Environmental, maternal, and reproductive risk factors for childhood acute lymphoblastic leukemia in Egypt: a case-control study.

BACKGROUND: Acute lymphocytic leukemia (ALL) is the most common pediatric cancer. The exact cause is not known in most cases, but past epidemiological research has suggested a number of potential risk factors. This study evaluated associations between environmental and parental factors and the risk for ALL in Egyptian children to gain insight into risk factors in this developing country. METHODS: We conducted a case-control design from May 2009 to February 2012. Cases were recruited from Children's Cancer Hospital, Egypt (CCHE). Healthy controls were randomly selected from the general population to frequency-match the cumulative group of cases by sex, age groups (<1; 1 - 5; >5 - 10; >10 years) and region of residence (Cairo metropolitan region, Nile Delta region (North), and Upper Egypt (South)). Mothers provided answers to an administered questionnaire about their environmental exposures and health history including those of the father. Odds ratios (ORs) and 95 % confidence intervals (CI) were calculated using logistic regression with adjustment for covariates. RESULTS: Two hundred ninety nine ALL cases and 351 population-based controls frequency-matched for age group, gender and location were recruited. The risk of ALL was increased with the mother's use of medications for ovulation induction (ORadj = 2.5, 95 % CI =1.2 -5.1) and to a lesser extend with her age (ORadj = 1.8, 95 % CI = 1.1 - 2.8, for mothers ≥ 30 years old). Delivering the child by Cesarean section, was also associated with increased risk (ORadj = 2.01, 95 % CI =1.24-2.81). CONCLUSIONS: In Egypt, the risk for childhood ALL appears to be associated with older maternal age, and certain maternal reproductive factors.

Evaluating the Role of Birth Weight and Gestational Age on Acute Lymphoblastic Leukemia Risk Among Those of Hispanic Ethnicity.

High birth weight is an established risk factor for childhood acute lymphoblastic leukemia (ALL), especially in children younger than 5 years of age at diagnosis. The goal of this study was to explore the association between being born large for gestational age and the risk for ALL by race/ethnicity to determine if the role of this risk factor differed by these characteristics. The authors compared birth certificate data of 575 children diagnosed with ALL who were younger than 5 years and included in the Texas Cancer Registry, Texas Department of Health, between the years 1995 and 2003 with 11,379 controls matched by birth year. Stratified odds ratios were calculated for risk of ALL by birth weight for gestational age, categorized in 3 groups, small, appropriate, and large for gestational age (SGA, AGA, and LGA, respectively), for each race/ethnicity group. The risk of developing ALL was higher among Hispanics who were LGA (odds ratio [OR] = 1.90, 95% confidence interval [CI]: 1.34-2.68) compared with LGA non-Hispanic whites (OR = 1.27, 95% CI: 0.87-1.86) after adjusting for infant gender, year of birth, maternal age, birth order, and presence of Down syndrome. However, the difference was not statistically significant. These results suggest that there may be differences in the association between higher growth in utero and risk of childhood ALL among Hispanics versus non-Hispanic whites.

Detection rates of trichomonas vaginalis, in different age groups, using real-time polymerase chain reaction.

OBJECTIVE: The study aimed to compare the overall detection rate of Trichomonas vaginalis to Chlamydia trachomatis and Neiserria gonorrhea and report detection rates by age groups. MATERIALS AND METHODS: Real-time polymerase chain reaction was used to detect the presence of T. vaginalis, C. trachomatis, and N. gonorrhea in cervical samples obtained from patients during gynecological examinations. A total of 78,428, 119,451, and 117,494 samples from women age 12 to 75 years were retrospectively analyzed for the presence of T. vaginalis, C. trachomatis, and N. gonorrhea, respectively. T. vaginalis and C. trachomatis detection rates in Florida, New Jersey, and Texas were calculated in different age groups. RESULTS: The overall detection rate was 4.3% for T. vaginalis, 3.8% for C. trachomatis, and 0.6% for N. gonorrhea. The overall detection rate of T. vaginalis in Florida was 4.7% (n = 22,504), in New Jersey was 3.6% (n = 22,249), and in Texas was 4.5% (n = 33,675). Calculation of infection rates with T. vaginalis revealed differences between selected age groups with the highest detection rates in all 3 states found in age group 46 to 55 years (6.2%), which was higher than the overall detection rates in other age groups (p < .05 for all states). For C. trachomatis, the highest detection rate was found in age group 12 to 25 years (7.3%). CONCLUSIONS: The overall infection rates of T. vaginalis were higher compared with those of C. trachomatis and N. gonorrhea. Detection rates of T. vaginalis were found to be highest among women age 46 to 55 years and may be due to T. vaginalis infiltrating the subepithelial glands and being detected only during hormone-induced or antibiotic-induced changes in the vaginal flora.

