Whole-genome sequencing unravels novel genetic determinants and regulatory pathways associated with triamcinolone acetonide-induced ocular hypertension

• Published in: Molecular genetics and genomics : MGG Vol. 298; no. 1; pp. 13 - 26
• Main Authors: Badrinarayanan, Lakshmi, Nagarajan, Hemavathy, Rishi, Pukhraj, Rishi, Ekta, George, Ronnie Jacob, Chitipothu, Srujana
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2023; Springer Nature B.V
• Subjects: Actin; Animal Genetics and Genomics; Biochemistry; Biomedical and Life Sciences; blood; brain; Cardiomyopathy; Cytoskeleton; DNA; DNA sequencing; Extracellular matrix; eyes; focal adhesions; genes; Genetic diversity; Genomes; genomics; Glucocorticoids - adverse effects; heart; Human Genetics; Humans; Hypertension; Inflammation; Intraocular Pressure; Life Sciences; Microbial Genetics and Genomics; microfilaments; Molecular dynamics; Ocular Hypertension - chemically induced; Ocular Hypertension - genetics; Original Article; OX40 Ligand; pathophysiology; Plant Genetics and Genomics; Retrospective Studies; Steroids; triamcinolone; Triamcinolone acetonide; Triamcinolone Acetonide - adverse effects; Whole genome sequencing; WGS whole-genome sequencing; SNPs-single nucleotide polymorphisms; TA-OHT-Triamcinolone acetonide-induced ocular hypertension; Focal adhesion, extracellular matrix signaling, and actin cytoskeleton reorganization pathways; Risk factors
• ISSN: 1617-4615; 1617-4623; 1617-4623
• DOI: 10.1007/s00438-022-01958-3

Glucocorticosteroids commonly used to treat certain ocular inflammatory conditions cause an unwarranted elevation in intraocular pressure (IOP) leading to steroid-induced ocular hypertension (OHT). This study aims to identify novel genetic variants in the Indian population associated with steroid responsiveness, specifically to that of intravitreal Triamcinolone acetonide (TA) injections, which leads to OHT in 27% of the TA-treated Indian subjects. Genetic determinants and pathways regulating TA-OHT progression were investigated by applying whole-genome sequencing (WGS) on DNA extracted from 53 blood samples that included TA responders and non-responders. Sequencing analysis yielded 45 intronic and 49 exonic variants to be associated with TA-OHT, which are known to play a vital role in eye, heart, brain, and bone deformities. Of these, the most significant genetic variant associated with TA-OHT was further considered for molecular dynamics (MD) simulation studies. Variants in the CRPPA, PLOD1, ARHGAP1, TIMELESS and TNFSF4 genes were found to be directly implicating TA-OHT. Furthermore, these genes were enriched in pathways associated with cardiomyopathy, focal adhesion, extracellular matrix, and actin cytoskeleton reorganization. MD simulation studies revealed that the top significant variant (rs141625803) in the CRPPA gene possesses a high pathogenic and structurally destabilizing effect. Thus, novel genetic variants that could be significantly associated with the TA-OHT progression were identified in this study. Validation of these targets in a larger cohort of patients along with their functional analysis would inform on the disease, thereby adding to the existing knowledge on the pathophysiology of TA-OHT.