Article type
Year
Abstract
Background: The prevalence of genetic association studies in the literature has increased exponentially over the past decade. Most are cross-sectional studies that present unique methodological challenges and risks of bias; they should be appraised accordingly when included in systematic reviews and meta-analyses.
Objectives: To develop a method for assessing risk of bias in genetic association studies and demonstrate its use in a review of the association between a genetic polymorphism (CYP2B6*6) and metabolism of a drug (methadone plasma concentration).
Methods: We searched Medline, EMBASE, CINAHL, PsycINFO, and Web of Science databases. Two independent reviewers included studies that reported methadone plasma concentration and the CYP2B6*6 polymorphism.
Results: We modified the Newcastle-Ottawa Scale to assess the risk of bias in studies of the effect of genetic polymorphisms on drug metabolism. We removed several categories highlighting the comparability of cohort or case/control selection and the importance of adequate follow-up between study groups,while also introducing categories that emphasize explicit outcome and genetic assessment. We identified seven studies assessing the association between methadone plasma concentration and the CYP2B6*6 polymorphism. Five were cross-sectional; two were case-control. Trough (R) methadone plasma concentration was higher in CYP2B6*6 homozygous carriers compared to non-carriers (SMD = 0.53; 95% CI 0.05–1.00; p = 0.03; I2 = 0%). Trough (S) methadone plasma concentration was higher in *6 haplotype homozygotes than in non-carriers, (SMD = 1.44; 95% CI 0.27–2.61; p = 0.04; I2 = 69%).
Conclusions: Participants homozygous for the CYP2B6*6 genotype have higher trough (R) and (S) methadone plasma concentrations compared to non-carriers, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers. We developed an instrument to appraise risk of bias in genetic association studies; it rates the evidence in this review to be of moderate quality and cautions our confidence in the estimates of association. This presentation will focus on that instrument and its application.
Objectives: To develop a method for assessing risk of bias in genetic association studies and demonstrate its use in a review of the association between a genetic polymorphism (CYP2B6*6) and metabolism of a drug (methadone plasma concentration).
Methods: We searched Medline, EMBASE, CINAHL, PsycINFO, and Web of Science databases. Two independent reviewers included studies that reported methadone plasma concentration and the CYP2B6*6 polymorphism.
Results: We modified the Newcastle-Ottawa Scale to assess the risk of bias in studies of the effect of genetic polymorphisms on drug metabolism. We removed several categories highlighting the comparability of cohort or case/control selection and the importance of adequate follow-up between study groups,while also introducing categories that emphasize explicit outcome and genetic assessment. We identified seven studies assessing the association between methadone plasma concentration and the CYP2B6*6 polymorphism. Five were cross-sectional; two were case-control. Trough (R) methadone plasma concentration was higher in CYP2B6*6 homozygous carriers compared to non-carriers (SMD = 0.53; 95% CI 0.05–1.00; p = 0.03; I2 = 0%). Trough (S) methadone plasma concentration was higher in *6 haplotype homozygotes than in non-carriers, (SMD = 1.44; 95% CI 0.27–2.61; p = 0.04; I2 = 69%).
Conclusions: Participants homozygous for the CYP2B6*6 genotype have higher trough (R) and (S) methadone plasma concentrations compared to non-carriers, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers. We developed an instrument to appraise risk of bias in genetic association studies; it rates the evidence in this review to be of moderate quality and cautions our confidence in the estimates of association. This presentation will focus on that instrument and its application.