Association of SALL1 (rs1362756), SIX6 (rs33912345), AFAP1 (rs4619890), and TMCO1 (rs2814471) variants with primary open-angle glaucoma in a Brazilian cohort

Primary Open Angle Glaucoma (POAG) is a complex, asymptomatic and progressive neurodegenerative disease with multifactorial etiology, encompassing ocular, genetic, systemic and environmental factors. It has been established as the foremost contributor to irreversible blindness worldwide. Thus, the identification and characterization of genetic susceptibility variants are essential for risk stratification, early detection, and the development of precision medicine strategies. Multiethnic Genome-Wide Association Studies (GWAS) identified single nucleotide variants (SNVs) including: rs1362756 ( SALL1 ), rs33912345 ( SIX6 ), rs2814471 ( TMCO1 ), and rs4619890 ( AFAP1 ) related to POAG pathophysiology and/or its related endophenotypes. Despite notable advances in comprehending the molecular underpinnings of POAG, investigations within admixed populations, such as the Brazilian population, remain limited. This genetic case-control genetic association study aimed to elucidate the correlation among the abovementioned SNVs, as potential risk variants for POAG development in a South and Southeastern Brazilian cohort. This investigation comprised 477 cases and 444 control subjects. All SNVs were genotyped through Taqman ® assays and validated by Sanger sequencing in 10% of the samples. Demographic data and genetic associations were estimated using multivariate logistic regression analysis. The case group consisted of 49.05% females, while the control cohort included 43.02% females ( p = 0.0148). There was no statistical difference in mean age between cases and controls ( p = 0.9068). Logistic regression assessment revealed significant associations between POAG development and rs33912345 ( SIX6 ) in homozygosity (CC; p = 0.0113), rs4619890 ( AFAP1 ) in homozygosity (GG; p = 0.0001) and rs2814471 ( TMCO1 ) in heterozygosity (CT; p = 0.0010) in this Brazilian cross-section. No significant association was found for rs1362756 ( SALL1 ) variant. Finally, gene–gene interaction analysis through binomial Generalized Linear Model did not identify statistically significant interaction effects; furthermore, blocks interactions were consistently non-significant, indicating no evidence that adding SNV terms improved model fit or explained POAG risk beyond main effects in this cohort. Our data indicate the rs33912345 ( SIX6 ), rs4619890 ( AFAP1 ) and rs2814471 ( TMCO1 ) as risk variants for POAG in a South and Southeastern Brazilian cohort. If validated in other regional populations, these findings could help to build the profile of POAG genetic risk variants in the country.