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211-P: Immunoregulatory gene polymorphisms and childhood acute lymphoblastic leukemia (ALL) susceptibility
S118
Abstracts
210-P
POLYMORPHISMS OF IRON REGULATORY GENES WITH IMMUNE FUNCTIONS ARE ASSOCIATED WITH CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) SUSCEPTIBILITY. Charronne F. Davis, Esma Ucisik-Akkaya, Thuy N. Do, M. Tevfik Dorak. Genomic Immunoepidemiology, HUMIGEN, Hamilton, NJ, USA. Aim: Innate immunity plays an important role in protection from infections and cancer. The iron regulatory genes ferroportin (SLC40A1), heme oxygenase (HMOX1), lactoferrin (LTF), lipocalin 2 (LCN2), hepcidin (HAMP), and natural-resistance associated macrophage proteins (NRAMP) type 1 and 2 (SLC11A1 and 2) are mediators of the “iron withdrawal” component of antimicrobial and anti-neoplastic immune defense. Besides other actions, the potent immune surveillance molecules interferon-gamma (IFNG) activates the iron withdrawal machinery during infections and interleukin-6 (IL6) induces hepcidin to sequester iron away, thereby reducing its availability for dividing microbes or cancer cells. Methods: We investigated associations between 28 polymorphisms of seven iron withdrawal-related genes and childhood ALL susceptibility in 114 cases and 388 newborn controls from Wales (UK) by TaqMan analysis. Results: SLC40A1 rs1439812 (P ⫽ 0.02), LTF rs1042073 (P ⫽ 0.01) and LCN2 rs878400 (P ⫽ 0.003) showed associations in the overall group. Associations with HMOX1 rs5755709, SLC11A1 rs1059823 and SLC11A2 rs422982 were sexually antagonistic (risk in males and protective in females, P for interaction with sex ⱕ 0.05 for all). The strongest association was with rs422982 (OR (per allele) ⫽ 1.7, P ⫽ 0.03 in males and OR (per allele) ⫽ 0.6, P ⫽ 0.04 in females; P (interaction) ⫽ 0.003) showing a clear gene-dosage effect. Conclusions: These results suggested the involvement of the iron withdrawal component of the immune surveillance machinery in childhood leukemia susceptibility and emphasized the importance of examination of sex effect in association studies.
211-P
IMMUNOREGULATORY GENE POLYMORPHISMS AND CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) SUSCEPTIBILITY. Esma Ucisik-Akkaya, Charronne F. Davis, Thuy N. Do, M. Tevfik Dorak. Genomic Immunoepidemiology, HUMIGEN, Hamilton, NJ, USA. Aim: The immune system is often implicated in the etiology of childhood ALL. Recent reports on associations of early childhood infections with subsequent leukemia development as well as the increased risk in males support a role for immune surveillance. Methods: We examined 145 SNPs from 56 HLA complex genes and 34 SNPs from 10 immune system or cytokine genes (NKG2D, CTLA4, IFNG, IL6, IL10, PKR, LIF, LTF, VEGF and EDN1) in 114 cases of childhood ALL and 388 newborn controls from Wales (UK) using TaqMan assays. Results: Besides previously found multiple independent associations with HLA complex and NKG2D region SNPs, we noted associations with SNPs in other genes that have been shown to modify risk for other cancers. Most of the significant associations were sex-specific: IFNG rs2069727 (OR ⫽ 0.53) and a PKR haplotype (OR ⫽ 0.45) in males only; IL6 rs1800797 (OR ⫽ 2.2), VEGFA rs1570360 (OR ⫽ 2.5) and EDN1 rs5370 (OR ⫽ 0.36) in females only. CTLA4 rs231775, a general cancer susceptibility marker, showed a male-specific risk association (OR ⫽ 2.3, 95% CI ⫽ 1.1 to 4.7, P ⫽ 0.04). Conclusions: In the literature, there seems to be a tendency to interpret results of similar studies in terms of their fit to the popular “dysregulated immune response to delayed infections” hypothesis. We favor a more direct approach and suggest that our results simply implicate immune surveillance in control of childhood leukemia as in other cancers. Similar associations of the same SNPs in other cancers and the sex effect support this assertion. Systematic studies of the genes involved in immune surveillance and unbiased interpretation of results may allow the identification of high-risk children before they develop leukemia.