An intronic polymorphism of IRF4 gene influences gene transcription in vitro and shows a risk association with childhood acute lymphoblastic leukemia in males.

The interferon regulatory factor (IRF) family of DNA-binding proteins regulates expression of interferon-inducible genes with roles in the immune response and carcinogenesis. IRF4 is involved in the differentiation of B and T cells and is overexpressed in B-cell malignancies as a result of c-REL (NF-kappaB) hyperactivation. IRF4 polymorphisms are associated with susceptibility to chronic lymphoid leukemia (CLL) and non-Hodgkin lymphoma (NHL). We examined 13 IRF4 SNPs in 114 cases of childhood acute lymphoblastic leukemia (ALL) and 388 newborn controls from Wales (U.K.) using TaqMan assays. IRF4 intron 4 SNP rs12203592 showed a male-specific risk association (OR=4.4, 95% CI=1.5 to 12.6, P=0.007). Functional consequences of the C>T substitution at this SNP were assessed by cell-based reporter assays using three different cell lines. We found a repressive effect of the rs12203592 wildtype allele C on IRF4 promoter activity (P<0.001) but no repression by the variant allele in any cell line tested. Thus, homozygosity for the rs12203592 variant allele would result in increased IRF4 expression. This increase would be compounded by high levels of NF-kappaB activity in males due to the absence of estrogen. IRF4 differs from other IRFs in its anti-interferon activity which interferes with immune surveillance. We propose that a detailed study of IRF4 can provide information on the mechanism of the sex effect and the role of immune surveillance in childhood ALL development.

Examination of genetic polymorphisms in newborns for signatures of sex-specific prenatal selection.

Success rate in human pregnancies is believed to be very low and sex-specific mechanisms may operate in prenatal loss. Assuming a sex-differential in prenatal loss exists, we examined genetic markers in biologically plausible targets in the HLA complex, other immune system-related and iron-regulatory genes in 388 healthy newborns from Wales (UK) using one sex as a control group for the other. Genotyping of 333 single nucleotide polymorphisms (SNPs) from 107 genes was achieved mainly by TaqMan assays. Twenty-two of autosomal SNPs showed frequency differences between 187 male and 201 female newborns either individually or as part of a haplotype. Of these, six markers (RXRB rs2076310, HLA complex haplotype HLA-DQA1 rs1142316-HLA-DRA rs7192-HSPA1B rs1061581, HIST1H1T rs198844, IFNG rs2069727, NKG2D rs10772266 and IRF4 heterozygosity) showed statistically robust differences between male and female newborns and multivariable modeling confirmed their independence. There were fewer males homozygote for combined wildtype genotypes of LIF rs929271, TP53 rs1042522 and MDM2 rs2279744 compared with females [OR = 0.3, 95% confidence interval (CI) = 0.1-0.8; P < 0.01] although these SNPs did not show any association individually. It is unlikely that SNPs have clinical utility as single markers in any trait with complex etiology but polygenic predictive models remain a possibility. If their validity is confirmed in larger studies of different populations and functional mechanisms of these preliminary associations are elucidated, these markers from the HLA complex, NKG2D region and cytokines may cumulatively have sufficient predictive value for susceptibility to prenatal selection in each sex.

