Molecular Variants in Genes related to the Response to Ocular Hypotensive Drugs in an Afro-Colombian Population

Aims: This study aimed to conduct an exploratory analysis of the pharmacogenomic variants involved in ocular hypotensive drugs to understand the individual differential response in an Afro-descendant population. Background: Glaucoma is the leading cause of irreversible blindness worldwide. The pharmacologic treatment available consists of lowering intraocular pressure by administering topical drugs. In Asian and Caucasian people, pharmacogenomic variants associated with the efficacy of these treatments have been identified. However, in Afro-descendant populations, there is a profound gap in this knowledge. Objective: This study identified the pharmacogenomic variants related to ocular hypotensive efficacy treatment in Afro-descendant individuals from the Archipelago of San Andres and Providence, Colombia. Methods: An analysis of whole-exome sequencings (WES), functional annotation, and clinical significance was performed for pharmacogenomic variants reported in PharmGKB databases; in turn, an in silico available prediction analysis was carried out for the novel variants. Results: We identified six out of 18 non-synonymous variants with a clinical annotation in PharmGKB. Five were classified as level three evidence for the hypotensive drugs; rs1801252 and rs1801253 in the ADRB1 gene and rs1042714 in the ADRB2 gene. These pharmacogenomic variants have been involved in a lack of efficacy of topical beta-blockers and higher systolic and diastolic pressure under treatment with ophthalmic timolol drug. The rs1045642 in the ABCB1 gene was associated with greater efficacy of treatments with latanoprost drug. Also, we found the haplotypes *17 for CYP2D6 and *10 for CYP2C19; both related to reducing the enzyme activity to timolol drug metabolization. In addition, we observed 50 novel potentially actionable variants; 36 synonymous, two insertion variants that caused frameshift mutations, and 12 non-synonymous, where five were predicted to be pathogenic based on several pathogenicity predictions. Conclusion: Our results suggested that the pharmacogenomic variants were found to decrease the ocular hypotensive efficacy treatment in a Colombian Afrodescendant population and revealed a significant proportion of novel variants with a potential to influence drug response.