title: Diagnostic utility of HFE variants in Spanish patients: association with HLA alleles and role in susceptibility to acute lymphoblastic leukemia.
abstract: Two single nucleotide polymorphisms (SNPs) in the Human Hemochromatosis (HFE) gene, C282Y and H63D, are the major variants associated to altered iron status and it is well known that these mutations are in linkage disequilibrium with certain Human Leukocyte Antigen (HLA)-A alleles. In addition, the C282Y SNP has been previously suggested to confer susceptibility to acute lymphoblastic leukemia (ALL). We have aimed to assess the diagnosis utility of these polymorphisms in a population of Spanish subjects with suspicion of hereditary iron overload and to evaluate the effect of their associations with HLA-A alleles on the susceptibility to ALL. Both the 63DD [OR=4.31 (1.7-11.2)] and 282YY (p for trend=0.02) genotypes were more frequently found among subjects with suspicion of iron overload than among controls. 282YY carriers displayed significantly higher transferrin saturation index (TSI) values (p<0.001) as well as serum iron (p=0.01) and ferritin (p=0.01) levels. In addition, transferrin levels were lower in these subjects (p=0.01). Likewise, patients who were carriers of the compound heterozygous diplotype (282CY/63HD) showed significantly higher TSI and serum iron and ferritin concentrations. The H63D SNP did not significantly affect the analytical parameters measured. All 282YY carriers and 69.2% of compound heterozygotes showed an altered biochemical index. The frequencies of the HFE SNPs in ALL pediatric patients were lower than those found in controls, whereas the HLA-A*24 allele was significantly overrepresented in the patients group [OR=3.76 (1.9-7.3)]. No HFE-HLA-A associations were found to modulate the ALL risk. These results suggest that it may be useful to test for both HFE H63D and C282Y polymorphisms in patients with iron overload, as opposed to just genotyping for the C282Y SNP, which is customary in some healthcare centers. These HFE variants and their associations with HLA-A alleles were not observed to be relevant for the susceptibility to ALL in our population.
authors.affiliation: Genetics Unit, Division of Pharmacology, University of Extremadura, Badajoz, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodríguez-López
authors.forename: Marisol
authors.initials: M
authors.lastname: Donoso
authors.forename: María
authors.initials: M
authors.lastname: Fernández-Cavada
authors.forename: Luz María
authors.initials: LM
authors.lastname: González
authors.forename: Aranza
authors.initials: A
authors.lastname: Margallo
authors.forename: César
authors.initials: C
authors.lastname: Corral
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gallego
authors.forename: María Teresa
authors.initials: MT
authors.lastname: García de Cáceres
authors.forename: Trinidad
authors.initials: T
authors.lastname: Herrera
authors.forename: Cristina
authors.initials: C
authors.lastname: González
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Vagace
authors.forename: Guillermo
authors.initials: G
authors.lastname: Gervasini
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000235:genetics*; D006432:Hemochromatosis / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007223:Infant; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D013030:Spain
chemical_list: C103673:HFE protein, human; D015234:HLA-A Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins