Sandeep Grover1, Ritushree Kukreti. 1. Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Delhi, India.
Abstract
PURPOSE: Increasing evidence suggests that genetic variants from ABCC2 transporter may be associated with an altered response to antiepileptic drugs (AEDs). However, the variability in the selective inclusion of genetic variants in different studies makes delineation of the causal variant/s difficult. Furthermore, the differences in the frequency distribution and linkage disequilibrium (LD) pattern among genetic variants in different populations add to the heterogeneity in the reported results. The aim of this study is to carry out a systematic assessment of the published studies by performing meta-analysis of the commonly reported genetic variants from ABCC2 with drug response in patients with epilepsy (PWE). METHODS: A literature search of the electronic databases namely Embase, Medline, Web of Science, and Cochrane database of systematic reviews available to the September 8, 2012 was performed. Pooled crude odds ratios (ORs) and 95% confidence intervals (CI) were calculated using both fixed-effect and random-effect models. KEY FINDINGS: A total of eight reports were identified as eligible studies, which included 1,294 good responders and 1,529 poor responders. Of all the commonly reported variants that included c.-24C>T or rs717620, c.1249G>A or rs2273697 (V417I) and c.3972C>T or rs3740066 (I1324I), we observed an overall significant association of high activity promoter variant c.-24C>T with drug response (TT + CT vs. CC: OR(dom) = 1.38 (1.11-1.71), p(dom) = 0.004, I(2) = 3%; CT vs. CC: OR(co-dom) = 1.28 (1.02-1.61), p(co-dom) = 0.03, I(2) = 0%; T vs. C: OR(all) = 1.34 (1.11-1.61), p(all) = 0.002, I(2) = 35%). However, all the associations were lost after testing for multiple corrections. Tests for publication bias did not reveal any significant influence on the observed results. SIGNIFICANCE: In summary, the results of our meta-analysis indirectly suggests possible role of the ABCC2 transporter at the blood brain barrier in altered drug response in PWE. Further studies are warranted in different ethnic groups to investigate the effects of the ABCC2 haplotypic variants and perform stratified analysis on the basis of different phenotypic covariates. Wiley Periodicals, Inc.
PURPOSE: Increasing evidence suggests that genetic variants from ABCC2 transporter may be associated with an altered response to antiepileptic drugs (AEDs). However, the variability in the selective inclusion of genetic variants in different studies makes delineation of the causal variant/s difficult. Furthermore, the differences in the frequency distribution and linkage disequilibrium (LD) pattern among genetic variants in different populations add to the heterogeneity in the reported results. The aim of this study is to carry out a systematic assessment of the published studies by performing meta-analysis of the commonly reported genetic variants from ABCC2 with drug response in patients with epilepsy (PWE). METHODS: A literature search of the electronic databases namely Embase, Medline, Web of Science, and Cochrane database of systematic reviews available to the September 8, 2012 was performed. Pooled crude odds ratios (ORs) and 95% confidence intervals (CI) were calculated using both fixed-effect and random-effect models. KEY FINDINGS: A total of eight reports were identified as eligible studies, which included 1,294 good responders and 1,529 poor responders. Of all the commonly reported variants that included c.-24C>T or rs717620, c.1249G>A or rs2273697 (V417I) and c.3972C>T or rs3740066 (I1324I), we observed an overall significant association of high activity promoter variant c.-24C>T with drug response (TT + CT vs. CC: OR(dom) = 1.38 (1.11-1.71), p(dom) = 0.004, I(2) = 3%; CT vs. CC: OR(co-dom) = 1.28 (1.02-1.61), p(co-dom) = 0.03, I(2) = 0%; T vs. C: OR(all) = 1.34 (1.11-1.61), p(all) = 0.002, I(2) = 35%). However, all the associations were lost after testing for multiple corrections. Tests for publication bias did not reveal any significant influence on the observed results. SIGNIFICANCE: In summary, the results of our meta-analysis indirectly suggests possible role of the ABCC2 transporter at the blood brain barrier in altered drug response in PWE. Further studies are warranted in different ethnic groups to investigate the effects of the ABCC2 haplotypic variants and perform stratified analysis on the basis of different phenotypic covariates. Wiley Periodicals, Inc.
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