174-P: HLA class III region genes HSPA1L/A/B polymorphisms and childhood leukemia risk

Abstracts

S93

173-P

HLA HAPLOTYPES IN A LEBANESE POPULATION. Manuela Testi,1 Pedro Cano,2 Martin Maiers,3 Edward Guerrero,2 Loren Gragert,3 William Klitz,4 Adlette I. Khoriaty,5 Marcelo Fernandez-Vina,2 Marco Andreani.1 1Immunogenetics Laboratory, Mediterranean Institute of Hematology, Rome, Italy; 2 Laboratory Medicine, UT M. D. Anderson Cancer, Houston, TX, USA; 3National Marrow Donor Program, Minneapolis, MN, USA; 4School of Public Health, University of California, Berkeley, CA, USA; 5Cronic Care Center, Beirut, Lebanon. Aim: To investigate HLA diversity in a Lebanese population. Methods: HLA typing was done in 426 Lebanese subjects (LEB) of 88 families. 347 haplotypes were defined. Typing was done by SBT. Results: HLA-A, B and DRB1 alleles in LEB represented 93.5, 90.0 and 95.4% of the alleles at these loci in European Americans (EA), and 89.4, 94.0 and 98.2% of the alleles of an Arab population from Israel. The frequency of A*0302, 0205, 0202, 0103, 3004, 2403 was unexpectedly high. A*3101, 3303, 2501, common in EA, were absent in LEB. B*3502, 1801, 4101, and 5201 have higher requency in LEB (gf⬎0.05). B*7301, 3508, 0706, 5108, 4006 and 4102, absent in EA is present in LEB. B*4402 is common in LEB and absent in Arabs. DRB1*1104, 1001, 0403, 1303, 1601, 1502, 0405 and 0402 have higher freqency than in EA. The most frequent haplotypes were A*2402-B*3502-DRB1*1104, A*0101-B*5701-DRB1*0701, A*2601-B*3501DRB1*1601, A*3301-B*1402-DRB1*0102, A*0202-B*4101-DRB1*1104, A*2601-B*3801-DRB1*1104 and A*0101-B*7301-DRB1*0405. Most of these haplotypes are absent in EA, Arabs and Ashkenazi Jewish. The 47 most common A-B-DRB1 blocks cover 39%t of LEB haplotypes, but only ⬍6% of Arab haplotypes and 2.5%t of EA haplotypes. Conclusions: In spite of the significant overlap in alleles, the LEB population shows a small haplotypic overlap with other populations. The development of registries of unrelated donors/CBU is necessary to best cover the needs of patients from this population.

174-P

HLA CLASS III REGION GENES HSPA1L/A/B POLYMORPHISMS AND CHILDHOOD LEUKEMIA RISK. Esma Ucisik-Akkaya,1 Brittany A. Morrison,1 Clara Gorodezky,2 M. Tevfik Dorak.1 1 Genomic Immunoepidemiology Lab, HUMIGEN LLC, The Institute for Genetic Immunology, Hamilton, NJ, USA; 2Dept of Immunology & Immunogenetics, InDRE, Secretary of Health, Mexico City, Mexico. Aim: Three heat shock protein (HSP) genes, HSPA1L, A1A and A1B are located within the HLA class III region. HSPs act as chaperones and stress signals and regulate natural killer cell response to cancer. HSP gene polymorphisms have been associated with autoimmunity and cancer due to their linkage disequilibrium with HLA alleles. Methods: To evaluate their association with childhood acute lymphoblastic leukemia (ALL), we examined HSPA1L rs2227956 (T493M), HSPA1A rs1043618 (5’UTR) and HSPA1A/B rs1061581 (Q351Q) by TaqMan assays or PCR-RFLP in 114 ALL cases and 389 controls from Wales, UK, in 100 Mexican Mestizo ALL cases and 253 controls and in a panel of 82 IHWG cell lines. Results: One haplotype (1-2-1) showed a highly significant increase in cases (6.8% vs 1.6%; P ⫽ 0.00005). Individually, rs1061581 was associated with protection, due to reduced risk conferred by heterozygosity (OR ⫽ 0.58; P ⫽ 0.01) and even stronger protection by homozygosity (OR ⫽ 0.28, P ⫽ 0.001) with additive model reaching significance (P ⫽ 0.0001). Although the protective allele of rs1061581 occurred more frequently on the HLA-DRB3 haplotypes (especially DRB1*03) in the cell line panel, this association was independent from the HLA-DRB4 association previously detected (adjusted P ⫽ 0.001). The rs1061581 association was replicated in the second case-control group from Mexico (OR (dominant model) ⫽ 2.04, P ⫽ 0.03). Conclusions: Given the known correlation between expression levels and the HSPA1L SNP rs2227956 included in the haplotypic association, these results are likely to indicate a primary association and warrant detailed assessment in childhood ALL development.