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Iron overload (hemochromatosis) can cause serious, symptomatic disease that is preventable if detected early and managed appropriately. The leading cause of hemochromatosis in populations of predominantly European ancestry is homozygosity of the C282Y variant in the HFE gene. Screening of adults for iron overload or associated genotypes is controversial, largely because of a belief that severe phenotypes are uncommon, although cascade testing of first-degree relatives of patients is widely endorsed. We contend that severe liver disease (cirrhosis or hepatocellular cancer) is not at all uncommon among older males with hereditary hemochromatosis. Our review of the published data from a variety of empirical sources indicates that roughly 1 in 10 male HFE C282Y homozygotes is likely to develop severe liver disease during his lifetime unless iron overload is detected early and treated. New evidence from a randomized controlled trial of treatment allows for evidence-based management of presymptomatic patients. Although population screening for HFE C282Y homozygosity faces multiple barriers, a potentially effective strategy for increasing the early detection and prevention of clinical iron overload and severe disease is to include HFE C282Y homozygosity in lists of medically actionable gene variants when reporting the results of genome or exome sequencing.

Background and Aim: Women who are homozygous for the p.C282Y mutation in the HFE gene are at much lower risk of iron overload-related disease than p.C282Y homozygous men, presumably because of the iron-depleting effects of menstruation and pregnancy. We used data from a population cohort study to model the impact of menstruation cessation at menopause on serum ferritin (SF) levels in female p.C282Y homozygotes, with p.C282Y/p.H63D simple or compound heterozygotes and those with neither p.C282Y nor p.H63D mutations (HFE wild types) as comparison groups. Methods: A sample of the Melbourne Collaborative Cohort Study was selected for the “HealthIron” study (n = 1438) including all HFE p.C282Y homozygotes plus a random sample stratified by HFE-genotype (p.C282Y and p.H63D). The relationship between the natural logarithm of SF and time since menopause was examined using linear mixed models incorporating spline smoothing. Results: For p.C282Y homozygotes, SF increased by a factor of 3.6 (95% CI (1.8, 7.0), P < 0.001) during the first 10 years postmenopause, after which SF continued to increase but at less than half the previous rate. In contrast, SF profiles for other HFE genotype groups increase more gradually and did not show a distinction between premenopausal and postmenopausal SF levels. Only p.C282Y homozygotes had predicted SF exceeding 200 μg/L postmenopause, but the projected SF did not increase the risk of iron overload-related disease. Conclusions: These data provide the first documented evidence that physiological blood loss is a major factor in determining the marked gender difference in expression of p.C282Y homozygosity.

Homozygosity for the p.C282Y substitution in the HFE protein encoded by the hemochromatosis gene on chromosome 6p (HFE) is a common genetic trait that increases susceptibility to iron overload. McLaren et al. used bivariate mixture modeling to analyze the joint population distribution of transferrin saturation (TS) and serum ferritin concentration (SF) measured for participants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. They identified four components (C1, C2, C3, and C4) with successively increasing means for TS and SF. They demonstrated that bivariate mixture modeling in TS and SF reflect the genetic locus of HFE and may isolate p.C282Y homozygotes from the general population. In the current study we used data from the another large cohort, the Australian HealthIron study of genetic and environmental modifiers of hereditary hemochromatosis, to validate the component analysis approach, to examine stability of component proportions over time and to determine if TS and SF values from an individual move between components at baseline and follow-up. Because sampling fractions from each p.C282Y / p.H63D genotype stratum are not equal, we used frequency weights based on the inverse of the probability of selection for invitation to participate. In the weighted female analytic cohorts, C4 captured most of C282Y homozygotes, and C2 was the largest component. We identified four components from the weighted male analytic cohort and C4 captured most of p.C282Y homozygotes. The bivariate mixture modeling approach suggested that the model is transferable from one white population to another, although estimated means within components may differ.

