Four variants in transferrin and HFE genes as potential markers of iron deficiency anaemia risk: an association study in menstruating women

Nutrition & Metabolism

M Pilar Vaquero³  Jose M Soria⁴  Eduardo Arroyo-Pardo¹  Alfonso Buil⁴  Stefania Bertoncini²  Anna Brichs⁴  Ana M Pérez-Granados³  Ana M López-Parra¹  Carlos Baeza-Richer¹  Ruth Blanco-Rojo³ 

[1] Department of Toxicology and Health Legislation, Faculty of Medicine, Complutense University of Madrid, Spain;Department of Biology, University of Pisa, Pisa, Italy;Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Spanish National Research Council (CSIC), Madrid, Spain;Unit of Genomic of Complex Diseases, Institute of Biomedical Research (II-B Sant Pau), Barcelona, Spain

关键词: genetic markers;    association study;    iron intake;    menstruating women;    SNP;    iron deficiency anaemia;    transferrin saturation;    serum transferrin;    HFE gene;    Transferrin gene;   

Others  :  820305
DOI  :  10.1186/1743-7075-8-69

 received in 2011-06-10, accepted in 2011-10-06,  发布年份 2011

【 摘 要 】

Background

Iron deficiency anaemia is a worldwide health problem in which environmental, physiologic and genetic factors play important roles. The associations between iron status biomarkers and single nucleotide polymorphisms (SNPs) known to be related to iron metabolism were studied in menstruating women.

Methods

A group of 270 Caucasian menstruating women, a population group at risk of iron deficiency anaemia, participated in the study. Haematological and biochemical parameters were analysed and 10 selected SNPs were genotyped by minisequencing assay. The associations between genetic and biochemical data were analysed by Bayesian Model Averaging (BMA) test and decision trees. Dietary intake of a representative subgroup of these volunteers (n = 141) was assessed, and the relationship between nutrients and iron biomarkers was also determined by linear regression.

Results

Four variants, two in the transferrin gene (rs3811647, rs1799852) and two in the HFE gene (C282Y, H63D), explain 35% of the genetic variation or heritability of serum transferrin in menstruating women. The minor allele of rs3811647 was associated with higher serum transferrin levels and lower transferrin saturation, while the minor alleles of rs1799852 and the C282Y and H63D mutations of HFE were associated with lower serum transferrin levels. No association between nutrient intake and iron biomarkers was found.

Conclusions

In contrast to dietary intake, these four SNPs are strongly associated with serum transferrin. Carriers of the minor allele of rs3811647 present a reduction in iron transport to tissues, which might indicate higher iron deficiency anaemia risk, although the simultaneous presence of the minor allele of rs1799852 and HFE mutations appear to have compensatory effects. Therefore, it is suggested that these genetic variants might potentially be used as markers of iron deficiency anaemia risk.

