabolism were found to be associated with IOP and POAG, a Mendelian randomization study did not find any evidence for a causal association between plasma lipid levels and POAG risk [296].…”

Glaucoma Heritability: Molecular Mechanisms of Disease

“…An important component of individualized medicine practices is recognition and understanding of the racial disparities associated with disease and outcomes. Specifically, POAG has been shown to present earlier and be more severe in patients of African descent as compared to those of European descent, and populations of African descent have a considerably higher disease burden as demonstrated by differences in disease prevalence across different populations [2,5]. Similarly, PACG is more prevalent in Asian populations as compared to European and African populations [2,5], while the mechanisms behind differences in risk remain largely unconfirmed.…”

“…This large sample also allowed for subgroup analysis, showing that there was heterogeneity between age and ethnicity. Findings showing different heritability estimates between White Europeans (h 2 = 0.47, 95% CI 0.37-0.57, p = 0.006), East Asians (h 2 = 0.49, 95% CI 0.40-0.59), and Other Populations (h 2 = 0.30, 95% CI 0.22-0.39) are particularly interesting given suspected genetic contributions to disease and genetic differences among different racial groups [5,8]. Additionally, it should be noted that IOP has also shown a genetic correlation with POAG (odds ratio 1.18, 95% CI 1.14-1.21, p = 1.8 × 10 −27 ) [15].…”

“…To date, a wide variety of genes have been associated with elevated IOP, including, but not limited to: ABCA1, ABO, ADAMTS8, ADAMTS17, ADAMTS18-NUDT7, AFAP1, ANGPT1, ANTXR1, ARHGEF12, ARID5B, ATXN2, CAV1-CAV2, CDKN2B-AS1, CELF1, CYP26A1-MYOF, FAM125B, FNDC3B, FOXC1, FOXP1, GAS7, GLCCI1-ICA1, GLIS3, GMDS, HIVEP3, INCA1, LMX1B, LOC171391, MADD, MIR548F3, MYBPC3, NDUFS3, NR1H3, PDDC1, PKHD1, PTPRJ, RAPSN, RPLP2-PNPLA2, SIX1/SIX6, SEPT9, SP11, TFEC-TES, TMCO1, and TXNRD2 [5,16]. It should be noted that all of these genes have not also been independently associated with POAG.…”

“…The association between NR1H3 and IOP may actually be explained by ABCA1, a POAG-susceptibility locus associated with ED populations as well as Asian populations [5,38,39]. ABCA1, the ATP-binding cassette transporter A1, is a transmembrane transporter involved in cholesterol homeostasis through the formation of high-density lipoprotein [40].…”