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Evaluation of polymorphisms in the sulfonamide detoxification genes NAT2, CYB5A, and CYB5R3 in patients with sulfonamide hypersensitivity

Sacco, James C.a; Abouraya, Mahmouda; Motsinger-Reif, Alisonc; Yale, Steven H.b; McCarty, Catherine A.b; Trepanier, Lauren A.a

doi: 10.1097/FPC.0b013e328357a735

Objective To determine whether polymorphisms in the sulfonamide detoxification genes, CYB5A (encoding cytochrome b5), CYB5R3 (encoding cytochrome b5 reductase), or NAT2 (encoding N-acetyltransferase 2) were over-represented in patients with delayed sulfonamide drug hypersensitivity, compared with control patients who tolerated a therapeutic course of trimethoprim–sulfamethoxazole without adverse event.

Methods DNA from 99 nonimmunocompromised patients with sulfonamide hypersensitivity who were identified from the Personalized Medicine Research Project at the Marshfield Clinic, and from 99 age-matched, race-matched, and sex-matched drug-tolerant controls, were genotyped for four CYB5A and five CYB5R3 polymorphisms, and for all coding NAT2 SNPs.

Results CYB5A and CYB5R3 SNPs were found at low allele frequencies (<3–4%), which did not differ between hypersensitive and tolerant patients. NAT2 allele and haplotype frequencies, as well as inferred NAT2 phenotypes, also did not differ between groups (60 vs. 59% slow acetylators). Finally, no difference in NAT2 status was found in a subset of patients with more severe hypersensitivity signs (drug reaction with eosinophilia and systemic symptoms) compared with tolerant patients.

Conclusion We found no evidence of a substantial involvement of these nine CYB5A or CYB5R3 polymorphisms in sulfonamide hypersensitivity risk, although minor effects cannot be completely ruled out. Despite careful medical record review and full resequencing of the NAT2 coding region, we found no association of NAT2 coding alleles with sulfonamide hypersensitivity (predominantly cutaneous eruptions) in this adult Caucasian population.

aDepartment of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison

bMarshfield Clinic Research Foundation, Marshfield, Wisconsin

cDepartment of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA

Present address: Catherine A. McCarty’s, Essentia Institute of Rural Health, Duluth, Minnesota, USA

Present address: Abouraya Mahmoud, FDA/Center for Veterinary Medicine, Bethesda, Maryland, USA

Correspondence to Lauren A. Trepanier, DVM, PhD, Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, Wisconsin 53706-1102, USA Tel: +1 608 265 9022; fax: +1 608 265 8020; e-mail:

Received January 10, 2012

Accepted June 20, 2012

© 2012 Lippincott Williams & Wilkins, Inc.