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Iron stores and HFE genotypes are not related to increased risk of first-time myocardial infarction: a prospective nested case-referent study.
Ekblom, K, Marklund, SL, Jansson, JH, Hallmans, G, Weinehall, L, Hultdin, J
International journal of cardiology. 2011;(2):169-72
Abstract
OBJECTIVES Our objectives were to study the relationship between iron stores, HFE genotypes and the risk for first-ever myocardial infarction. METHODS First-ever myocardial infarction cases (n=618) and double matched referents from the Northern Sweden Health and Disease Cohort Study were studied in a prospective nested case-referent setting. Plasma iron, total iron binding capacity, transferrin iron saturation and ferritin were analyzed, as well as several confounders. HFE C282Y and H63D genotypes were determined. RESULTS There was an inverse risk association for myocardial infarction in the highest quartiles of iron (OR 0.68; 95% CI 0.48-0.96) and transferrin iron saturation (OR 0.62; 95% CI 0.42-0.89) in men. This association, however, was lost after adjusting for C-reactive protein. Women homozygous for H63D had a higher risk for myocardial infarction. CONCLUSIONS No risk association between high iron stores and first-ever myocardial infarction was found. The higher risk in female H63D homozygotes is probably not related to iron metabolism.
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2.
HFE genotypes in patients with chronic pancreatitis and pancreatic adenocarcinoma.
Hucl, T, Kylanpää-Bäck, ML, Witt, H, Künzli, B, Lempinen, M, Schneider, A, Kemppainen, E, Löhr, M, Friess, H, Ockenga, J, et al
Genetics in medicine : official journal of the American College of Medical Genetics. 2007;(7):479-83
Abstract
PURPOSE The homozygous p.C282Y variant of the HFE gene is a major risk factor for hereditary hemochromatosis, a disorder of iron metabolism resulting in progressive iron accumulation in a variety of organs including the pancreas. Heterozygosity of p.C282Y and p.H63D may increase susceptibility to chronic liver and pancreatic disease. This study determines the frequencies of p.C282Y and p.H63D alterations in patients with chronic pancreatitis and pancreatic adenocarcinoma. METHODS In total, 958 patients (349 with alcoholic pancreatitis, 343 with idiopathic pancreatitis, 64 with familial chronic pancreatitis, 34 with acute pancreatitis, and 168 with pancreatic adenocarcinoma) were enrolled and compared with 681 healthy and 100 alcoholic controls. Furthermore, 45 parent-offspring trios were included for segregation analysis. Genotyping of p.C282Y and p.H63D was performed by restriction fragment length polymorphism or melting curve analyses. RESULTS No significant differences were found in heterozygosity for p.C282Y and p.H63D when patients with alcoholic (8.0/21.5%), idiopathic (7.3/24.5%), or familial (9.8/23.0%) pancreatitis, or pancreatic adenocarcinoma (5.4/28.6%) were compared with healthy (6.2/24.8%) and alcoholic (7.0/25.0%) controls. Neither genotype was associated with the presence of secondary diabetes mellitus in patients with chronic pancreatitis. CONCLUSION Although hemochromatosis is associated with pancreatic pathology, the p.C282Y and p.H63D variants do not play a significant role in the pathogenesis of chronic pancreatitis or pancreatic adenocarcinoma.
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3.
Structure-based prediction of MHC-peptide association: algorithm comparison and application to cancer vaccine design.
Schiewe, AJ, Haworth, IS
Journal of molecular graphics & modelling. 2007;(3):667-75
Abstract
Peptide vaccination for cancer immunotherapy requires identification of peptide epitopes derived from antigenic proteins associated with the tumor. Such peptides can bind to MHC proteins (MHC molecules) on the tumor-cell surface, with the potential to initiate a host immune response against the tumor. Computer prediction of peptide epitopes can be based on known motifs for peptide sequences that bind to a certain MHC molecule, on algorithms using experimental data as a training set, or on structure-based approaches. We have developed an algorithm, which we refer to as PePSSI, for flexible structural prediction of peptide binding to MHC molecules. Here, we have applied this algorithm to identify peptide epitopes (of nine amino acids, the common length) from the sequence of the cancer-testis antigen KU-CT-1, based on the potential of these peptides to bind to the human MHC molecule HLA-A2. We compared the PePSSI predictions with those of other algorithms and found that several peptides predicted to be strong HLA-A2 binders by PePSSI were similarly predicted by another structure-based algorithm, PREDEP. The results show how structure-based prediction can identify potential peptide epitopes without known binding motifs and suggest that side chain orientation in binding peptides may be obtained using PePSSI.
