title: A study of HLA class I and class II 4-digit allele level in Stevens-Johnson syndrome and toxic epidermal necrolysis.
abstract: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are represented by rare but life-threatening cutaneous adverse reactions to different drugs. Previous studies have found that in a Han Chinese population from Taiwan and other Asian Countries, a strong genetic association between HLA-class I alleles (B*15:02, B*58:01) and SJS and TEN was induced by carbamazepine and allopurinol, respectively. To identify genetic markers that covered the MHC region, we carried out a case-control association enrolling 20 Caucasian patients with SJS/TEN. Our patient series included 10 cases related to paracetamol, 7 to allopurinol and 3 to different drugs (plaquenil, itraconazol, nabumetone). Healthy controls were represented by 115 Caucasian bone marrow or stem cell donors. The HLA-A*, B*, C*, DRB1*, DQB1*, DQA1* and DPB1* genotyping were determined. The frequencies of HLA-A*33:03 as well as C*03:02 and C*08:01 were significantly higher in SJS/TEN patient subgroup showing allopurinol drug-induced severe cutaneous adverse reactions (SCAR) as compared to controls (28.6% vs 0%, P=0.00002, Pc=0.0011; 28.6% vs 0%, P=0.00002, Pc=0.001; 28.6% vs 0%, P=0.00002, Pc=0.001, respectively). In the same subgroup the frequencies of B*58:01, DRB1*15:02 and DRB1*13:02 alleles, although considerably higher than in control group (42.8% vs 5.2%, P=0.003; 28.6% vs 1.7%, P=0.005; 28.6% vs 3.5%, P=0.037, respectively), appeared no more statistically different after P correction (Pc=0.248; Pc=0.29; Pc=1.00, respectively). In addition, in 10 of the 20 SJS/TEN patient subgroup with paracetamol-induced SCAR no statistically significant association with HLA alleles could be found. However, in the same SJS/TEN patient subgroup showing allopurinol drug-induced SCAR, haplotype analysis indicated that B*58:01, DRB1*13:02 and DRB1*15:02 alleles, that in a single allele analysis lost statistical significance after P correction, may still confer susceptibility, because the B*58:01-DRB1*13:02 and DRB1*15:02-DQB1*05:02 are positively associated with the disease (14.2% vs 0.43%, P= 0.00001, Pc=0.00028; 14.2% vs 0.43%, P=0.00001, Pc=0.00028, respectively). Our results show that in contrast to SCAR-related to paracetamol, where HLA alleles do not appear to be involved, HLA molecules behave as a strong risk factor for SCAR-related to allopurinol even when a limited number of patients are considered.
authors.affiliation: HLA Laboratory, Immunohematology and Transfusion Medicine Unit, Niguarda Ca' Granda Hospital, Milano, Italy. attcris@bls.it
authors.forename: A F
authors.initials: AF
authors.lastname: Cristallo
authors.forename: J
authors.initials: J
authors.lastname: Schroeder
authors.forename: A
authors.initials: A
authors.lastname: Citterio
authors.forename: G
authors.initials: G
authors.lastname: Santori
authors.forename: G M
authors.initials: GM
authors.lastname: Ferrioli
authors.forename: U
authors.initials: U
authors.lastname: Rossi
authors.forename: G
authors.initials: G
authors.lastname: Bertani
authors.forename: S
authors.initials: S
authors.lastname: Cassano
authors.forename: P
authors.initials: P
authors.lastname: Gottardi
authors.forename: N
authors.initials: N
authors.lastname: Ceschini
authors.forename: F
authors.initials: F
authors.lastname: Barocci
authors.forename: G
authors.initials: G
authors.lastname: Ribizzi
authors.forename: V
authors.initials: V
authors.lastname: Cutrupi
authors.forename: R
authors.initials: R
authors.lastname: Cairoli
authors.forename: V
authors.initials: V
authors.lastname: Rapisarda
authors.forename: E A
authors.initials: EA
authors.lastname: Pastorello
authors.forename: S
authors.initials: S
authors.lastname: Barocci
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013262:Stevens-Johnson Syndrome / Q000235:genetics* / Q000276:immunology; D055815:Young Adult
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II