An extensive analysis of the hereditary hemochromatosis gene HFE and neighboring histone genes: associations with childhood leukemia.

The most common mutation of the HFE gene C282Y has shown a risk association with childhood acute lymphoblastic leukemia (ALL) in Welsh and Scottish case-control studies. This finding has not been replicated outside Britain. Here, we present a thorough analysis of the HFE gene in a panel of HLA homozygous reference cell lines and in the original population sample from South Wales (117 childhood ALL cases and 414 newborn controls). The 21 of 24 variants analyzed were from the HFE gene region extending 52 kb from the histone gene HIST1H1C to HIST1H1T. We identified the single-nucleotide polymorphism (SNP) rs807212 as a tagging SNP for the most common HFE region haplotype, which contains wild-type alleles of all HFE variants examined. This intergenic SNP rs807212 yielded a strong male-specific protective association (per allele OR = 0.38, 95% CI = 0.22-0.64, P (trend) = 0.0002; P = 0.48 in females), which accounted for the original C282Y risk association. In the HapMap project data, rs807212 was in strong linkage disequilibrium with 25 other SNPs spanning 151 kb around HFE. Minor alleles of these 26 SNPs characterized the most common haplotype for the HFE region, which lacked all disease-associated HFE variants. The HapMap data suggested positive selection in this region even in populations where the HFE C282Y mutation is absent. These results have implications for the sex-specific associations observed in this region and suggest the inclusion of rs807212 in future studies of the HFE gene and the extended HLA class I region.

Ethnic and geographical differences in HLA associations with the outcome of hepatitis C virus infection.

BACKGROUND: The association of human leukocyte antigen (HLA) genes with the outcome of hepatitis C virus (HCV) infection may be modified by ethnic and geographical differences. RESULTS: HLA-A, -C, -DRB1 and -DQB1 genotyping were performed in a Midwestern American cohort of 105 HCV infected subjects among which 49 cleared HCV infection and 56 had persistent viral infection. A new protective association of HLA-Cw*05 to HCV infection of all ethnic populations was identified (OR = 0.12, 95% CI = 0.01-0.97, P = 0.03). It was surprising that HLA-A*02 (P for interaction = 0.02) and HLA-DRB1*12 (P for interaction = 0.05) showed statistical interaction with race indicating opposite associations in Caucasians (OR = 2.74 for A*02 and 2.15 for DRB1*12) and non-Caucasians (OR = 0.41 for A*02 and 0.15 for DRB1*12). In addition, HLA-DRB1*01 (OR = 0.26), DQB1*05 (OR = 0.23) and the haplotype DRB1*01-DQB1*05 (OR = 0.19) showed strong associations with viral clearance in Caucasians. The protective associations of A*03 (OR = 0.20) and DQB1*03 (OR = 0.20) were exclusive to non-Caucasians. In contrast, DQB1*02 (OR = 2.56, 95% CI = 1.15-7.71, P = 0.02) and the haplotype DRB1*07-DQB1*02 (OR = 5.25, 95% CI = 1.04-26.6, P = 0.03) were risk markers in Caucasians. CONCLUSION: The associations of HLA-A*02 and HLA-DRB1*12 with HCV infection are opposite with different races. HLA-A*03, Cw*05, DRB1*01, DQB1*03 and DQB1*05 are associated with viral clearance while HLA-DRB1*07 and DQB1*02 are risk markers for viral persistence of HCV infection in Midwestern Americans. These results reveal ethnically and geographically different distribution of HLA-genes which are associated with the outcome of HCV infection.

Hereditary hemochromatosis gene (HFE) variants are associated with birth weight and childhood leukemia risk.

