A genetic epidemiologic study of hemochromatosis

The goal of genetic epidemiology is to study the genetic etiology of diseases. There were t\vo main aims for the present thesis. The first aim was to study the effects of the hemochromatosis gene (HFE) mutations on serum iron levels and disease associated conditions. Secondly, we aimed at identifYing other genes involved in hemochromatosis. Numerous studies have been carried out on the genetics and epidemiology of hemochromatosis. Still there is a lot of controversies in the literature as to what the contributions of HFE gene mutations are to liver diseases, diabetes mellitus, and vascular pathology. Most controversies are due to differences in study designs, casedefinition of hemochromatosis, ethnic composition of populations studied, risk modifiers, and genetic heterogeneity. In order to translate the results of genetic research into public health policies, population-based studies are necessary to evaluate the impact of the gene on risk of disease, mortality and quality of life. In this thesis, we have used a population-based cohort study of elderly individuals, the Rotterdam Study, to quantifY the effect of HFE mutations on several disorders

Heritability of serum iron, ferritin and transferrin saturation in a genetically isolated population, the Erasmus Rucphen Family (ERF) study

Background: Iron has been implicated in the pathogenesis of various disorders. Mutations in the HFE gene are associated with an increase in serum iron parameters. The aim of this study was to estimate the heritability in serum iron parameters explained by HFE. Methods: Ninety families (980 subjects) were included in the present analysis. Heritability estimation was conducted using the variance component method. The likelihood ratio test was used to compare models. Phenotypic and genetic correlations between serum iron parameters were calculated. Results: The heritability (h 2 ± SE) estimates were 0.23 ± 0.07 (p < 0.0001) for iron, 0.29 ± 0.09 (p < 0.0001) for ferritin and 0.28 ± 0.07 (p < 0.0001) for transferrin saturation while adjusting for age, age 2 and sex. The HFE genotypes explained between 2 to 6% of the sex and age-adjusted variance in serum iron, ferritin and transferrin saturation. There was a high genetic correlation between serum iron parameters, suggesting pleiotropy between these traits. Conclusion: A substantial proportion of the variance of iron, ferritin and transferrin saturation can be explained by additive genetic effects, independent of sex and age. The HFE genotypes explained a considerable proportion of serum iron parameters and may be an important factor in the complex iron network. Copyrigh

The H63D variant in the HFE gene predisposes to arthralgia, chondrocalcinosis and osteoarthritis

Objectives: To investigate the relation between the HFE C282Y and H63D variants with arthralgia and joint pathology in the population-based Rotterdam Study. Methods: From a cohort of 7983 people aged 55 years and over, 2095 randomly drawn subjects were genotyped for C282Y and H63D variants. We compared the frequency of arthralgia, and the presence of chondrocalcinosis, osteophytes, joint space narrowing and radiographic osteoarthritis in hand, hip and knee joints, and Heberden's nodes in carriers of HFE variants with that in non-carriers. Results: Overall, there was a significantly higher frequency of arthralgia (odds ratio 1.6; 95% CI 1.0 to 2.6), oligoarthralgia (2.3; 1.2 to 4.4) and Heberden's nodes (2.0; 1.1 to 3.8) in H63D homozygotes compared with non-carriers. In subjects aged 65 years or younger, H63D homozygotes had significantly more often polyarthralgia (3.1; 1.3 to 7.4), chondrocalcinosis in hip or knee joints (4.7; 1.2 to 18.5), and more hand joints with osteophytes (6.1±1.0 vs 4.4±0.3), space narrowing (2.8±0.5 vs 1.0±0.1), radiographic osteoarthritis (4.4±0.7 vs 2.0±0.2) and Heberden's nodes (3.1; 1.3 to 12.8) than non-carriers. We found no relation of arthralgia or joint pathology to C282Y, but compound heterozygotes had a significantly higher frequency of arthralgia (2.9; 1.0 to 9.3), chondrocalcinosis in hip joints (6.5; 1.8 to 22.3), and an increased number of osteophytes in knee (6.9±1.2, n = 5 vs 2.4±0.1) joints at a later age (>65 years). Conclusions: The HFE H63D variant may explain, at least in part, the prevalence of arthralgia in multiple joints sites, chondrocalcinosis, and hand osteoarthritis in the general population

Mutations in the hemochromatosis gene (HFE) and stroke

BACKGROUND AND PURPOSE: Increased serum iron is found to be a risk factor for stroke. Carriers of HFE C282Y and H63D mutations have elevated serum iron levels and may have an increased risk for stroke. We studied the association between HFE gene mutations, carotid atherosclerosis, and stroke. METHODS: We compared the frequency of the HFE C282Y and H63D gene mutations in 202 prevalent and incident cases of stro

The role of hemochromatosis C282Y and H63D gene mutations in type 2diabetes: findings from the Rotterdam Study and meta-analysis

Lette

The association between H63D mutations in HFE and amyotrophic lateral sclerosis in a Dutch population

Background: Mutations in HFE, a gene defect that can disrupt iron metabolism, have been implicated in increasing the risk of developing amyotrophic lateral sclerosis (ALS). Objective: To further establish the association between ALS and HFE mutations by investigating whether HFE mutations are associated with an increased risk of developing ALS in a population in the Netherlands and by pooling our results with those from previous studies. Design: Retrospective study. Setting: Tertiary referral center for neuromuscular disorders. Participants: Genotyping for 2 common HFE mutations was performed in 289 patients with ALS and 5886 population-based controls in the Netherlands between January 1, 2000, and December 31, 2004. Main Outcome Measures: Development of ALS and clinical phenotype were compared among the different HFE genotypes, adjusting for known prognostic factors such as age at onset and sex. Results: Homozygosity for H63D was associated with an increased risk of developing ALS (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.1- 4.1). After pooling our results with those from previous studies, a positive association between H63D homozygotes (OR, 2.7; 95% CI, 1.7-4.4), heterozygotes (OR, 1.5; 95% CI, 1.0-2.1), and mutation carriers (OR, 1.7; 95% CI, 1.1-2.5) was found. Within the patient group, heterozygosity for the H63D mutation was associated with a higher age at onset. Conclusions: These findings suggest that H63D mutations in HFE play a role in the pathogenesis of ALS in various populations. This association might involve a later-onset subset of ALS