Long Non-Coding RNAs Gene Variants as Molecular Markers for Diabetic Retinopathy Risk and Response to Anti-VEGF Therapy

Hala M F Mohammad; Ahmed A Abdelghany; Essam Al Ageeli; Shahad W Kattan; Ranya Hassan; Eman A Toraih; Manal S Fawzy; Naglaa Mokhtar

doi:10.2147/PGPM.S322463

Long Non-Coding RNAs Gene Variants as Molecular Markers for Diabetic Retinopathy Risk and Response to Anti-VEGF Therapy

Pharmgenomics Pers Med. 2021 Aug 14:14:997-1014. doi: 10.2147/PGPM.S322463. eCollection 2021.

Authors

Hala M F Mohammad^{1

2}, Ahmed A Abdelghany³, Essam Al Ageeli⁴, Shahad W Kattan⁵, Ranya Hassan⁶, Eman A Toraih^{7

8}, Manal S Fawzy^{9

10}, Naglaa Mokhtar^{10

11}

Affiliations

¹ Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
² Central Laboratory, Center of Excellence in Molecular and Cellular Medicine (CEMCM), Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
³ Department of Ophthalmology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
⁴ Department of Clinical Biochemistry (Medical Genetics), Faculty of Medicine, Jazan University, Jazan, Saudi Arabia.
⁵ Department of Medical Laboratory, College of Applied Medical Sciences, Taibah University, Yanbu, Saudi Arabia.
⁶ Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
⁷ Department of Surgery, Tulane University, School of Medicine, New Orleans, LA, USA.
⁸ Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
⁹ Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
¹⁰ Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia.
¹¹ Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

Abstract

Background: Long non-coding RNAs (lncRNAs) play essential roles in molecular diagnosis and therapeutic response in several diseases.

Purpose: For the first time, we aimed to evaluate the association of four lncRNAs TUG1 (rs7284767G/A), MIAT (rs1061540T/C), MALAT1 (rs3200401C/T), and SENCR (rs12420823C/T) variants with susceptibility to diabetic retinopathy (DR), disease severity, and early therapeutic response to intravitreous anti-vascular endothelial growth factor aflibercept therapy.

Patients and methods: This case-control study enrolled 126 adult patients with type 2 diabetes. TaqMan assays using Real-Time PCR were run for genotyping. Multivariable regression analyses were applied to assess the role of each polymorphism after the adjustment of covariates.

Results: Carriers of TUG1 A/G and MIAT T/C and C/C genotypes were more likely to develop DR [OR=3.15 (95% CI=1.15-8.64), and OR=4.31 (95% CI=1.78-10.47)], while MALAT1 T/C conferred protection (OR=0.40, 95% CI=0.16-0.99). For TUG1, MALAT1, MIAT, and SENCR genotype combinations, GTCT and GCCC had a higher disease risk (P=0.012). For disease severity, MIAT T/T homozygosity was associated with higher DR grade [33.3% (T/T) vs 10% (C/C) and 4.2% (C/T) carriers, P=0.012]. Otherwise, patients with the SENCR T variant exhibited better pre-treatment best-corrected visual acuity level (p=0.021). Following aflibercept administration, carrying the TUG1 A or MIAT T/C was associated with a poor therapeutic response (OR=5.02, 95% CI=1.60-15.76, and OR=10.23, 95% CI=1.51-69.15, respectively).

Conclusion: The lncRNAs TUG1 (rs7284767G/A) and MIAT (rs1061540T/C) were associated with increased DR susceptibility and poor response to aflibercept treatment, while MALAT1 (rs3200401C/T) conferred protection to DR. These genetic determinants could be useful in DR risk stratification and pharmacogenetics after validation in large-scale studies.

Keywords: MALAT1; MIAT; SENCR; TUG1; aflibercept; diabetic retinopathy.

Grants and funding

There is no funding to report.