BACKGROUND: Our original studies reported an association between the iron-metabolism gene HFE and risk of childhood acute lymphoblastic leukemia (ALL), and a birth weight association in ALL. Through its effect on cell proliferation, iron is involved in both fetal development and cancer. We hypothesize that HFE links higher infant birth weight with leukemia risk and that maternal HFE genotype modifies this association. PROCEDURE: Nine hundred ninety-five infants and their mothers from the North Cumbria Community Genetics Project, and 163 incident childhood ALL cases from the Newcastle Haematology Biobank were genotyped for HFE, HAMP, TFRC variants and 21 genomic control loci. Cord blood iron levels were measured in 217 control infants. RESULTS: Three HFE variants showed correlations with birth weight with a gene-dosage relationship in males (gender effect). The association was stronger in homozygotes for TFRC S142G and when the mother was positive for any HFE variant (maternal effect). The genotypes expected to increase fetal iron levels correlated with birth weight in males and their association with ALL was stronger in females who, we postulate, could not offset iron excess by increasing their weight. CONCLUSIONS: Certain materno-fetal genotype combinations that increase fetal iron exposure showed associations with higher birth weight in males and somewhat higher ALL risk in females. Gender-specific use of iron during fetal growth may lead to this dichotomy in birth weight change. Only the materno-fetal genotype combinations that increase iron levels most extremely correlated with birth weight and ALL risk in males.

Sex-specific incidence and temporal trends in solid tumours in young people from Northern England, 1968-2005.

BACKGROUND: This study examined sex-specific patterns and temporal trends in the incidence of solid tumours in the Northern Region of England from 1968 to 2005. This updates earlier analyses from the region where sex was not considered in depth. Sex-specific analyses were carried out to determine whether sex differences might provide clues to aetiology. METHODS: Details of 3576 cases, aged 0-24 years, were obtained from a specialist population-based cancer registry. There were 1843 males (886 aged 0-14 years and 957 aged 15-24 years) and 1733 females (791 aged 0-14 years and 942 aged 15-24 years). Age-standardized incidence rates (per million population) were calculated. Linear regression was used to analyze temporal trends in incidence and annual percentage changes were estimated. Analyses were stratified by sex and by age-group. RESULTS: There were marked differences in incidence patterns and trends between males and females and also between age-groups. For males central nervous system (CNS) tumours formed the largest proportion of under-15 cases and germ cell tumours was the largest group in the 15-24's, whilst for females CNS tumours dominated in the under-15's and carcinomas in the older group. For 0-14 year olds there were male-specific increases in the incidence of rhabdomyosarcoma (2.4% per annum; 95% CI: 0.2%-4.5%) and non-melanotic skin cancer (9.6%; 95% CI: 0.0%-19.2%) and female-specific increases for sympathetic nervous system tumours (2.2%; 95% CI: 0.4%-3.9%), gonadal germ cell tumours (8.6%; 95% CI: 4.3%-12.9%) and non-gonadal germ cell tumours (5.4%; 95% CI: 2.8%-7.9%). For 15-24 year olds, there were male-specific increases in gonadal germ cell tumours (1.9%; 95% CI: 0.3%-3.4%), non-gonadal germ cell tumours (4.4%; 95% CI: 1.1%-7.7%) and non-melanotic skin cancer (4.7%; 95% CI: 0.5%-8.9%) and female-specific increases for osteosarcoma (3.5%; 95% CI: 0.5%-6.5%), thyroid cancer (2.8%; 95% CI: 0.1%-5.6%) and melanoma (4.6%; 95% CI: 2.2%-7.1%). CONCLUSION: This study has highlighted notable differences between the sexes in incidence patterns and trends for solid tumours. Some of these sex-specific differences could have been obscured if males and females had been analysed together. Furthermore, they suggest aetiological differences or differential susceptibility to environmental factors between males and females.

Role of natural killer cells and killer immunoglobulin-like receptor polymorphisms: association of HLA and KIRs.

Natural killer cells play an important role in innate immunity. They act against infected and transformed cells as part of the immune surveillance process. Their interactions with the human leukocyte antigens (HLAs) create a situation where they may act against donor hematopoietic cells following stem cell transplantation. Both killer immunoglobulin-like receptors (KIRs) and HLA types of donor and recipient are relevant in the generation of graft-vs-leukemia or graft-vs-host reactions. This chapter reviews the current knowledge on the involvement of natural killer cells in the events following hematopoietic stem cell transplantation, the structure of the genetic complex encoding the KIRs and provides a PCR-based genotyping scheme for KIR genes.

