Association of CYP 2C9*3 with phenytoin‐induced Stevens‐Johnson syndrome and toxic epidermal necrolysis: A systematic review and meta‐analysis

Summary What is known and objective Stevens‐Johnson syndrome ( SJS ) and toxic epidermal necrolysis ( TEN ) are severe cutaneous adverse reactions that can be induced by phenytoin ( PHT ). CYP 2C9*3 is the key enzyme in PHT metabolism. The aim of this meta‐analysis was to evaluate the association between CYP 2C9*3 and PHT ‐induced SJS / TEN . Methods An extensive search was performed in multiple databases, including the Cochrane Library, EMBASE , PubMed, OVID and EBSCO . Studies exploring the relationship between CYP 2C9*3 and PHT ‐induced SJS and TEN were included. Odds ratios ( OR s) with corresponding 95% confidence intervals ( CI ) were calculated for dichotomous data. Data analysis was performed using Review Manager (version 5.3). Results and discussion Four studies, with 117 PHT ‐induced SJS / TEN cases and 338 matched controls ( PHT ‐tolerant patients) or 4231 population controls (general population), were identified. SJS and TEN were found to be significantly associated with the CYP 2C9*3 allele, comparing both matched controls ( OR , 8.93; 95% CI , 2.63‐30.36; P  = .0005) with substantial heterogeneity (I 2  = 46%) and population controls ( OR , 8.88; 95% CI , 5.01‐15.74; P  < .00001). What is new and conclusion A significant association between CYP 2C9*3 and PHT ‐induced SJS / TEN was identified, especially in a Thai population. CYP 2C9*3 is thus a credible predictive genetic marker of PHT ‐induced SJS / TEN . Further multicenter studies and large prospective observational studies are, however, still required to determine the influence of CYP 2C*3 on blood levels of PHT and its metabolites, and their association with SJS / TEN .