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Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 September 2002, Vol. 100, No. 6, pp. 2268-2268 CORRESPONDENCE To the editor: Tumor necrosis factor  promoter polymorphisms and liver abnormalities of homozygotes for the 845G>A (C282Y) hereditary hemochromatosis mutation Although many opinions have been offered regarding the penetrance of hemochromatosis in homozygotes for the 845G>A (C282Y) HFE mutation, a controlled study has shown that very few of these individuals develop clinical disease.1 Clearly, the homozygous state is a necessary but not sufficient condition for the development of the clinical disease. Finding the other factors that may play a significant role is of great importance, particularly if population screening for hemochromatosis is to be carried out. The studies of Fargion et al2 suggesting that polymorphisms in the tumor necrosis factor alpha (TNF-) promoter may be such modifiers of the hemochromatosis phenotype were, therefore, of special interest. In particular, it was suggested that the polymorphism at nucleotide 238 may protect against cirrhosis in homozygotes for hemochromatosis. The population studied by Fargion et al was drawn from patients who had been diagnosed clinically as having hemochromatosis. We have had the opportunity to genotype a large number of patients attending a health appraisal clinic, patients with a median age of 56 who represent the full spectrum of the phenotype associated with the homozygous state for the C282Y mutation. We found that among the 152 homozygotes detected there was a very broad range of putative disease manifestations and ferritin levels.1 If TNF- genotypes had an effect on the hemochromatosis phenotype we might expect to see it in this population. Collagen IV levels are an excellent surrogate for hepatic fibrosis in hemochromatosis,3 and, indeed, we have found that there is a slight excess of individuals with elevated collagen IV levels in homozygotes for the C282Y mutation, even among those without manifest liver disease.1 Figure 1 shows the relationship of serum collagen IV levels to TNF- promoter genotype in homozygotes for the C282Y mutation. Clearly, there is no major difference between these measurements of liver damage in the population that we have studied. Table 1 compares the serum collagen, aspartate transaminase (AST), and ferritin levels in homozygotes for the C282Y mutation with different TNF- promoter genotypes. View larger version (20K): [in this window] [in a new window]   Figure 1. The distribution of plasma collagen IV levels in subjects with the C282Y/C282Y genotype. Plasma collagen IV levels are a surrogate for hepatic fibrosis. The horizontal lines represent the geometric mean of collagen levels. Although the means are slightly lower in the heterozygous subjects, the difference does not approach statistical significance. Neither does a nonparametric analysis (Mann-Whitney) show a statistically significant difference.                                View this table: [in this window] [in a new window]   Table 1. The relationship between TNF- promoter genotype and serum collagen IV, AST, and ferritin levels in C282Y homozygotes TNF- promoter polymorphisms may be a risk factor for liver damage; if so, the effect is so small that it cannot be shown even with a group of more than 100 patients homozygous for the C282Y mutation. There must be other, more powerful, influences on the expression of the HFE mutations. So far our attempt to find such polymorphisms in the coding regions or promoters of HFE, calreticulin, 2-microglobulin, transferrin, transferrin receptor-2, DMT1 (nRamp2), ferroportin, transferrin receptor-1, IRP-1, IRP-2, hepcidin, the ferritin light and heavy chains, and ceruloplasmin have been unsuccessful. The search for genetic and environmental factors that influence the hemochromatosis phenotype must go on. Ernest Beutler and Terri Gelbart Correspondence: Ernest Beutler, The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA 92037; e-mail: beutler{at}scripps.edu. Acknowledgments Supported by grant DK53505-02 from the National Institutes of Health and the Stein Endowment Fund. References 1. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of the 845GA (C282Y) HFE hereditary hemochromatosis mutation. Lancet. 2002;359:211-218[CrossRef][Medline] [Order article via Infotrieve]. 2. Fargion S, Valenti L, Dongiovanni P, et al. Tumor necrosis factor alpha promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis. Blood. 2001;97:3707-3712[Abstract/Free Full Text]. 3. George DK, Ramm GA, Walker NI, Powell LW, Crawford DHG. Elevated serum type IV collagen: a sensitive indicator of the presence of cirrhosis in haemochromatosis. J Hepatol. 1999;31:47-52[Medline] [Order article via Infotrieve]. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. H. Atkinson, K. A. Rockett, G. Morgan, P. A. Bejon, G. Sirugo, M. A. O'Connell, N. Hanchard, D. P. Kwiatkowski, and A. M. Prentice Tumor necrosis factor SNP haplotypes are associated with iron deficiency anemia in West African children Blood, November 15, 2008; 112(10): 4276 - 4283. [Abstract] [Full Text] [PDF] M. J. Wood, L. W. Powell, and G. A. Ramm Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis Blood, May 1, 2008; 111(9): 4456 - 4462. [Abstract] [Full Text] [PDF] P.-A. Krayenbuehl, F. E. Maly, M. Hersberger, P. Wiesli, A. Himmelmann, K. Eid, P. Greminger, W. Vetter, and G. Schulthess Tumor Necrosis Factor-{alpha} -308G>A Allelic Variant Modulates Iron Accumulation in Patients with Hereditary Hemochromatosis Clin. Chem., August 1, 2006; 52(8): 1552 - 1558. [Abstract] [Full Text] [PDF] L Valenti, D Conte, A Piperno, P Dongiovanni, A L Fracanzani, M Fraquelli, A Vergani, C Gianni, L Carmagnola, and S Fargion The mitochondrial superoxide dismutase A16V polymorphism in the cardiomyopathy associated with hereditary haemochromatosis J. Med. Genet., December 1, 2004; 41(12): 946 - 950. [Abstract] [Full Text] [PDF] E. Beutler The HFE Cys282Tyr mutation as a necessary but not sufficient cause of clinical hereditary hemochromatosis Blood, May 1, 2003; 101(9): 3347 - 3350. 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