Cohort- and time-specific associations of CTLA4 genotypes with HIV-1 disease progression.

BACKGROUND: CTLA4 in the chromosome 2q33 region encodes cytotoxic T-lymphocyte (CTL) associated antigen 4, which downregulates CTL responses. We examined the relationships between common CTLA4 variants and several outcomes of HIV-1 infection in adults and adolescents. METHODS: We studied 765 HIV-1-infected persons: 558 Caucasian seroconverters from three cohorts (MACS, ACS, and DCG) and 207 infected adolescents (mostly female) from another cohort (REACH) of mixed ethnicity. Single nucleotide polymorphisms in CTLA4 promoter (-1147C/T, -658C/T, -318C/T), coding sequence (49A/G) and the 3' untranslated region (CT60A/G) were resolved by PCR-based techniques. Repeated measures and survival analyses were used to test allelic and haplotypic associations with HIV-1 viral load (VL) and time to AIDS, respectively. RESULTS: Individuals carrying -318T or the (-1147) T-(-318) T haplotype had elevated HIV-1 VL in MACS and REACH but reduced VL in DCG and ACS participants. Time-dependent associations of CTLA4-318T with VL were observed in MACS and REACH (P = 0.03-0.09). In Cox regression models adjusted for age and established contributory markers in CCR5 and HLA class I genes, CTLA4-318T was associated with rapid progression to AIDS in MACS (relative hazard 1.69; 95% confidence interval, 1.15-2.49; P < 0.01) as opposed to a non-significant slower disease progression in ACS and no appreciable association in DCG. CONCLUSIONS: Association of CTLA4 genotypes with clinical and virological outcomes following HIV-1 infection appeared to vary with time and among the cohorts. Further analyses in conjunction with other biologically and positionally related genes, such as CD28 and ICOS, may help explain the disparate findings.

Positive and negative associations of human leukocyte antigen variants with the onset and prognosis of adult glioblastoma multiforme.

Associations of genetic factors with malignant gliomas have been modest. We examined the relationships of human leukocyte antigen (HLA) and related polymorphisms to glioblastoma multiforme in adult Caucasians (non-Hispanic Whites) from the San Francisco Bay area. For 155 glioblastoma multiforme patients and 157 control subjects closely matched by ethnicity, age, and gender, PCR-based techniques resolved alleles at HLA-A, -B, -C, and -DRB1 loci along with short tandem repeat polymorphisms of MICA exon 5 and TNFb. By multivariable logistic regression, B*13 and the B*07-Cw*07 haplotype were positively associated with glioblastoma multiforme (P=0.01 and <0.001, respectively), whereas Cw*01 was the only variant showing a negative association (P=0.05). Among glioblastoma multiforme patients, progression to death after diagnosis was slower in those with A*32 (relative hazard, 0.45; P<0.01) and faster in those with B*55 (relative hazard, 2.27; P<0.01). Thus, both the occurrence and the prognosis of glioblastoma multiforme could be associated with specific but different HLA genotypes. B*07 and the B*07-Cw*07 haplotype are much more common in Caucasians than other ethnic groups in the U.S., which may partially explain the higher incidence of glioblastoma multiforme in Caucasians.

Transmission of HIV-1 and HLA-B allele-sharing within serodiscordant heterosexual Zambian couples.

Factors that might increase risk of HIV-1 transmission include age, sex, and amount of HIV-1 RNA in plasma, but findings for HLA allele-sharing are not in agreement. We tested the hypothesis that allele sharing at HLA loci is associated with increased risk of transmission of HIV-1 infection in cohabiting heterosexual Zambian couples. We studied 125 initially serodiscordant partners with sequence-confirmed interpartner HIV-1 transmission and 104 couples who were persistently serodiscordant, and we analysed relations with molecularly typed HLA-A, B, and C alleles by survival techniques. After adjustment for other genetic and non-genetic risk factors seen with heterosexual transmission of HIV-1 in this cohort, sharing of HLA-B alleles was independently associated with accelerated intracouple transmission (relative hazard 2.23, 95% CI 1.52-3.26, p<0.0001). Selective pressure by HLA-B alleles on transmitted viruses accords with current understanding of the effect of B locus polymorphism in HIV-1 and perhaps other infections.