【 授权许可】

   
2011 Blanco-Rojo et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]World Health Organization: Worldwide prevalence of anaemia 1993-2005. WHO Global Database on Anaemia. Geneva; 2008.
• [2]World Health Organization: Assessing the iron status of populations. Geneva; 2007.
• [3]Whitfield JB, Treloar S, Zhu G, Powell LW, Martin NG: Relative importance of female-specific and non-female-specific effects on variation in iron stores between women. Br J Haematol 2003, 120:860-866.
• [4]Hentze MW, Muckenthaler MU, Galy B, Camaschella C: Two to tango: regulation of Mammalian iron metabolism. Cell 2010, 142:24-38.
• [5]Swinkels DW, Janssen MC, Bergmans J, Marx JJ: Hereditary hemochromatosis: genetic complexity and new diagnostic approaches. Clin Chem 2006, 52:950-968.
• [6]Andrews NC: Forging a field: the golden age of iron biology. Blood 2008, 112:219-230.
• [7]Beutler E, Gelbart T, Lee P, Trevino R, Fernandez MA, Fairbanks VF: Molecular characterization of a case of atransferrinemia. Blood 2000, 96:4071-4074.
• [8]Iolascon A, De Falco L, Beaumont C: Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis. Haematologica 2009, 94:395-408.
• [9]Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR, Mayo MM, Samuel SM, Strouse JJ, Markianos K, et al.: Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 2008, 40:569-571.
• [10]Sarria B, Navas-Carretero S, Lopez-Parra AM, Perez-Granados AM, Arroyo-Pardo E, Roe MA, Teucher B, Vaquero MP, Fairweather-Tait SJ: The G277S transferrin mutation does not affect iron absorption in iron deficient women. Eur J Nutr 2007, 46:57-60.
• [11]Aisen P: The G277S mutation in transferrin does not disturb function. Br J Haematol 2003, 121:674-675.
• [12]Delanghe J, Verstraelen H, Pynaert I, Debels L, Taes Y, Verhasselt B, De Henauw S, Temmerman M: Human transferrin G277S mutation and iron deficiency in pregnancy. Br J Haematol 2006, 132:249-250.
• [13]Sarria B, López-Parra AM, Navas-Carretero S, Pérez-Granados AM, Baeza C, Arroyo-Pardo E, Vaquero MP: Hepcidin, transferrin (exon 7), and hemochromatosis genotyping suggests that haplotype block analysis is the best strategy for predicting iron deficiency phenotype in women. Nutrition Research 2007, 27:672-678.
• [14]Soranzo N, Spector TD, Mangino M, Kuhnel B, Rendon A, Teumer A, Willenborg C, Wright B, Chen L, Li M, et al.: A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet 2009, 41:1182-1190.
• [15]Ganesh SK, Zakai NA, van Rooij FJ, Soranzo N, Smith AV, Nalls MA, Chen MH, Kottgen A, Glazer NL, Dehghan A, et al.: Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. Nat Genet 2009, 41:1191-1198.
• [16]Chambers JC, Zhang W, Li Y, Sehmi J, Wass MN, Zabaneh D, Hoggart C, Bayele H, McCarthy MI, Peltonen L, et al.: Genome-wide association study identifies variants in TMPRSS6 associated with hemoglobin levels. Nat Genet 2009, 41:1170-1172.
• [17]Benyamin B, Ferreira MA, Willemsen G, Gordon S, Middelberg RP, McEvoy BP, Hottenga JJ, Henders AK, Campbell MJ, Wallace L, et al.: Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat Genet 2009, 41:1173-1175.
• [18]Benyamin B, McRae AF, Zhu G, Gordon S, Henders AK, Palotie A, Peltonen L, Martin NG, Montgomery GW, Whitfield JB, Visscher PM: Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. Am J Hum Genet 2009, 84:60-65.
• [19]Remacha AF, Souto JC, Soria JM, Buil A, Sarda MP, Lathrop M, Blangero J, Almasy L, Fontcuberta J: Genomewide linkage analysis of soluble transferrin receptor plasma levels. Ann Hematol 2006, 85:25-28.
• [20]de Groot CP, van Staveren WA, Dirren H, Hautvast JG: Summary and conclusions of the report on the second data collection period and longitudinal analyses of the SENECA Study. Eur J Clin Nutr 1996, 50(Suppl 2):S123-124.
• [21]Navas-Carretero S, Perez-Granados AM, Schoppen S, Vaquero MP: An oily fish diet increases insulin sensitivity compared to a red meat diet in young iron-deficient women. Br J Nutr 2009, 102:546-553.
• [22]DIAL Alce ingenieria [http://www.alceingenieria.net/nutricion.htm] webcite
• [23]Worwood M: HFE Mutations as risk factors in disease. Best Pract Res Clin Haematol 2002, 15:295-314.
• [24]Bertoncini S, Blanco-Rojo R, Baeza C, Arroyo-Pardo E, Vaquero MP, Lopez-Parra AM: A novel SNaPshot assay to detect genetic mutations related to iron metabolism. Genet Test Mol Biomarkers 2011, 15:173-179.
• [25]Whitfield JB, Cullen LM, Jazwinska EC, Powell LW, Heath AC, Zhu G, Duffy DL, Martin NG: Effects of HFE C282Y and H63D polymorphisms and polygenic background on iron stores in a large community sample of twins. Am J Hum Genet 2000, 66:1246-1258.
• [26]Institute of Medicine: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington DC; 2001.
• [27]Navas-Carretero S, Perez-Granados AM, Schoppen S, Sarria B, Carbajal A, Vaquero MP: Iron status biomarkers in iron deficient women consuming oily fish versus red meat diet. J Physiol Biochem 2009, 65:165-174.
• [28]Blanco-Rojo R, Perez-Granados AM, Toxqui L, Gonzalez-Vizcayno C, Delgado MA, Vaquero MP: Efficacy of a microencapsulated iron pyrophosphate-fortified fruit juice: a randomised, double-blind, placebo-controlled study in Spanish iron-deficient women. Br J Nutr 2011, 105:1652-1659.
• [29]Toxqui L, De Piero A, Courtois V, Bastida S, Sanchez-Muniz FJ, Vaquero MP: Iron deficiency and overload. Implications in oxidative stress and cardiovascular health. Nutr Hosp 2010, 25:350-365.
• [30]McLaren CE, Garner CP, Constantine CC, McLachlan S, Vulpe CD, Snively BM, Gordeuk VR, Nickerson DA, Cook JD, Leiendecker-Foster C, et al.: Genome-wide association study identifies genetic Loci associated with iron deficiency. PLoS One 2011, 6:e17390.
• [31]Zakin MM, Baron B, Guillou F: Regulation of the tissue-specific expression of transferrin gene. Dev Neurosci 2002, 24:222-226.
• [32]Beutler E, Felitti V, Gelbart T, Waalen J: Haematological effects of the C282Y HFE mutation in homozygous and heterozygous states among subjects of northern and southern European ancestry. Br J Haematol 2003, 120:887-893.
• [33]Datz C, Haas T, Rinner H, Sandhofer F, Patsch W, Paulweber B: Heterozygosity for the C282Y mutation in the hemochromatosis gene is associated with increased serum iron, transferrin saturation, and hemoglobin in young women: a protective role against iron deficiency? Clin Chem 1998, 44:2429-2432.
• [34]Rossi E, Olynyk JK, Cullen DJ, Papadopoulos G, Bulsara M, Summerville L, Powell LW: Compound heterozygous hemochromatosis genotype predicts increased iron and erythrocyte indices in women. Clin Chem 2000, 46:162-166.
• [35]Motulsky AG: Genetics of hemochromatosis. N Engl J Med 1979, 301:1291.
• [36]Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA: Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab 2009, 9:217-227.
• [37]Darshan D, Frazer DM, Anderson GJ: Molecular basis of iron-loading disorders. Expert Rev Mol Med 2010, 12:e36.
• [38]Constantine CC, Anderson GJ, Vulpe CD, McLaren CE, Bahlo M, Yeap HL, Gertig DM, Osborne NJ, Bertalli NA, Beckman KB, et al.: A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis. Br J Haematol 2009, 147:140-149.
• [39]Blanco-Rojo R, Pérez-Granados AM, López-Parra AM, Baeza C, Bertoncini S, Arroyo-Pardo E, Vaquero MP: Variants in transferrin gene affect iron metabolism and response to an iron supplemented food in menstruating women. J Nutrigenet Nutrigenomics 2010, 3:72.