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4.
Perceptions and attitudes about HFE genotyping among college-age adults.
Hicken, BL, Foshee, A, Tucker, DC
Journal of genetic counseling. 2005;(6):465-72
Abstract
PURPOSE Examine young adults' attitudes about HFE genotyping. METHODS 121 college students read about hemochromatosis, transferrin saturation measurement (iron test), and HFE genotyping. Interest in testing and knowledge and attitudes about genetic testing were assessed. Participants were randomly assigned to predict either their response to a positive HFE genotype (genotype group) or a positive iron test (phenotype group). RESULTS 71% preferred the iron test, but most would undergo either test. Learning risk and early detection/prevention were the most commonly perceived benefits; limited information about health and negative emotional consequences were the most commonly perceived disadvantages. The genotype and phenotype groups did not differ in expected worry, perceived severity, perceived risk, and preventability of organ damage. After reading the description provided, participants answered 78% of knowledge questions correctly. CONCLUSIONS Young adults view HFE genotyping positively and report few disadvantages, but prefer the iron test for its information about current health. They appear to be receptive to public health screening for hemochromatosis.
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5.
Genetic hemochromatosis update.
Brissot, P, Le Lan, C, Lorho, R, Gaboriau, F, Lescoat, G, Loréal, O
Acta gastro-enterologica Belgica. 2005;(1):33-7
Abstract
Hereditary Hemochromatosis is an autosomal recessive disease, characterized by chronic iron overload. It is mainly due to mutations of the HFE-1 gene. In the large majority of patients, the substitution of tyrosine for cysteine at amino acid 282 (C282Y) is found at the homozygous state. Since the HFE-1 hemochromatosis identification, several other entities of iron overload have been individualized. In the present article, the frequency, penetrance and pathophysiology of HFE-1 hemochromatosis as well as various clinical presentations resulting from different mutations affecting different proteins involved in iron metabolism are described.
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6.
Beware of multiple comparisons: a study of symptoms associated with mutations of the HFE hemochromatosis gene.
Waalen, J, Beutler, E
Clinica chimica acta; international journal of clinical chemistry. 2005;(1-2):128-34
Abstract
BACKGROUND Studies involving a large number of comparisons have a high likelihood of finding statistically significant associations by chance alone (Type 1 error). Genetic association studies are particularly prone to this pitfall. We tested the effect of multiple comparisons in a study of symptoms among subjects genotyped for mutations of the HFE hemochromatosis gene. METHODS Two randomly selected groups were created from a dataset of 30,917 white adult subjects genotyped for the C282Y and H63D mutations of the HFE gene. Frequency of symptoms among subjects with different HFE genotypes was compared to sex-matched wild type controls in Random Group 1 (hypothesis generation). Statistically significant associations (p<0.05 by chi2) were then tested in Random Group 2 (hypothesis testing). RESULTS A total of 101/1765 associations in men and 116/2015 associations in women were statistically significant in Random Group 1. Of these, 12 associations in men and 13 associations in women were also statistically significant in Random Group 2, 11 of which were specific to hemochromatosis. None of the remaining 14 associations (6 in men and 8 in women) involved symptoms with a biologically plausible relationship to hemochromatosis or iron overload. CONCLUSIONS Genetic association studies should be scrutinized for the possibility of Type 1 error.
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7.
Low serum transferrin levels in HFE C282Y homozygous subjects are associated with low CD8(+) T lymphocyte numbers.