Genetic markers in a multi-ethnic sample for childhood acute lymphoblastic leukemia risk.

Genome-wide association studies have identified multiple risk loci for childhood acute lymphoblastic leukemia (ALL), but mostly in European/White populations, despite Hispanics having a greater risk. We re-examined single nucleotide polymorphisms (SNPs) of known associations with childhood ALL and known human leukocyte antigen (HLA) region lymphoma risk markers in a multi-ethnic population. Significant associations were found in two ARID5B variants (rs7089424 and rs10821936). We replicated a strong risk association in non-Hispanic White males with rs2395185, a protective marker for lymphoma. Another HLA region marker, rs2647012, showed a risk association among Hispanics only, while a strong protective association was found with rs1048456, a follicular lymphoma risk marker. Our study validated this new case-control sample by confirming genetic markers associated with childhood ALL, and yielded new associations with lymphoma markers. Despite positive results, our study did not provide any clues as to why Hispanics have a higher susceptibility to childhood leukemia, suggesting that environmental factors may have a strong contribution.

C-C chemokine receptor 2 and C-C chemokine receptor 5 genotypes in patients treated for chronic hepatitis C virus infection.

We explored the influence of the major CCR5 promoter or coding region variants as haplotypes and genotypes in a cohort of 250 chronically infected HCV patients receiving combined interferon/ ribavirin therapy. No haplotype, including the D32-bearing haplotype (G*2) reportedly associated in homozygotes with high HCV viral load (VL), showed a similar effect. Patients with genotype C/G*2 showed slightly lower median VL (p = 0.05). Neither the G*2 haplotype nor the C/G*2 genotype influenced viral dynamics during the initial 12 wk of treatment (p = 0.53). The genotype E/E was more frequent among sustained responders (15.5%) than non-responders (7.8%), and VL declined further among E/E homozygotes during the initial 12 wk of treatment, particularly those with HCV genotype 1 (p = 0.016). Differential receptor expression due to E/E homozygosity in HCV infection remains to be confirmed.

Quantitative detection of T-cell activation markers by real-time PCR in renal transplant rejection and correlation with histopathologic evaluation.

BACKGROUND: The quest for noninvasive methods to diagnose rejection in solid-organ transplants has been rejuvenated by recent observations that specific cytotoxic T-cell markers are up-regulated during rejection. METHODS: We developed a one-step real-time polymerase chain reaction (PCR) method allowing reliable detection of the expression of several T-cell genes within a relatively short period of time. The assay is highly sensitive and reproducible with a wide dynamic range allowing accurate quantification of target mRNA in as little as 3 pg total RNA. The utility of this assay in detecting renal allograft rejection was evaluated. Peripheral blood mononuclear cells were collected from 27 patients undergoing kidney allograft biopsies for renal dysfunction after transplantation. Expression of the T-cell activation markers, granzyme B, perforin, and HLA-DRA, was quantified and correlated to the histopathologic changes in the renal biopsies. RESULTS: In cases with allograft rejection (n=8), peripheral lymphocyte expression was increased for granzyme B (P <0.001) and perforin (P <0.08) compared with cases without rejection (n=19). Granzyme B mRNA up-regulation showed the highest specificity for detecting rejection (95%). Moreover, HLA-DRA mRNA was significantly up-regulated (P <0.0016) and had the highest sensitivity (88%) detecting rejection. The up-regulation of both granzyme B and HLA-DRA was most specific in detecting rejection, P<0.001. CONCLUSIONS: These data demonstrate that a rapid test of target gene up-regulation using real-time PCR can be used as an aid in the diagnosis of kidney allograft rejection. This is also the first report on the possible utility of HLA-DRA mRNA up-regulation as a marker for kidney transplant rejection.

