High-resolution HLA genotyping and severe cutaneous adverse reactions in lamotrigine-treated patients.
BACKGROUND
Severe cutaneous adverse reactions (SCARs) are associated with over 200 medicines including lamotrigine, an antiepileptic drug. Previous studies have suggested the involvement of immune mechanisms in the development of drug-induced SCARs.


METHODS
High-resolution HLA genotyping was performed for 65 patients of European ancestry treated with lamotrigine (22 cases with lamotrigine-induced SCARs and 43 controls on lamotrigine without SCAR-related symptoms). Association of HLA genetic variants with SCARs in these patients were evaluated by contrasting allele frequencies between the cases and the controls for each of 112 HLA four-digit alleles.


RESULTS
Five alleles were observed with higher frequencies in the cases compared with the treated controls with exact P values less than 0.05. These include B*5801 (P = 0.037), previously reported to be associated with allopurinol-induced SCARs. Marginal association evidence was also observed for alleles Cw*0718 and DQB1*0609, both of which were strongly correlated with B*5801. Other alleles identified were A*6801 (P = 0.012) and DRB1*1301 (P = 0.045). In contrast to the study of carbamazepine-induced Stevens-Johnson syndrome in Han Chinese patients, none of the cases carried B*1502. Accounting for the large number of hypothesis tests conducted, none of the associations identified were statistically significant.


CONCLUSIONS
No single major HLA-related genetic risk factor was identified for lamotrigine-induced SCARs in patients of European origin. Only suggestive evidence was obtained for B*5801, A*6801, Cw*0718, DQB1*0609, and DRB1*1301. Confirmation of these results in a larger, independent sample is needed to determine whether any of the HLA alleles identified are truly associated with the development of lamotrigine-induced SCARs.
Kazeem
Gbenga R
GR
GlaxoSmithKline, Harlow, UK. gbenga.r.kazeem@gsk.com
Cox
Charles
C
Aponte
Jennifer
J
Messenheimer
John
J
Brazell
Celia
C
Nelsen
Andrew C
AC
Nelson
Matthew R
MR
Foot
Elizabeth
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000700:Analgesics; D000927:Anticonvulsants / Q000009:adverse effects*; D016022:Case-Control Studies; D002648:Child; D005260:Female; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D013262:Stevens-Johnson Syndrome / Q000139:chemically induced / Q000208:ethnology / Q000209:etiology / Q000235:genetics*; D014227:Triazines / Q000009:adverse effects*; D044465:White People; D055815:Young Adult
D000700:Analgesics; D000927:Anticonvulsants; D006680:HLA Antigens; D014227:Triazines; D000077213:Lamotrigine