Background Oral food challenge is the main tool for diagnosing food allergy, but there is little data on the reaction profiles of young children undergoing challenges, nor how these reactions compare to reactions on accidental ingestion in the community. Objectives To compare reaction profiles from food challenges and parent-reported reactions on accidental ingestion, and assess predictors of severe reactions. Methods HealthNuts is a longitudinal population-based cohort study of 5276 1-year-old infants. Infants underwent skin prick tests and those with identifiable wheals were offered food challenges. Food challenges were repeated at age 4 years in those with previous food allergy or reporting new food allergies. Community-reported reactions were ascertained from parent questionnaires. Results Food challenges were undertaken in 916 children at age 1 year and 357 children at age 4 years (a total of 2047 peanut, egg, or sesame challenges). Urticaria was the most common sign in positive challenges at both ages (age 1 year, 88.7%, and age 4 years, 71.2%) although angioedema was significantly more common at age 4 years (40.1%) than at age 1 year (12.9%). Anaphylaxis was equally uncommon at both ages (2.1% and 2.8% of positive challenges at ages 1 and 4 years, respectively) but more common for peanut than for egg (4.5% and 1.2% of positive challenges at ages 1 and 4 years, respectively). The patterns of presenting signs reported during community reactions were similar to those observed in formal food challenges. Serum food-specific IgE levels of 15 kU/L or more were associated with moderate to severe reactions but skin prick test was not. Conclusions There was a shift from the most common presenting reaction of urticaria during food challenges toward more angioedema in older children. Serum food-specific IgE levels were associated with reaction severity.

Women who are homozygous for the p.C282Y mutation in the HFE gene are at much lower risk of iron overload-related disease than p.C282Y homozygous men, presumably because of the iron-depleting effects of menstruation and pregnancy. We used data from a population cohort study to model the impact of menstruation cessation at menopause on serum ferritin (SF) levels in female p.C282Y homozygotes, with p.C282Y/p.H63D simple or compound heterozygotes and those with neither p.C282Y nor p.H63D mutations (HFE wild types) as comparison groups.A sample of the Melbourne Collaborative Cohort Study was selected for the "HealthIron" study (n = 1438) including all HFE p.C282Y homozygotes plus a random sample stratified by HFE-genotype (p.C282Y and p.H63D). The relationship between the natural logarithm of SF and time since menopause was examined using linear mixed models incorporating spline smoothing.For p.C282Y homozygotes, SF increased by a factor of 3.6 (95% CI (1.8, 7.0), P 0.001) during the first 10 years postmenopause, after which SF continued to increase but at less than half the previous rate. In contrast, SF profiles for other HFE genotype groups increase more gradually and did not show a distinction between premenopausal and postmenopausal SF levels. Only p.C282Y homozygotes had predicted SF exceeding 200 μg/L postmenopause, but the projected SF did not increase the risk of iron overload-related disease.These data provide the first documented evidence that physiological blood loss is a major factor in determining the marked gender difference in expression of p.C282Y homozygosity.

BACKGROUND: Questionnaire-based studies investigating blood donation history rely on the accurate recall of information from participants for results to be valid. This study aimed to retrieve electronic records from a national blood donation service and link them to self-reported history of donation to assess agreement between the two sources. STUDY DESIGN AND METHODS: Between 2004 and 2006, a sample of participants of northern European descent was selected from the Melbourne Collaborative Cohort Study (n = 31,192) to participate in the "HealthIron" study (n = 1438). A total of 1052 participants completed questionnaires that included questions about blood donation history. In 2009, consenting participants' records were linked to the Australian Red Cross Blood Service (ARCBS) to provide information on blood donations made between 1980 and follow-up (2004-2006). Those who commenced blood donation before 1980 were excluded. RESULTS: A total of 718 participants were available for analysis. Of these, 394 (55%) provided signed consent, including 182 (82%) of the 227 participants who self-reported ever donating blood. The two data sources were concordant for 331 (87%) of participants, with a κ statistic of 0.74 (SE, 0.05) indicating a high level of agreement. Participants tended to overstate by a factor of 2.0 (95% confidence interval, 1.7-2.2) the number of donations they had made when compared with ARCBS records. CONCLUSION: Participants in studies assessing self-reported blood donation history are likely to correctly indicate whether or not they have ever donated blood. Quantitative estimates are potentially inaccurate and could benefit from validating a sample of records to quantify the bias.