A male-specific increase in the HLA-DRB4 (DR53) frequency in high-risk and relapsed childhood ALL.

Previous studies reported significant HLA-DR associations with various leukemias one of which is with HLA-DRB4 (DR53) family in male patients with childhood ALL. We have HLA-DR-typed 212 high-risk or relapsed patients with childhood (n=114) and adult (n=98) ALL and a total of 250 healthy controls (118 children, 132 adult) by PCR-SSP analysis. The members of the HLA-DRB3 (DR52) family were underrepresented in patients most significantly for HLA-DRB1*12 (P=0.0007) and HLA-DRB1*13 (P=0.0001). In childhood ALL, the protective effect of DRB3 was evident in homozygous form (P=0.001). The DRB4 marker frequency was increased in males with childhood ALL (67.4%) compared to age- and sex-matched controls (42.1%, P=0.003) and female patients (35.7%, P=0.004). Besides being a general marker for increased susceptibility to childhood ALL in males, HLA-DRB4 is over-represented in high-risk patients. These results further suggest that the HLA system is one of the components of genetic susceptibility to leukemia but mainly in childhood and in boys only.

Hemochromatosis gene in leukemia and lymphoma.

The gene causing hereditary hemochromatosis (HH), HFE is an HLA class I-like gene with no known immunological function but indirectly related to the immune functions because of its role in iron transport. It is located 6.5 Mb telomeric to HLA-A. The most common mutation of HFE, C282Y, has a Celtic origin and most patients with HH are homozygous for it in Northern European populations. While there is an enormously increased risk for hepatocellular cancer in hemochromatosis that is attributed to the toxic effects of iron, the risk for extra-hepatic cancers is also increased slightly. Recent studies have found genetic associations between several cancers and C282Y but only in the presence of a particular allele of the transferrin receptor gene. This suggests that the increased cancer risk is more likely due to the effects of iron. In childhood acute lymphoblastic leukemia (ALL), however, there is a strong association of C282Y with a gender effect in two different Celtic populations. This association does not require homozygosity for C282Y or an interaction with the transferrin receptor gene, and is male-specific. The other HFE mutation H63D does not confer increased risk to childhood ALL. Acute myeloblastic leukemia and Hodgkin's disease in adults do not have an association with HFE. Its male-specificity, occurrence in childhood and the lack of a gene-dosage effect suggest that the C282Y association in childhood ALL may reflect the involvement of another HLA-linked gene in leukemia susceptibility.

Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes.

Hereditary hemochromatosis (HFE) variants correlating with body iron levels have shown associations with cancer risk, including childhood acute lymphoblastic leukemia (ALL). Using a multi-ethnic sample of cases and controls from Houston, TX, we examined two HFE variants (rs1800562 and rs1799945), one transferrin receptor gene (TFRC) variant (rs3817672) and three additional iron regulatory gene (IRG) variants (SLC11A2 rs422982; TMPRSS6 rs855791 and rs733655) for their associations with childhood ALL. Being positive for either of the HFE variants yielded a modestly elevated odds ratio (OR) for childhood ALL risk in males (1.40, 95% CI=0.83-2.35), which increased to 2.96 (95% CI=1.29-6.80) in the presence of a particular TFRC genotype for rs3817672 (P interaction=0.04). The TFRC genotype also showed an ethnicity-specific association, with increased risk observed in non-Hispanic Whites (OR=2.54, 95% CI=1.05-6.12; P interaction with ethnicity=0.02). The three additional IRG SNPs all showed individual risk associations with childhood ALL in males (OR=1.52-2.60). A polygenic model based on the number of variant alleles in five IRG SNPs revealed a linear increase in risk among males with the increasing number of variants possessed (OR=2.0 per incremental change, 95% CI=1.29-3.12; P=0.002). Our results replicated previous HFE risk associations with childhood ALL in a US population and demonstrated novel associations for IRG SNPs, thereby strengthening the hypothesis that iron excess mediated by genetic variants contributes to childhood ALL risk.