Evidence that an HLA-DQA1-DQB1 haplotype influences susceptibility in childhood common acute lymphoblastic leukaemia in boys provides further support for an infection-related aetiology

Taylor, G. Malcolm; Dearden, S.; Payne, Nanetta; Ayres, Michelle; Gokhale, David; Birch, John; Blair, Vilray P.; Stevens, Robert G.; Will, Andrew; Eden, O. B.

doi:10.1038/bjc.1998.540

Cited by 49 publications

(30 citation statements)

References 15 publications

(1 reference statement)

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“…Another important finding in the present study was the male specificity of the HSP association. The sex effect in extended HLA complex associations with childhood ALL has already been reported by us and others (Taylor et al 1998;Dorak et al 1999a, b;Ng et al 2006). Notably, the positive correlation between high HSP serum levels and lung cancer susceptibility is also observed in males only (Suzuki et al 2006).…”

Section: Discussionsupporting

confidence: 64%

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

Ucisik-Akkaya

Davis

Gorodezky

et al. 2010

Cell Stress and Chaperones

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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.

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Section: Discussionsupporting

confidence: 64%

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

Ucisik-Akkaya

Davis

Gorodezky

et al. 2010

Cell Stress and Chaperones

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“…A study of HLA haplotypes in common-ALL has shown that a specific DQA1/DQB1 haplotype is associated with susceptibility in males, but not in females. 16 Together these results and the current data on incidence trends support the hypothesis that common-ALL is aetiologically linked to delayed exposure to common infections. 17 In contrast to ALL, AML has displayed stable incidence rates over the 45-year period and, from previous studies based on the MCTR, 14,15 has shown neither seasonal variation nor space-time clustering.…”

Section: Discussionsupporting

confidence: 61%

Examination of temporal trends in the incidence of childhood leukaemias and lymphomas provides aetiological clues

et al. 2001

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The age-sex distributions and temporal trends in incidence of leukaemia and lymphoma from the Manchester Children's Tumour Registry (MCTR), 1954-1998, are reported. This 45-year study includes 1795 children, all of whom had a histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses all the children were under 15 years of age and were resident in a geographically defined area of northwest England covered by the MCTR. Log-linear modelling identified significant linear increases in acute lymphoblastic leukaemia (ALL) (average annual increase 0.7%; P = 0.005) and in Hodgkin's disease (HD) (1.2%, P = 0.04), but not in acute myeloid leukaemia (AML), nor in non-Hodgkin's lymphoma (NHL). The increase in ALL was most pronounced amongst males, aged 1-4 years, and is likely to be due to precursor Bcell leukaemias. The increases in ALL and HD are discussed in relation to current hypotheses suggesting a role for infection. Additionally, a non-linear cohort effect was identified for NHL (P = 0.008), which may indicate the involvement of environmental factors other than infection. Leukemia (2001) 15, 1612-1618.

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“…However, very few studies have focused on possible familial links between autoimmunity and hematopoietic malignancies in adults. Familial Hodgkin's lymphoma, and possibly also acute lymphocytic leukemia, is linked to HLA class II (41,42), as is the case for most autoimmune diseases (43). Studies in both humans and mice have demonstrated associations between autoimmune disorders in the family and risk of CLL (20,44).…”

Section: Ekströ M Et Almentioning

confidence: 99%

Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first‐degree relatives

Ekström¹,

Hjalgrim²,

Brandt³

et al. 2003

Arthritis & Rheumatism

249

152

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Objective. Patients with rheumatoid arthritis (RA) are at increased risk for malignant lymphomas. Both conditions display a familial aggregation, and there are reports of RA and malignant lymphomas occurring in the same families. This study was undertaken to determine the risk of malignant lymphomas in first-degree relatives of RA patients, in order to investigate whether the increased risk of malignant lymphomas in RA could be due to genetic or environmental risk factors common to both conditions, rather than being a consequence of the rheumatic disease.Methods. Using Swedish nationwide and population-based registers, we identified 76,527 patients hospitalized with RA in 1964-1999 and 70,290 firstdegree relatives of a subset of these patients. These subjects were followed up for more than 3 decades, and information on cancer occurrence was recorded.Results. Patients with RA had a significantly increased risk of malignant lymphomas (535 cases; standardized incidence ratio [SIR] 2.00, 95% confidence interval [95% CI] 1.83-2.17), which was apparent for up to 2 decades of followup. Among the first-degree relatives without RA, no increased risk of malignant lymphomas was found overall, although modest and nonsignificantly elevated risk estimates were observed in subgroups. With respect to childhood cancer (0-14 years of age), we observed an increased risk of Hodgkin's lymphoma (5 cases; SIR 3.18, 95% CI 1.03-7.42).Conclusion. Patients with RA are at a markedly, but possibly time-limited, increased risk for malignant lymphomas. There is little to suggest a prominent role for coinherited or common environmental risk factors in malignant lymphomas arising in the context of RA. Instead, lymphomas complicating RA appear to be a direct consequence of the inflammation or its treatment.

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Evidence that an HLA-DQA1-DQB1 haplotype influences susceptibility in childhood common acute lymphoblastic leukaemia in boys provides further support for an infection-related aetiology

Cited by 49 publications

References 15 publications

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

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

Examination of temporal trends in the incidence of childhood leukaemias and lymphomas provides aetiological clues

Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first‐degree relatives

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