Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA

Beutler, Ernest; Felitti, Vincent J.; Koziol, James A.; Ho, Ngoc J.; Gelbart, Terri

doi:10.1016/s0140-6736(02)07447-0

Cited by 761 publications

(607 citation statements)

References 30 publications

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“…While iron accumulation in the pancreas can cause diabetes and in the heart can lead to cardiomyopathy, there is little evidence that HH variants increase the risk of these diseases among the general population. 39,40 In support of this, the prevalence of the HFE p.Cys282Tyr variant within the ESP data set is very similar to that observed in large population studies from North America, 17,22 indicating that there is no enrichment of this mutation.…”

Section: Discussionsupporting

confidence: 78%

“…By far the most common pathogenic variant was HFE p.Cys282Tyr, which is present at the highest frequency among non-Finnish Europeans (allele frequency 5.14%), similar to that reported in various European populations (allele frequencies ranging from 0 to 14%). 5,17,22 An additional 42 HH-causing variants were identified among the three data sets, and 40 unreported variants that are predicted to have major functional or structural effects on the encoded proteins were also used in our analysis. Using the allele frequencies of these variants, we could determine that all the recessively inherited forms of non-HFE HH are predicted to be rare.…”

Section: Discussionmentioning

confidence: 99%

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The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data

Wallace

Subramaniam

2016

Genetics in Medicine

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Purpose:The prevalence of HFE-related hereditary hemochromatosis (HH) among European populations has been well studied. There are no prevalence data for atypical forms of HH caused by mutations in HFE2, HAMP, TFR2, or SLC40A1. The purpose of this study was to estimate the population prevalence of these non-HFE forms of HH.Methods: A list of HH pathogenic variants in publically available next-generation sequence (NGS) databases was compiled and allele frequencies were determined.Results: Of 161 variants previously associated with HH, 43 were represented among the NGS data sets; an additional 40 unreported functional variants also were identified. The predicted prevalence of HFE HH and the p.Cys282Tyr mutation closely matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2-, HFE2-, and HAMP-related forms are predicted to be rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. Significantly, SLC40A1 variants that have been previously associated with autosomal-dominant ferroportin disease were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans. Conclusion:We have, for the first time, estimated the population prevalence of non-HFE HH. This methodology could be applied to estimate the population prevalence of a wide variety of genetic disorders.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data

Wallace

Subramaniam

2016

Genetics in Medicine

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“…Several case reports have described familial Fe deficiency anaemia that is unresponsive to oral Fe therapy and incompletely responsive to parenteral Fe therapy (57)(58)(59) . Further, mutation of the hereditary haemochromatosis (HEF) gene is well-known as the most common cause of hereditary haemochromatosis (60,61) .…”

Section: Discussionmentioning

confidence: 99%

Iron intake does not significantly correlate with iron deficiency among young Japanese women: a cross-sectional study

Asakura

Sasaki

Murakami

et al. 2009

Public Health Nutr.

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Objectives: We evaluated the association of nutrient intake with Fe deficiency with regard to lifestyle factors and health condition in young Japanese women. Uniquely among developed countries, dietary habits render Japanese populations vulnerable to Fe deficiency, owing to their relatively low intake of Fe and high intake of Fe absorption inhibitors, such as green tea and soyabeans. Design: A cross-sectional study. Setting and subjects: The subjects were 1019 female Japanese dietetic students aged 18-25 years. Dietary habits during the preceding month were assessed using a previously validated, self-administered, diet history questionnaire. Blood analysis was performed to assess body Fe status. Subjects were categorized with Fe deficiency when their serum ferritin levels were ,12 ng/ml. Twenty-nine dietary variables, i.e. intakes of energy, sixteen nutrients including Fe and twelve food groups, were analysed using multivariate logistic regression models adjusted for possible confounders. Results: Of the subjects, 24?5 % were categorized with Fe deficiency. However, no dietary factors assessed were significantly associated with Fe deficiency. The risk of Fe deficiency was significantly lower in women with infrequent or no menstrual cycles than in those with regular cycles (OR 5 0?58; 95 % CI 0?34, 1?00) and significantly higher in women with heavy menstrual flow than in women with average flow, albeit that these were self-reported (OR 5 1?83; 95 % CI 1?35, 2?48). Conclusions: These results suggest that dietary habits, including Fe intake, do not significantly correlate with Fe deficiency among young Japanese women.

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“…For HH, a major issue in relation to whether community screening should be introduced is the disease penetrance. 4,5 Our recent longitudinal study indicates that penetrance in YY male subjects is considerable, but is low in YY female subjects. 4 These issues are important not only in deciding whether to introduce screening in the community, but also for individuals in deciding whether they wish to have screening.…”

Section: Discussionmentioning

confidence: 99%

“…Controversy exists regarding the penetrance of disease in those homozygous for this mutation. A large cross-sectional study reported a penetrance of less than 1% 5 although the methodology of this study was criticised. [6][7][8] We conducted a longitudinal study of disease in 142 individuals homozygous for this mutation and found a minimum penetrance for iron overload-related disease of 28.4% for male subjects and 1.2% for female subjects.…”

Section: Introductionmentioning

confidence: 87%

ironXS: high-school screening for hereditary haemochromatosis is acceptable and feasible

et al. 2012

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As the results of the Human Genome Project are realised, screening for genetic mutations that predispose to preventable disease is becoming increasingly possible. How and where such screening should best be offered are critical, unanswered questions. This study aimed to assess the acceptability and feasibility of genetic screening for preventable disease, using the model of hereditary haemochromatosis, in high-school students. Screening was offered for the HFE C282Y substitution to 17 638 students. Questionnaires were administered at the time of screening (Q1) and approximately 1 month after results were communicated (Q2). Outcomes assessed were uptake of screening, change in scores of validated anxiety, affect and health perception scales from Q1 to Q2, knowledge and iron indices in C282Y homozygous individuals. A total of 5757 (32.6%) students had screening and 28 C282Y-homozygous individuals (1 in 206) were identified, and none of the 27 individuals who had iron indices measures had significant iron overload. There was no significant change in measures of anxiety, affect or health perception in C282Y homozygous or non-homozygous individuals. Over 86% of students answered each of five knowledge questions correctly at Q1. Genetic population-based screening for a preventable disease can be offered in schools in a way that results in minimal morbidity for those identified at high risk of disease. The results of this study are not only relevant for haemochromatosis, but for other genetic markers of preventable disease such as those for cardiovascular disease and cancer.

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Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA

Cited by 761 publications

References 30 publications

The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data

The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data

Iron intake does not significantly correlate with iron deficiency among young Japanese women: a cross-sectional study

ironXS: high-school screening for hereditary haemochromatosis is acceptable and feasible

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