Hemochromatosis gene (HFE)-associated hereditary hemochromatosis (HH) is a genetic predisposition to iron overload and subsequent signs and symptoms of disease that potentially affects approximately 80,000 persons in Australia and almost 1 million persons in the United States. Most clinical cases are homozygous for the Cys282Tyr (C282Y) mutation in the HFE gene, with serum ferritin (SF) concentration >1000 μg/L as the strongest predictor of cirrhosis. The optimal treatment regimen for those with SF concentrations above the normal range but

The risk of hemochromatosis-related morbidity is unknown among HFE compound heterozygotes (C282Y/H63D). We used a prospective population-based cohort study to estimate the prevalence of elevated iron indices and hemochromatosis-related morbidity for compound heterozygotes. In all, 31,192 subjects of northern European descent were genotyped for HFE C282Y and H63D. An HFE-genotype stratified random sample of 1,438 subjects, followed for an average of 12 years to a mean age of 65 years, completed questionnaires and gave blood. Clinical examinations were blinded to HFE genotype. A total of 180 (84 males) clinically examined C282Y/H63D participants were compared with 330 (149 males) controls with neither HFE mutation; 132 (65 males) and 270 (122 males), respectively, had serum iron measures at both timepoints. Mean serum ferritin (SF) and transferrin saturation (TS) were significantly greater for male and female compound heterozygotes than for wild-types at baseline and follow-up (all P < 0.02) except for females who were premenopausal at baseline, where SF was similar in both genotype groups. For subjects with serum measures from both baseline and follow-up, mean SF and TS levels did not change significantly for men or for postmenopausal women, but for premenopausal women SF levels increased from 43 to 109 μg/L for compound heterozygotes and from 35 to 64 μg/L for wild-types (both P < 0.001). Male and female compound heterozygotes had a similar prevalence of hemochromatosis-related morbidity to wild-types. One of 82 males and zero of 95 females had documented iron overload-related disease. Conclusion: For male compound heterozygotes, mean iron indices do not change during middle age but for female compound heterozygotes menopause results in increased mean SF. Although compound heterozygotes might maintain elevated iron indices during middle age, documented iron overload-related disease is rare.

The risk of hemochromatosis-related morbidity for HFE simple heterozygosity for either the C282Y or H63D substitutions in the HFE protein was assessed using a prospective community-based cohort study.HFE genotypes were measured for 31,192 persons of northern European descent, aged between 40 and 69 years when recruited to the Melbourne Collaborative Cohort Study, and subjects were followed for an average of 12 years. For a random sample of 1438 participants stratified according to HFE genotype, two sets of biochemical iron indices performed 12 years apart and, at follow-up only, the presence/absence of six disease features associated with hereditary hemochromatosis were obtained. Summary data for 257 (139 female) C282Y simple heterozygotes and 123 (74 female) H63D simple heterozygotes were compared with 330 (181 female) controls with neither HFE mutation.At baseline, mean transferrin saturation (TS) (95% confidence interval) and prevalence of TS 55% were 35.14% (33.25, 37.04) and 3/112 (3%), 33.03% (29.9, 36.15) and 0/39 (0%), and 29.67% (27.93, 31.4) and 3/135 (2%) for C282Y, H63D and wild-type male participants, respectively. At follow-up, mean TS levels remained similar to baseline levels for both men and women irrespective of simple heterozygosity for either mutation. No HFE C282Y or H63D simple heterozygotes had documented iron overload (based on hepatic iron measures or serum ferritin greater than 1000 mg/L at baseline with documented therapeutic venesection).No documented iron overload was observed for HFE simple heterozygotes for either C282Y or H63D, and morbidity for both HFE simple heterozygote groups was similar to that of HFE wild-type participants.

The Effectiveness of Venesection Therapy for Haemochromatosis Symptoms Hereditary haemochromatosis (HH) is an autosomal recessive disorder, characterized by iron overload, and it is the commonest genetic condition affecting people of northern European ancestry. In most HH cases (>90%), a homozygous C282Y missense mutation on the HFE gene is the causeThe aim of this study was to determine if (1) the main symptoms of haemochromatosis, fatigue and arthritis, are improved by venesection therapy, and (2) to determine the number of venesections required to reach the target ferritin level.

Background Food allergy has been associated with lower weight and height in cross-sectional studies in children; however, this has not been investigated in longitudinal studies to explore growth over time, and previous studies have not accounted for coexisting eczema. Objective The objective of this study was to examine the association of IgE-mediated food allergy and eczema with anthropometric measures at 1 and 4 years of age. Methods In the HealthNuts population-based cohort, infants recruited at age 1 year underwent a skin prick test to egg, peanut, and sesame; those sensitized had oral food challenges. Food challenges repeated at 4 years determined food allergy persistence or resolution. Eczema was defined as parent report of eczema diagnosis. Parent-reported weight and height and child health record data were used to calculate age- and sex-adjusted percentiles from World Health Organization charts. Multivariable linear regression models were fitted to examine the effect of food allergy and eczema on weight and height controlling for potential confounders. Results Children with both food allergy and eczema at age 1 had lower percentiles for mean weight (51.3 vs 58.3 percentile, P = .001) and height (48.4 vs 53.4, P = .028) at age 1 compared with those with neither condition. There was no difference for children with only food allergy or eczema at age 1. By age 4, children with persistent food allergy and persistent eczema, but not those with resolved food allergy, were still shorter and lighter. Conclusions Children with both food allergy and eczema were shorter and lighter throughout early childhood, with more pronounced differences in those with persistent food allergy.

Questionnaire-based studies investigating blood donation history rely on the accurate recall of information from participants for results to be valid. This study aimed to retrieve electronic records from a national blood donation service and link them to self-reported history of donation to assess agreement between the two sources.Between 2004 and 2006, a sample of participants of northern European descent was selected from the Melbourne Collaborative Cohort Study (n = 31,192) to participate in the "HealthIron" study (n = 1438). A total of 1052 participants completed questionnaires that included questions about blood donation history. In 2009, consenting participants' records were linked to the Australian Red Cross Blood Service (ARCBS) to provide information on blood donations made between 1980 and follow-up (2004-2006). Those who commenced blood donation before 1980 were excluded.A total of 718 participants were available for analysis. Of these, 394 (55%) provided signed consent, including 182 (82%) of the 227 participants who self-reported ever donating blood. The two data sources were concordant for 331 (87%) of participants, with a κ statistic of 0.74 (SE, 0.05) indicating a high level of agreement. Participants tended to overstate by a factor of 2.0 (95% confidence interval, 1.7-2.2) the number of donations they had made when compared with ARCBS records.Participants in studies assessing self-reported blood donation history are likely to correctly indicate whether or not they have ever donated blood. Quantitative estimates are potentially inaccurate and could benefit from validating a sample of records to quantify the bias.

Objective The evidence for an association between mutations in the HFE (hemochromatosis) gene and the risk of hip or knee osteoarthritis is inconsistent. Total joint replacement is considered a surrogate measure for symptomatic end-stage osteoarthritis. We examined the relationship between HFE gene mutations and risk of total hip and knee replacement using a prospective cohort study. Methods The Melbourne Collaborative Cohort Study recruited participants between 1990 and 1994. Participants born in Australia, New Zealand, the United Kingdom, or Ireland ( n = 27,848) were genotyped for the HFE C282Y mutation. Total hip and knee replacements for osteoarthritis during 2001 to 2009 were ascertained from the Australian Orthopaedic Association National Joint Replacement Registry. Hazard ratios (HR)/odds ratios (OR) and confidence intervals (CI) were obtained from Cox regression or logistic regression. Results Compared with those with no C282Y mutation, C282Y homozygotes had an increased risk of single total hip replacement (HR 1.94, 95% CI 1.04-3.62) and bilateral total hip replacement (OR 5.86, 95% CI 2.36-14.57) for osteoarthritis, adjusting for age, sex, body mass index, and educational level. Only 3 C282Y homozygotes had single total knee replacement; the HR was 0.51 (95% CI 0.16-1.57). C282Y/H63D compound heterozygosity was not related to the risk of total hip or knee replacement. Conclusions HFE C282Y homozygosity was associated with an increased risk of both single and bilateral total hip replacement for osteoarthritis.

There is emerging evidence that there are genetic modifiers of iron indices for HFE gene mutation carriers at risk of hereditary hemochromatosis. A random sample, stratified by HFE genotype, of 863 from a cohort of 31 192 people of northern European descent provided blood samples for genotyping of 476 single nucleotide polymorphisms (SNPs) in 44 genes involved in iron metabolism. Single SNP association testing, using linear regression models adjusted for sex, menopause and HFE genotype, was conducted for four continuously distributed outcomes: serum ferritin (log transformed), transferrin saturation, serum transferrin, and serum iron. The SNP rs884409 in CYBRD1 is a novel modifier specific to HFE C282Y homozygotes. Median unadjusted serum ferritin concentration decreased from 1194 microg/l (N = 27) to 387 microg/l (N = 16) for male C282Y homozygotes and from 357 microg/l (N = 42) to 69 microg/l (N = 12) for females, comparing those with no copies to those with one copy of rs884409. Functional testing of this CYBRD1 promoter polymorphism using a heterologous expression assay resulted in a 30% decrease in basal promoter activity relative to the common genotype (P = 0.004). This putative genetic modifier of iron overload expression accounts for 11% (95% CI 0.4%, 22.6%) of the variance in serum ferritin levels of C282Y homozygotes.

Abstract 5281 Bivariate mixture modeling was used to analyze joint population distributions of transferrin saturation (TS) and serum ferritin concentration (SF) measured in the Hemochromatosis and Iron Overload Screening (HEIRS) Study (McLaren et al.Translational Research 2008 151(2), 97−109). Four components (C1, C2, C3, and C4) were identified with successively age−adjusted increasing means for TS and SF from data contributed by 26,832 African Americans, 12,620 Asians, 12,264 Hispanics, and 43,254 whites. We used data from the Australian “HealthIron” study of genetic and environmental modifiers of hereditary hemochromatosis to validate the mixture model approach for component analysis and to determine whether the component distributions appear to be stable over time or whether an individual's TS and SF values move from one component to another. Between 2004−2006, a sample of participants of northern European descent was selected from the Melbourne Collaborative Cohort Study (n=31,192 (17,951 women) recruited 1990–1994) to participate in the HealthIron study (n=1,438 (783 women)). Of these, 1,052 (579 women) participated in CAPI interviews and clinical examination. We applied the bivariate mixture modeling approach to TS and SF data from HealthIron. Follow−up data were excluded for individuals who were treated after baseline evaluations. The EMMIX program was used to predict component membership for HealthIron participants using the model based on the HEIRS data alone. Component transition probabilities over time were estimated as observed proportions. Analyses were performed separately for baseline and follow−up data. Four components (C1, C2, C3, C4) with successively age−adjusted increasing means for TS and SF, were identified using baseline data from 926 whites (426 men, 500 women) and using follow−up data from 771 whites (341 men, 430 women). At baseline, the largest component, C2, had normal mean TS (28% for women, 35% for men) and SF (139 mg/L for women, 309 μg/L for men), higher than the upper 95% confidence limits for means in analyses of HEIRS data. At follow−up, the largest component, C2, had normal mean TS (29% for women, 33% for men) and SF (124 μg/L for women, 183 μg/L for men) consisting of component proportions 0.64 for women and 0.72 for men. C3 and C4 had progressively higher mean values for TS and SF with progressively lower component proportions. At baseline, C1 had mean TS values of 15% for women (27% for men), and mean SF values of 23 mg/L for women (59 mg/L for men), similar to those found using HEIRS data. At follow−up, C1 had mean TS values of 18% for women and men, and mean SF values of 21 μg/L for women and 20 μg/L for men. Only female C282Y homozygotes for the iron gene, HFE, showed evidence that component transition probabilities shifted significantly over time;19 of 49 (39%) had TS and SF values that were in the same bivariate component at baseline and follow−up (Test of Symmetry, p=0.014). As for analyses of data from the HEIRS Study, a mixture of four components was found in data from HealthIron participants suggesting that the model is transferable from one white population to another, although estimated means within components may differ. The longitudinal aspect of this study illustrates that, with the exception of female C282Y homozygotes, the components of the mixture distributions are largely stable over time. Disclosures: No relevant conflicts of interest to declare.

were challenged by in vivo collagenase treatment, increased staining of the chondrocytes was seen. Conclusions: We identified a genetic variant on chromosome 19 to be associated with cartilage thickness and hip OA. The variant is located in a gene showing an expression pattern that supports a role in chondrogenetic differentiation. GWAS for underlying endophenotypes might be a prolific route to identify risk loci for complex diseases such as OA.