Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster.
OBJECTIVE
The use of carbamazepine (CBZ), the most commonly prescribed antiepileptic drug, is hampered by the occurrence of severe, potentially lethal hypersensitivity reactions. The pathogenesis of hypersensitivity is not yet known, but immune mechanisms are involved. Predisposition to CBZ hypersensitivity is likely to be genetically determined, and genes within the major histocompatibility complex (MHC) have been implicated. The heat shock protein (HSP70) gene cluster is located in the MHC class III region.


METHODS
Using a case-control study design, we compared 61 patients with CBZ hypersensitivity (22 with a severe reaction) to 44 patients on CBZ with no signs of hypersensitivity and 172 healthy controls. The genotyping strategy involved identification of common and rare single nucleotide polymorphisms (SNPs) within the HSP70 gene cluster by sequencing, estimation of linkage disequilibrium (LD) and haplotype structure, and thereafter, analysis of SNP/haplotype frequencies in the cases and controls. Population substructure was evaluated by genotyping of 34 microsatellites.


RESULTS
Twenty-five SNPs were detected across the three HSP70 genes. Analyses revealed that alleles G, T and C at the SNPs HSPA1A +1911 C/G, HSPA1A +438 C/T and HSPA1L +2437 T/C, respectively, were associated with protection from serious hypersensitivity reactions to CBZ, with the associated alleles falling on a common haplotype. We were unable to detect the presence of population stratification in our patients and controls.


CONCLUSIONS
Our data show that HSP70 gene variants are associated with serious CBZ hypersensitivity reactions, but whether this is causal or reflects LD with another gene within the MHC requires further study.
Department of Pharmacology and Therapeutics, The University of Liverpool, Sherrington Building, Ashton Street, Liverpool, UK.
Ana
A
Alfirevic
Tracy
T
Mills
Pauline
P
Harrington
Tracy
T
Pinel
James
J
Sherwood
Ansar
A
Jawaid
John C
JC
Smith
Ruth E
RE
March
Bryan J
BJ
Barratt
David W
DW
Chadwick
B
B
Kevin Park
Munir
M
Pirmohamed
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002220:Carbamazepine / Q000009:adverse effects*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity / Q000235:genetics*; D014644:Genetic Variation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D005810:Multigene Family; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index
D018840:HSP70 Heat-Shock Proteins; D002220:Carbamazepine