Macedo, MF, Cruz, E, Lacerda, R, Porto, G, de Sousa, M
Blood cells, molecules & diseases. 2005;(3):319-25
Abstract
Hereditary hemochromatosis (HH) is a genetic iron overload disease, in the majority of cases associated with homozygosity for the C282Y mutation of the HFE gene. In spite of this genetic homogeneity, there is a great clinical heterogeneity among HH patients. Low CD8(+) lymphocyte numbers have been associated with a more severe expression of iron overload in HH patients, and in experimental models of iron overload. HH patients present low serum transferrin levels. Transferrin is an indispensable resource for lymphopoiesis. Lymphocyte homeostasis follows general ecology rules of population dynamics that involve competition for limiting resources. In the present study, we questioned whether transferrin levels could be associated with the anomalies seen previously in lymphocyte subset numbers in HH patients. Transferrin levels, total and subset T lymphocyte counts were done in 426 apparently healthy subjects genotyped for HFE. All HFE C282Y carriers presented significantly lower serum transferrin levels than the wild type group, a difference that could not be explained solely by the degree of iron overload. Significant differences were also seen in transferrin levels between males and females, with females presenting higher average serum Transferrin levels. In the population of subjects with Transferrin levels lower than 248 mg/dl, a positive correlation was seen between the peripheral CD8(+) lymphocyte numbers and serum transferrin levels (R(2) = 2.41; r = 0.16; P = 0.018). To test the possible limiting resource effect of transferrin, the correlation between transferrin levels and CD8(+) lymphocyte numbers was scrutinized in 34 HH patients, homozygous for the C282Y mutation. In the homozygous males, where the lowest average transferrin levels were seen, another highly significant correlation was observed between Transferrin levels and CD8(+) numbers. This correlation points to a possible role of transferrin as a limiting resource for MHC class I dependent lymphocyte proliferation, an effect that was not observed in C282Y homozygous female patients.
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8.
Mutations of the hemochromatosis gene in Italian candidate blood donors with increased transferrin saturation.
Velati, C, Marlianici, E, Rigamonti, D, Barillari, G, Chiavilli, F, Fugiani, P, Garozzo, G, Lancieri, M, Rinaldi, S, Testa, D, et al
The hematology journal : the official journal of the European Haematology Association. 2003;(6):436-40
Abstract
The aim of this study was to analyze the role of HFE mutations in blood donors with iron parameters suggesting iron overload, taking into account the regional distribution of HFE mutations in Italy. We studied 5880 subjects undergoing evaluation for blood donation eligibility, from different areas of Italy. Abnormal iron parameters were defined as transferrin saturation (TS) >50% or >45% and serum ferritin (SF) >300 or >250 microg/ml in males and females, respectively. Subjects with increased TS and/or SF were re-tested and typed for HFE mutations C282Y and H63D. A total of 548 individuals had increased iron parameters at first testing. In total, 179/548 were available for retesting, and in 109 increased TS and/or SF were confirmed. Increased TS was confirmed in 25 individuals, among whom three were C282Y homozygotes and six were compound heterozygotes for C282Y and H63D. Increased TS was more frequent in northern Italy than in southern regions. In individuals with increased TS and/or SF, the frequency of C282Y and H63D was 0.13 and 0.21 in northern-Italy versus 0.05 and 0.45 in southern Italy (P=0.004 for H63D). Nine out of 10 individuals carrying hemochromatosis-associated genotypes (including compound heterozygosity for C282Y and H63D) originated from northern regions. Among controls, the allelic frequencies of C282Y and H63D were 0.037 and 0.16 in the northern regions and 0.015 and 0.16 in the southern regions. In conclusion, over one-third of individuals with persistently altered TS carried hemochromatosis-associated genotypes, confirming that a diagnostic approach based on TS and genotyping of selected cases may represent a viable screening procedure.
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A combined bioinformatic approach oriented to the analysis and design of peptides with high affinity to MHC class I molecules.
Del Carpio, CA, Hennig, T, Fickel, S, Yoshimori, A
Immunology and cell biology. 2002;(3):286-99
Abstract
We report on a new method to compute the antigenic degree of peptides from available experimental data on peptide binding affinity to class I MHC molecules. The methodology is a combination of two strategies at different levels of information. The first, at the primary structure level, consists in expressing the peptides binding activity as a profile of amino acid contributions, amino acid similarity being accounted for by their characteristic physicochemical properties and their position within the sequence. The higher level of the strategy is based on a meticulous analysis of the contact interface of the peptides with the cleft constituting the receptor region of a particular class I MHC molecule. Interaction interfaces are inferred by docking the peptide onto the receptor groove of the MHC molecule; evaluation of the affinity of the peptide to the receptor is then performed by analysis of the electrostatic and hydrophobic energies on points of the interaction interface. The result is a robust system for analysis of peptide affinity to class I MHC molecules since while the first analysis dictates the composition of active sequences at the amino acid level, the second translates this information to the atomic level, where the molecular interaction can be analyzed in terms of the intrinsic interatomic forces and energies. Evaluation results for the methodology are encouraging since high affinity peptides are reflected by high scores at both levels of information, and are proportionally lower for peptides of medium and lower affinity for which interaction surfaces show relatively lower electrostatic complementarity and hydrophobic correlation than for the former.