Abstracts
210-P
POLYMORPHISMS OF IRON REGULATORY GENES WITH IMMUNE FUNCTIONS ARE ASSOCIATED WITH CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) SUSCEPTIBILITY. Charronne F. Davis, Esma Ucisik-Akkaya, Thuy N. Do, M. Tevfik Dorak. Genomic Immunoepidemiology, HUMIGEN, Hamilton, NJ, USA. Aim: Innate immunity plays an important role in protection from infections and cancer. The iron regulatory genes ferroportin (SLC40A1), heme oxygenase (HMOX1), lactoferrin (LTF), lipocalin 2 (LCN2), hepcidin (HAMP), and natural-resistance associated macrophage proteins (NRAMP) type 1 and 2 (SLC11A1 and 2) are mediators of the “iron withdrawal” component of antimicrobial and anti-neoplastic immune defense. Besides other actions, the potent immune surveillance molecules interferon-gamma (IFNG) activates the iron withdrawal machinery during infections and interleukin-6 (IL6) induces hepcidin to sequester iron away, thereby reducing its availability for dividing microbes or cancer cells. Methods: We investigated associations between 28 polymorphisms of seven iron withdrawal-related genes and childhood ALL susceptibility in 114 cases and 388 newborn controls from Wales (UK) by TaqMan analysis. Results: SLC40A1 rs1439812 (P ⫽ 0.02), LTF rs1042073 (P ⫽ 0.01) and LCN2 rs878400 (P ⫽ 0.003) showed associations in the overall group. Associations with HMOX1 rs5755709, SLC11A1 rs1059823 and SLC11A2 rs422982 were sexually antagonistic (risk in males and protective in females, P for interaction with sex ⱕ 0.05 for all). The strongest association was with rs422982 (OR (per allele) ⫽ 1.7, P ⫽ 0.03 in males and OR (per allele) ⫽ 0.6, P ⫽ 0.04 in females; P (interaction) ⫽ 0.003) showing a clear gene-dosage effect. Conclusions: These results suggested the involvement of the iron withdrawal component of the immune surveillance machinery in childhood leukemia susceptibility and emphasized the importance of examination of sex effect in association studies.
211-P
IMMUNOREGULATORY GENE POLYMORPHISMS AND CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) SUSCEPTIBILITY. Esma Ucisik-Akkaya, Charronne F. Davis, Thuy N. Do, M. Tevfik Dorak. Genomic Immunoepidemiology, HUMIGEN, Hamilton, NJ, USA. Aim: The immune system is often implicated in the etiology of childhood ALL. Recent reports on associations of early childhood infections with subsequent leukemia development as well as the increased risk in males support a role for immune surveillance. Methods: We examined 145 SNPs from 56 HLA complex genes and 34 SNPs from 10 immune system or cytokine genes (NKG2D, CTLA4, IFNG, IL6, IL10, PKR, LIF, LTF, VEGF and EDN1) in 114 cases of childhood ALL and 388 newborn controls from Wales (UK) using TaqMan assays. Results: Besides previously found multiple independent associations with HLA complex and NKG2D region SNPs, we noted associations with SNPs in other genes that have been shown to modify risk for other cancers. Most of the significant associations were sex-specific: IFNG rs2069727 (OR ⫽ 0.53) and a PKR haplotype (OR ⫽ 0.45) in males only; IL6 rs1800797 (OR ⫽ 2.2), VEGFA rs1570360 (OR ⫽ 2.5) and EDN1 rs5370 (OR ⫽ 0.36) in females only. CTLA4 rs231775, a general cancer susceptibility marker, showed a male-specific risk association (OR ⫽ 2.3, 95% CI ⫽ 1.1 to 4.7, P ⫽ 0.04). Conclusions: In the literature, there seems to be a tendency to interpret results of similar studies in terms of their fit to the popular “dysregulated immune response to delayed infections” hypothesis. We favor a more direct approach and suggest that our results simply implicate immune surveillance in control of childhood leukemia as in other cancers. Similar associations of the same SNPs in other cancers and the sex effect support this assertion. Systematic studies of the genes involved in immune surveillance and unbiased interpretation of results may allow the identification of high-risk children before they develop leukemia.