Lack of Association between Single Nucleotide Polymorphism rs3811647 in the TF Gene and Iron Status in Patients with Iron Deficiency and Control Subjects

Abstract 4257

Iron in the plasma is bound to transferrin. The total iron binding capacity (TIBC) represents the maximum amount of iron that can be bound and is directly related to transferrin concentration. TIBC and serum transferrin concentration are increased in iron deficiency and decreased in iron overload. Recently, an association was reported between single nucleotide polymorphisms (SNPs) in the transferrin gene, TF, on chromosome 3q22.1, and serum transferrin levels (Benyamin et al. Am J Hum Genet. 2009;84:60-65). In the current study, we investigated whether the association between SNP rs3811647 in TF and transferrin levels (assessed by measurement of TIBC) is attributable to an effect on regulation of body iron status. The Personalized Medicine Research Project (PMRP) is the largest population-based biobank in the US containing genetic, phenotypic and environmental information on approximately 20,000 people. PMRP is part of the NHGRI-funded eMERGE (www.gwas.net) network. Previously, genotyping was performed on selected PMRP samples with the Illumina Human660W-Quad BeadChip platform. Eligible participants in the current study were 491 white men age ≥ 25 y and 747 white women ≥ 50 y with serum ferritin (SF) values collected between 1985 and 2010. Exclusion criteria included a diagnosis of celiac disease and previous phlebotomy treatment for hemochromatosis. Using TIBC as a marker of serum transferrin for eligible participants having multiple measurements, mean TIBC and median serum ferritin were considered in analyses. Subsets of participants included cases of iron deficiency with multiple measurements of SF ≤ 12 μg/L and iron-replete controls (all measurements of SF > 100 μg/L in men, all SF > 50 μg/L in women). Regression analysis was used to examine the association between outcomes (case-control status, natural log of serum ferritin, TIBC) and each of 54 SNPs, adjusted for gender. These SNPS included three in iron genes (rs3811647 in TF, rs1800562 in HFE, and rs2302591 in FLVCR2) and were selected for analysis on the basis of a GWAS of iron-related measures conducted in a separate study of iron deficient cases and iron-replete controls identified in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Statistical significance was defined as a SNP showing a p-value for association less than 0.001; the threshold is based on a nominal alpha of 0.05 with Bonferroni multiple test correction for the total number of SNPs analyzed. Genotypes were coded as 0, 1, or 2, indicating the number of copies of the less frequent of the two alleles in the genotype. Values for mean TIBC were analyzed for 1175 individuals (726 women, 449 men); median SF was analyzed for 1143 participants (693 women, 450 men). In the subset analyses, there were 258 cases with iron deficiency and 505 controls. The strongest statistical evidence for association with TIBC was found for SNP rs3811647 in the TF gene (observed p-value = 6.05 × 10^-6, adjusted for gender). The minor allele frequency for SNP rs3811647 was 0.34. The regression slope parameter was 14.5, indicating that increasing copies of the minor allele were associated with increasing levels of TIBC. In contrast, there was no significant association with SF (observed p=0.22) or case vs. control status (odds ratio 1.26, observed p=0.21), adjusted for gender. For the C282Y mutation in the HFE gene, increasing copies of the minor allele were associated with decreasing levels of TIBC (observed p-value = 0.002, adjusted for gender). The fact that SNP rs3811647 in the TF gene was associated with TIBC levels but showed no significant association with either serum ferritin or the presence of iron deficiency does not support a role for the SNP in regulation of body iron status. Thus, the SNP may affect TIBC independently of iron status. Elevation of transferrin levels could help withhold iron from microorganisms, conferring protection from infection. Use of TIBC as an index of iron deficiency may be confounded by the existence in the population of the minor allele in the rs3811647 genotype, resulting in elevation of TIBC without a corresponding decrease in body storage iron.