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Cell Stress and Chaperones

, Volume 15, Issue 5, pp 475–485 | Cite as

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

  • Esma Ucisik-Akkaya
  • Charronne F. Davis
  • Clara Gorodezky
  • Carmen Alaez
  • M. Tevfik Dorak
Original Paper

Abstract

Three heat shock protein 70 (HSP70) genes, HSPA1L, HSPA1A, and HSPA1B, are located within the human leukocyte antigen (HLA) class III region. HSPs act as stress signals and regulate natural killer cell response to cancer. HSP70 gene polymorphisms show disease associations partly due to their linkage disequilibrium with HLA alleles. To systematically evaluate their associations with childhood acute lymphoblastic leukemia (ALL), we examined the three functional single nucleotide polymorphisms (SNPs) rs2227956 (T493M) in HSPA1L, rs1043618 in HSPA1A 5′UTR, and rs1061581 (Q351Q) in HSPA1B by TaqMan assays or polymerase chain reaction–restriction fragment length polymorphism in 114 ALL cases and 414 controls from Wales (UK), in 100 Mexican Mestizo ALL cases and 253 controls belonging to the same ethnic group, and in a panel of 82 HLA-typed reference cell line samples. Homozygosity for HSPA1B rs1061581 minor allele G was associated with protection (odds ratio (OR) = 0.37, 95% confidence interval (CI) = 0.16–0.78; P = 0.007) with gene-dosage effect (additive model) reaching significance (P = 0.0001) in the Welsh case–control group. This association was replicated in the second case–control group from Mexico (OR (recessive model) = 0.49, 95% CI = 0.24–0.96; P = 0.03), and the pooled analysis yielded a strong association (Mantel–Haenszel OR = 0.43, 95% CI = 0.27–0.69, P = 0.0004). The association was stronger in males in each group and in the pooled analysis. A three-SNP haplotype including the major allele A of rs1061581 showed a highly significant increase in Welsh cases compared with respective controls (6.7% vs 1.8%; P = 0.0003) due to the difference between male cases and controls. The protective allele of rs1061581 occurred more frequently on the HLA-DRB3 haplotypes (especially DRB1*03) in the cell line panel, but the HSPA1B association was independent from the HLA-DRB4 association previously detected in the same case–control group from Wales (adjusted P = 0.001). Given the cancer promoting roles played by HSPs intracellularly as well as roles in immune surveillance when expressed on the cell surface and the known correlations between expression levels and the HSP polymorphisms, these results are likely to indicate a primary association and warrant detailed assessment in childhood ALL development.

Keywords

Genetic predisposition to disease Heat shock protein gene polymorphism HLA complex Sex effect Association study Childhood leukemia susceptibility 

Notes

Acknowledgments

This work was funded intramurally by HUMIGEN LLC, The Institute for Genetic Immunology (Hamilton, New Jersey, USA). Ucisik-Akkaya, Davis, and Dorak are employees of HUMIGEN LLC. The Mexican component of the study was financially supported by Fundacion Comparte Vida AC and by CONACyT in Mexico City.

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Copyright information

© Cell Stress Society International 2009

Authors and Affiliations

  • Esma Ucisik-Akkaya
    • 1
  • Charronne F. Davis
    • 1
  • Clara Gorodezky
    • 2
  • Carmen Alaez
    • 2
  • M. Tevfik Dorak
    • 1
  1. 1.Genomic Immunoepidemiology LaboratoryHUMIGEN LLC, The Institute for Genetic ImmunologyHamiltonUSA
  2. 2.The Department of Immunology and ImmunogeneticsInstituto de Diagnostico y Referencia Epidemiologicos (InDRE), Secretary of HealthMexicoMexico

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