Genome-Wide Association Study in Immunocompetent Patients with Delayed Hypersensitivity to Sulfonamide Antimicrobials.
BACKGROUND
Hypersensitivity (HS) reactions to sulfonamide antibiotics occur uncommonly, but with potentially severe clinical manifestations. A familial predisposition to sulfonamide HS is suspected, but robust predictive genetic risk factors have yet to be identified. Strongly linked genetic polymorphisms have been used clinically as screening tests for other HS reactions prior to administration of high-risk drugs.


OBJECTIVE
The purpose of this study was to evaluate for genetic risk of sulfonamide HS in the immunocompetent population using genome-wide association.


METHODS
Ninety-one patients with symptoms after trimethoprim-sulfamethoxazole (TMP-SMX) attributable to "probable" drug HS based on medical record review and the Naranjo Adverse Drug Reaction Probability Scale, and 184 age- and sex-matched patients who tolerated a therapeutic course of TMP-SMX, were included in a genome-wide association study using both common and rare variant techniques. Additionally, two subgroups of HS patients with a more refined clinical phenotype (fever and rash; or fever, rash and eosinophilia) were evaluated separately.


RESULTS
For the full dataset, no single nucleotide polymorphisms were suggestive of or reached genome-wide significance in the common variant analysis, nor was any genetic locus significant in the rare variant analysis. A single, possible gene locus association (COL12A1) was identified in the rare variant analysis for patients with both fever and rash, but the sample size was very small in this subgroup (n = 16), and this may be a false positive finding. No other significant associations were found for the subgroups.


CONCLUSIONS
No convincing genetic risk factors for sulfonamide HS were identified in this population. These negative findings may be due to challenges in accurately confirming the phenotype in exanthematous drug eruptions, or to unidentified gene-environment interactions influencing sulfonamide HS.
Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
Jennifer M
http://orcid.org/0000-0002-3021-5075
JM
Reinhart
Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, North Carolina, United States of America.
Alison
A
Motsinger-Reif
Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, North Carolina, United States of America.
Allison
A
Dickey
Marshfield Clinic Research Foundation, Marshfield, Wisconsin, United States of America.
Steven
S
Yale
Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
Lauren A
LA
Trepanier
D000890:Anti-Infective Agents / Q000009:adverse effects*; D003875:Drug Eruptions / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000009:adverse effects*
D000890:Anti-Infective Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination