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Vascular endothelial growth factor gene polymorphisms and association with age related macular degeneration in Indian patients.

ABSTRACT: BACKGROUND:Age-related macular degeneration (AMD) is an important cause of visual impairment in elderly people. AMD is a multifactorial disease in which both environmental and genetic factors have been implicated. Various single nucleotide polymorphisms (SNPs) have been found to be associated with AMD. AIM:This study was aimed to investigate the association of polymorphisms in VEGF genes with age related macular degeneration (AMD) in Indian patients. METHOD:Genotyping for the VEGF - 1154 (G > A), - 2578 (C > A), + 405 (G > C) and - 460 (C > T) SNPs was performed in 100 AMD patients and 100 controls by polymerase chain reaction (PCR), restriction fragment length polymorphism (PCR-RFLP) and sequencing method. RESULTS:Out of the four SNPs, heterozygous genotypes of VEGF - 1154 G > A (OR = 2.58, p = 0.0035), + 460 C > T (OR = 2.90, p = 0.0046), and + 405 G > C (OR = 2.02, p = 0.02) have shown susceptible association with AMD. However, VEGF - 2578 C > A did not show any statistical significance. Further A-A-G-T haplotype comprising of three mutant alleles revealed risk association (OR = 12.7, p = 0.0030) with AMD. CONCLUSION:The present study suggests significant genetic associations for VEGF - 1154 G > A, + 460 C > T, and + 405 G > C polymorphisms with AMD. Early detection of individuals with risk to these SNPs could lead to strategies for prevention, early diagnosis, and management of AMD.

SUBMITTER: Gupta D

PROVIDER: S-EPMC5006127 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Vascular endothelial growth factor gene polymorphisms and association with age related macular degeneration in Indian patients.

Gupta Divya D Gupta Vani V Singh Vinita V Prakash Swayam S Agrawal Suraksha S Chawla Shobhit S Phadke Shubha R SR

Meta gene 20160722

<h4>Background</h4>Age-related macular degeneration (AMD) is an important cause of visual impairment in elderly people. AMD is a multifactorial disease in which both environmental and genetic factors have been implicated. Various single nucleotide polymorphisms (SNPs) have been found to be associated with AMD.<h4>Aim</h4>This study was aimed to investigate the association of polymorphisms in VEGF genes with age related macular degeneration (AMD) in Indian patients.<h4>Method</h4>Genotyping for t ...[more]

PMID: 27617226

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Project description:PurposeA previously published study demonstrated a pharmacogenetic association between the minor alleles of 2 VEGFR2 single nucleotide polymorphisms (SNPs) and greater improvement in visual acuity (VA) to treatment with ranibizumab, an anti-vascular endothelial growth factor (VEGF) drug, in patients with neovascular age-related macular degeneration (AMD). We evaluated whether this association was replicated among patients who participated in the Comparison of AMD Treatments Trials (CATT) or the Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation (IVAN) trial.DesignCohort studies within randomized clinical trials.ParticipantsEight hundred thirty-five patients participating in CATT and 512 patients participating in IVAN.MethodsEach patient was genotyped for the SNPs rs4576072 and rs6828477 in the VEGFR2 gene.Main outcomes measuresMean change in VA from baseline to 1 year after initiation of treatment with ranibizumab or bevacizumab. Differences in VA response between the patient group homozygous for the minor allele of each SNP and the other genotype groups were evaluated with analysis of variance. Differences in VA response by the number of minor alleles present for either SNP or both combined were evaluated with tests of linear trend. Analyses were conducted separately for CATT and IVAN participants and with both the studies combined.ResultsNo statistically significant difference in mean change in VA was identified between genotypes of either SNP (P ≥ 0.05). Furthermore, a stepwise analysis failed to show a significant interaction for either SNP based on the number of minor alleles present. The lack of association was similar in both the CATT and IVAN cohorts and whether the analysis combined patients treated with either ranibizumab or bevacizumab or when restricted to patients treated with ranibizumab only.ConclusionsThe CATT and IVAN data do not support a pharmacogenetic association between the 2 VEGFR2 SNPs, rs4576072 and rs6828477, and change in VA in response to anti-VEGF therapy in patients with neovascular AMD.

