Allelic variants of CD40 and CD40L genes interact to promote antibiotic-induced cutaneous allergic reactions.
BACKGROUND
The danger hypothesis provides a new perspective of the mechanisms underlying drug allergy. In this study, we evaluated associations between variations in the genes involved in danger signal pathways and antibiotic-induced cutaneous allergic reactions (AICARs).


METHODS
Two hundred cases with urticaria, angio-oedema, maculopapular rash, and erythema multiforme caused by antibiotics were extracted from the database of the Adverse Drug Reaction Research Group in Korea. All cases were confirmed by an allergy specialist. Causative antibiotics included penicillin, cephalosporin, quinolone, and others (approximately 40 different types). Ten single nucleotide polymorphisms (SNPs) in seven genes (-318C>T, +49A>G, and +6230G>A in CTLA4, IVS+17T>C in CD28, -3479T>G and I170V in CD86, -1C>T in CD40, -3458A>G in CD40LG, -308G>A in TNF, and -31T>C in IL1B) were scored for cases and for healthy subjects without a history of AICARs.


RESULTS
Our analysis failed to reveal differences in the distribution of the 10 SNPs between cases and controls. However, we could find a gene-gene interaction between -1C>T in CD40 and -3458A>G in CD40L using multifactor dimensionality reduction analysis. Subjects with minor alleles of both SNPs showed a significant risk for developing AICARs [P=0.017, odds ratio (OR) (95% confidence interval)=2.93 (1.20-7.97)].


CONCLUSIONS
Our findings suggest that a genetic interaction between CD40 and CD40L favours the development of AICARs.
Kim
Sae-H
SH
Department of Internal Medicine, Institute of Allergy and Clinical Immunology, Seoul National University College of Medicine, Seoul, Korea.
Lee
J-E
JE
Kim
Sang-H
SH
Jee
Y-K
YK
Kim
Y-K
YK
Park
H-S
HS
Min
K-U
KU
Park
H-W
HW
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics; D051940:B7-2 Antigen / Q000235:genetics; D018106:CD28 Antigens / Q000235:genetics; D019013:CD40 Antigens / Q000235:genetics*; D023201:CD40 Ligand / Q000235:genetics*; D060908:CTLA-4 Antigen; D003875:Drug Eruptions / Q000235:genetics* / Q000276:immunology*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics; D007723:Korea; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D055815:Young Adult
D000900:Anti-Bacterial Agents; D015703:Antigens, CD; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand