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

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 genedosage 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.

Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study

“…These youngest infants may be more susceptible to the development of acute leukemia in utero, because specific HLA-DRB and HLA-DRQ haplotypes have been associated with different forms of leukemia and may be linked to polymorphisms in heat-shock protein genes (HSPA1A and HSPA1B) located in the HLA class III region. 41,44 Polymorphisms of HSPA1A, HSPA1B, and other inflammatory or immunomodulatory genes, such as IL-8 or VCAN, also have been reported to influence susceptibility to cancer. 45,46 In conclusion, we have developed gene expression classifiers that improve outcome prediction in infant ALL, beyond the well-established prognostic factors of patient age and MLL gene rearrangement status.…”

Genetic effect of an A/G polymorphism in the HSP70 gene on thermotolerance in chicken

“…SNPs in non-coding regions can regulate the binding activity of transcriptional factors by altering the structure of some transcriptional domain binding sites (Jeng et al, 2008;Shibata et al, 2009;Ucisik-Akkaya et al, 2010). Using statistical analysis, Mukai et al (2005) found that SNP in the 5'-untranslated region of the CD40 gene had some influence on its expression, and Ordovás et al (2008) found the g.763G>C SNP in the 5'-untranslated region of the bovine FASN gene affects its promoter activity.…”

SNP Association Mapping across the Extended Major Histocompatibility Complex and Risk of B-Cell Precursor Acute Lymphoblastic Leukemia in Children

“…As reviewed previously [55], the two approaches should be viewed as complementary strategies for identification of disease associated loci as they both have their respective strengths and weaknesses depending on the study being conducted. A review of the literature identified six xMHC childhood ALL candidate gene studies of non-classical HLA loci, and statistically significant associations have been reported for SNPs of the HFE , HSPA1B and BAT3 genes [56,57,58]. None of the SNPs specifically examined in these studies were genotyped as part of the current mapping panel which precluded our ability to directly evaluate these previous associations.…”