Project description:Importance:Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in nAMD. Objective:To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD. Design, Setting, and Participants:In this multicenter genome-wide association study, 678 patients with nAMD with genome-wide genotyping data were included in the discovery phase; 1380 additional patients with nAMD were genotyped for selected common variants in the replication phase. All participants received 3 monthly injections of bevacizumab or ranibizumab. Clinical data were evaluated for inclusion/exclusion criteria from October 2014 to October 2015, followed by data analysis from October 2015 to February 2016. For replication cohort genotyping, clinical data collection and analysis (including meta-analysis) was performed from March 2016 to April 2017. Main Outcomes and Measures:Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline. Results:Of the 2058 included patients, 1210 (58.8%) were women, and the mean (SD) age across all cohorts was 78 (7.4) years. Patients included in the discovery cohort and most of the patients in the replication cohorts were of European descent. The mean (SD) baseline VA was 51.3 (20.3) Early Treatment Diabetic Retinopathy Study (ETDRS) score letters, and the mean (SD) change in VA after the loading dose of 3 monthly injections was a gain of 5.1 (13.9) ETDRS score letters (ie, 1-line gain). Genome-wide single-variant analyses of common variants revealed 5 independent loci that reached a P value less than 10 × 10-5. After replication and meta-analysis of the lead variants, rs12138564 located in the CCT3 gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; β, 0.034; SE, 0.008; P = 1.38 × 10-5). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 (P = 4.22 × 10-7) and UNC93B1 (P = 6.09 × 10-7) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1 genes lost a mean (SD) VA of 30.6 (17.4) ETDRS score letters (ie, loss of 6.09 lines) and 26.5 (13.8) ETDRS score letters (ie, loss of 5.29 lines), respectively, after 3 months of anti-VEGF treatment. Conclusions and Relevance:We propose that there is a limited contribution of common genetic variants to variability in nAMD treatment response. Our results suggest that rare protein-altering variants in the C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.

Project description:BACKGROUND:Age-related macular degeneration (AMD) is a common cause of severe vision loss in people 55 years and older. OBJECTIVES:The objective of this review was to investigate the effects of anti-VEGF (vascular endothelial growth factor) modalities for treating neovascular AMD. SEARCH STRATEGY:We searched CENTRAL, MEDLINE, EMBASE and LILACS. We handsearched ARVO abstracts for 2006, 2007 for ongoing trials. SELECTION CRITERIA:We included randomized controlled trials (RCTs). DATA COLLECTION AND ANALYSIS:Two review authors independently extracted data. We contacted trial authors for additional data. We summarized outcomes as relative risks (RR), number needed to treat (NNT) and weighted mean differences. MAIN RESULTS:We included five RCTs of good methodological quality. All five trials were conducted by pharmaceutical companies. An intention-to-treat analysis using the last observation carried forward method was done in most trials. Two trials compared pegaptanib versus sham. One trial compared ranibizumab versus sham, another compared ranibizumab/sham verteporfin PDT versus verteporfin PDT/sham ranibizumab, and the final trial compared ranibizumab plus verteporfin PDT versus verteporfin PDT alone. Fewer patients treated with pegaptanib lost 15 or more letters of visual acuity at one year follow-up compared to sham (pooled relative risk (RR) 0.71; 95% confidence interval (CI) 0.61 to 0.84). The NNT was 6.67 (95% CI 4.35 to 14.28) for 0.3 mg pegaptanib, 6.25 (95% CI 4.17 to 12.5) for 1 mg pegaptanib and 14.28 (95% CI 6.67 to 100) for 3 mg pegaptanib. In a trial of ranibizumab versus sham, RR for loss of 15 or more letters visual acuity at one year was 0.14 (95% CI 0.1 to 0.22) in favour of ranibizumab. The NNT was 3.13 (95% CI 2.56 to 3.84) for 0.3 mg ranibizumab and 3.13 (95% CI 2.56 to 3.84) for 0.5 mg ranibizumab. In a trial of ranibizumab versus verteporfin PDT, RR for loss of 15 or more letters at one year was 0.13 (95% CI 0.07 to 0.23) favouring ranibizumab. The NNT was 3.33 (95% CI 2.56 to 4.76) for 0.3 mg ranibizumab and 3.12 (95% CI 2.43 to 4.17) for 0.5 mg ranibizumab. In another trial of combined ranibizumab plus verteporfin PDT versus verteporfin PDT, RR for loss of 15 or more letters at one year favoured combined therapy (RR 0.3 (95% CI 0.15 to 0.60). The NNT was 4.35 (95% CI 2.78 to 11.11). Pooled RR for gain of 15 or more letters visual acuity at one year was 5.81 (95% CI 3.29 to 10.26) for ranibizumab versus sham, 6.79 (95% CI 3.41 to 13.54) for ranibizumab/sham verteporfin PDT versus verteporfin PDT/sham ranibizumab, and 4.44 (95% CI 1.40 to 14.08) for ranibizumab plus verteporfin PDT versus verteporfin PDT. Frequency of endophthalmitis in included studies was between 0.7% to 4.7% with ranibizumab and 1.3% with pegaptanib. Improvement in vision-specific quality of life was reported for both treatments. AUTHORS' CONCLUSIONS:Pegaptanib and ranibizumab reduce the risk of visual acuity loss in patients with neovascular AMD. Ranibizumab causes gains in visual acuity in many eyes. Quality of life and cost will be important for treatment decisions. Other agents blocking VEGF are being tested in ongoing trials.

Dataset Information

Vascular endothelial growth factor gene polymorphisms and association with age related macular degeneration in Indian patients.

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Vascular endothelial growth factor gene polymorphisms and association with age related macular degeneration in Indian patients.

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