Abstract
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.
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Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Funding
Authors would thank the Indian Council of Medical Research for providing funding (82/19/2012/PHGEN (TF)/BMS) and student fellowship (45/2/2020. HUM/BMS) to perform the whole-genome sequencing study and analysis. The authors would like to thank Medgenome Bangalore for providing the WGS technical analysis.
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LB-performed sample collection, carried out wet-lab experiments, data analysis, and manuscript writing. HN-performed data analysis, and manuscript writing. PR-provided clinical samples explained the drug response of the subjects and their clinical characterization. EPR-provided clinical samples explained the drug response of the subjects and their clinical characterization. RJG-provided clinical samples explained the drug response of the subjects and their clinical characterization. SC-project conceptualization, data analysis, manuscript writing, and editing.
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Badrinarayanan, L., Nagarajan, H., Rishi, P. et al. Whole-genome sequencing unravels novel genetic determinants and regulatory pathways associated with triamcinolone acetonide-induced ocular hypertension. Mol Genet Genomics 298, 13–26 (2023). https://doi.org/10.1007/s00438-022-01958-3
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DOI: https://doi.org/10.1007/s00438-022-01958-3