Analysis of IL-10, IL-4 and TNF-alpha polymorphisms in drug-induced liver injury (DILI) and its outcome.
OBJECTIVE
The aim of this study was to assess whether genetic polymorphism of three important candidate cytokine genes, IL-10 (-1082G/A, -819C/T, and -592C/A), IL-4 (-590C/T) and TNF-alpha (-308G/A), play a role in the susceptibility to developing drug-induced liver injury (DILI), and in determining its phenotypic expression and severity.


METHODS
Cytokine genotyping was analysed using TaqMan 5' allelic discrimination assay in 140 DILI patients (mean age 51 y, range 13-82, with equal sex distribution) included in the Spanish Registry and 268 healthy controls.


RESULTS
Genotypes, haplotypes and allele frequencies were similar for both cases and controls. The low IL-10 producing haplotype was more prevalent in DILI patients with the absence of peripheral blood eosinophilia (Pc=0.004, OR=5.29, 95% CI: 2.04-13.67), revealing significantly lower median eosinophil counts (0.19 x 10(9)L; P<0.0002) compared to the intermediate (0.24 x 10(9)L) and high (0.40 x 10(9)L) IL-10 haplotypes. All cases with serious DILI outcome carried low or intermediate IL-10 producing haplotype and had normal or low eosinophil counts.


CONCLUSIONS
IL-10, IL-4 and TNF-alpha genetic polymorphisms were not related to the risk of developing DILI. Low IL-10 producing haplotype is associated with low eosinophil count, absence of eosinophilia and may be associated with worse clinical outcome from DILI.
Pachkoria
Ketevan
K
Servicio de Farmacología Clínica, Facultad de Medicina, Departmento de Farmacología, Boulevard Louis Pasteur, 32, Campus de Teatinos s/n, 29071 Málaga, Spain.
Lucena
M Isabel
MI
Crespo
Esperanza
E
Ruiz-Cabello
Francisco
F
Lopez-Ortega
Susana
S
Fernandez
M A Carmen
MA
Romero-Gomez
Manuel
M
Madrazo
Ana
A
Durán
Jose Antonio
JA
de Dios
Ana Malcon
AM
Borraz
Yolanda
Y
Navarro
Jose Maria
JM
Andrade
Raúl J
RJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics*; D004804:Eosinophils / Q000166:cytology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006239:Haplotypes; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D015995:Prevalence; D011401:Promoter Regions, Genetic / Q000235:genetics; D012042:Registries; D012307:Risk Factors; D012720:Severity of Illness Index; D013030:Spain / Q000453:epidemiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016207:Cytokines; C508598:IL4 protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4