HLA-DRB, -DQA, and -DQB polymorphism in celiac disease and enteropathy-associated T-cell lymphoma: Common features and additional risk factors for malignancy

Abstract CD is a gluten-sensitive enteropathy, strongly associated with expression of the DQA 1 ∗ 0501, DQB 1 ∗ 0201 genotype. CD patients have an increased risk of malignancy, particularly EATCL. However, it is controversial as to whether adults with EATCL represent a subgroup of patients with CD or should be regarded as a distinct entity. To investigate the genetic relationship between CD and EATCL, HLA class II DREI, DQA1, and DQB1 typing of peripheral blood, frozen or paraffin-embedded biopsy tissue obtained from Caucasian patients with CD ( n = 91) or EATCL ( n = 47) was performed by PCR-SSOP typing. Genotype frequencies were compared with those observed in 151 unrelated control individuals. A total of 83 (91%) of 91 CD patients were of DQA1 ∗ 0501, DQB1 ∗ 0201 genotype( p c −6 , RR = 522.2), compared with 40 (93%) of 43 EATCL patients ( p c −6 , RR = 44.2) with amplifiable DNA versus 35 (23%) of 151 controls. DRB1 ∗ 03 frequencies were also elevated in both patient groups (79 of 91 in CD [87%; p c −6 , RR = 24.5] and 38 of 40 in EATCL [95%; p c −6 , RR = 70.7]) compared with controls (32 of 151, 21%). These results confirm previous studies of HLA associations in CD and also suggest that EATCL arises in individuals with the DQA1 ∗ 0501, DQB1 ∗ 0201 CD-predisposing genotype. However, the frequency of DRB1∗03,04 heterozygotes was significantly increased in the EATCL group (16 of 40, 40%) compared with both control individuals (3 of 151, 2%; p c −6 , RR = 32.9) and uncomplicated CD patients (6 of 91, 7%; p c = 0.04, RR = 9.4). Conversely, DRB1 ∗ 03,03 homozygotes and DRB1 ∗ 03,07 heterozygotes were significantly increased in frequency in the CD but not the EATCL series, compared with controls (for DRB1 ∗ 03,03, p c = 0.006, RR = 8.5; for DRB1 ∗ 03,07, p c = 0.06, RR = 7.9), reflecting a significant decrease in DRB1 ∗ 07 frequency in the EATCL patient group (8%) as compared with the CD series (39%; p c = 0.017, RR = 0.13). In addition, none of the 38 DQA1 ∗ 0501, DQB1 ∗ 0201 EATCL patients were homozygous for DQB1 ∗ 0201, compared with 44 of 83 (53%) DQA1 ∗ 0501, DQB1 ∗ 0201 CD patients ( p c −6 , RR ∗ 0501, DQB1 ∗ 0201 controls ( p c ∗ 0501, DQB 1 ∗ 0201 CD-predisposing genotype, additional HLA-DR/DQ-associated alleles acting independently or in association with known CD-associated genotypes may represent a risk factor for EATCL.