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1.  Bivariate mixture modeling of transferrin saturation and serum ferritin concentration in Asians, African Americans, Hispanics, and whites in the Hemochromatosis and Iron Overload Screening (HEIRS) Study 
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. Four components (C1, C2, C3, and C4) with successively age-adjusted increasing means for TS and SF were identified in data from 26,832 African Americans, 12,620 Asians, 12,264 Hispanics, and 43,254 whites. The largest component, C2, had normal mean TS (21% to 26% for women, 29% to 30% for men) and SF (43–82 μg/L for women, 165–242 μg/L for men), which consisted of component proportions greater than 0.59 for women and greater than 0.68 for men. C3 and C4 had progressively greater mean values for TS and SF with progressively lesser component proportions. C1 had mean TS values less than 16% for women (<20% for men) and SF values less than 28 μg/L for women (<47 μg/L for men). Compared with C2, adjusted odds of iron deficiency were significantly greater in C1 (14.9–47.5 for women, 60.6–3530 for men), adjusted odds of liver disease were significantly greater in C3 and C4 for African-American women and all men, and adjusted odds of any HFE mutation were increased in C3 (1.4–1.8 for women, 1.2–1.9 for men) and in C4 for Hispanic and white women (1.5 and 5.2, respectively) and men (2.8 and 4.7, respectively). Joint mixture modeling identifies a component with lesser SF and TS at risk for iron deficiency and 2 components with greater SF and TS at risk for liver disease or HFE mutations. This approach can identify populations in which hereditary or acquired factors influence metabolism measurement.
doi:10.1016/j.trsl.2007.10.002
PMCID: PMC3785302  PMID: 18201677
2.  Accuracy of Family History of Hemochromatosis or Iron Overload: The Hemochromatosis and Iron Overload Screening Study 
Background & Aims
The aim of this study was to assess the analytic validity of self-reported family history of hemochromatosis or iron overload.
Methods
A total of 141 probands, 549 family members, and 641 controls participated in the primary care Hemochromatosis and Iron Overload Screening Study. Participants received a postscreening clinical examination and completed questionnaires about personal and family histories of hemochromatosis or iron overload, arthritis, diabetes, liver disease, and heart disease. We evaluated sensitivities and specificities of proband-reported family history, and concordance of HFE genotype C282Y/C282Y in probands and siblings who reported having hemochromatosis or iron overload.
Results
The sensitivities of proband-reported family history ranged from 81.4% for hemochromatosis or iron overload to 18.4% for liver disease; specificities for diabetes, liver disease, and heart disease were greater than 94%. Hemochromatosis or iron overload was associated with a positive family history across all racial/ethnic groups in the study (odds ratio, 14.53; 95% confidence intervals, 7.41–28.49; P < .0001) and among Caucasians (odds ratio, 16.98; 95% confidence intervals, 7.53–38.32; P < .0001). There was 100% concordance of HFE genotype C282Y/C282Y in 6 probands and 8 of their siblings who reported having hemochromatosis or iron overload.
Conclusions
Self-reported family history of hemochromatosis or iron overload can be used to identify individuals whose risk of hemochromatosis or iron overload and associated conditions is increased. These individuals could benefit from further evaluation with iron phenotyping and HFE mutation analysis.
doi:10.1016/j.cgh.2008.04.003
PMCID: PMC3779058  PMID: 18585964
3.  Serum ferritin concentrations and body iron stores in a multicenter, multiethnic primary-care population 
American journal of hematology  2008;83(8):618-626.
How often elevated serum ferritin in primary-care patients reflects increased iron stores (normally 0.8 g in men, 0.4 g in women) is not known. The Hereditary Hemochromatosis and Iron Overload Screening (HEIRS) study screened 101,168 primary-care participants (44% Caucasians, 27% African-Americans, 14% Asians/Pacific Islanders, 13% Hispanics, 2% others). Follow-up clinical evaluation was performed in 302 of 333 HFE C282Y homozygotes regardless of iron measures and 1,375 of 1,920 nonhomozygotes with serum ferritin >300 μg/L (men), >200 μg/L (women) and transferrin saturation >50% (men), >45% (women). Quantitative phlebotomy was conducted in 122 of 175 C282Y homozygotes and 122 of 1,102 nonhomozygotes with non-transfusional serum ferritin elevation at evaluation. The estimated prevalence in the Caucasian population of C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 20 per 10,000 men and 4 per 10,000 women; this constellation was predictive of iron stores >4 g in men and >2 g in women. The estimated prevalence per 10,000 of non-C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 7 among Caucasians, 13 among Hispanics, 20 among African Americans, and 38 among Asians and Pacific Islanders, and this constellation was predictive of iron stores >2 g but <4 g. In conclusion, serum ferritin >900 μg/L after initial elevations of both serum ferritin and transferrin saturation is predictive of mildly increased iron stores in multiple ethnic populations regardless of HFE genotype. Serum ferritin >900 μg/L in male C282Y homozygotes is predictive of moderately increased iron stores.
doi:10.1002/ajh.21179
PMCID: PMC3773165  PMID: 18429050
4.  Dietary iron intake and serum ferritin concentration in 213 patients homozygous for the HFEC282Y hemochromatosis mutation 
BACKGROUND:
HFEC282Y homozygotes have an increased risk for developing increased iron stores and related disorders. It is controversial whether dietary iron restrictions should be recommended to such individuals.
OBJECTIVE:
To determine whether dietary iron content influences iron stores in HFEC282Y homozygotes as assessed by serum ferritin concentration.
DESIGN:
Serum ferritin concentration was measured and a dietary iron questionnaire was completed as part of the evaluation of 213 HFEC282Y homozygotes who were identified through screening of >100,000 primary care patients at five HEmochromatosis and IRon Overload Screening (HEIRS) Study Field Centers in the United States and Canada.
RESULTS:
No significant relationships between serum ferritin concentration and dietary heme iron content, dietary nonheme iron content or reports of supplemental iron use were found.
CONCLUSION:
These results do not support recommending dietary heme or nonheme iron restrictions for HFEC282Y homozygotes diagnosed through screening in North America.
PMCID: PMC3378281  PMID: 22720276
Haemochromatosis; Hemochromatosis; Iron overload; Iron supplementation
5.  Next Generation Analytic Tools for Large Scale Genetic Epidemiology Studies of Complex Diseases 
Genetic epidemiology  2011;36(1):22-35.
Over the past several years, genome-wide association studies (GWAS) have succeeded in identifying hundreds of genetic markers associated with common diseases. However, most of these markers confer relatively small increments of risk and explain only a small proportion of familial clustering. To identify obstacles to future progress in genetic epidemiology research and provide recommendations to NIH for overcoming these barriers, the National Cancer Institute sponsored a workshop entitled “Next Generation Analytic Tools for Large-Scale Genetic Epidemiology Studies of Complex Diseases” on September 15–16, 2010. The goal of the workshop was to facilitate discussions on (1) statistical strategies and methods to efficiently identify genetic and environmental factors contributing to the risk of complex disease; and (2) how to develop, apply, and evaluate these strategies for the design, analysis, and interpretation of large-scale complex disease association studies in order to guide NIH in setting the future agenda in this area of research. The workshop was organized as a series of short presentations covering scientific (gene-gene and gene-environment interaction, complex phenotypes, and rare variants and next generation sequencing) and methodological (simulation modeling and computational resources and data management) topic areas. Specific needs to advance the field were identified during each session and are summarized.
doi:10.1002/gepi.20652
PMCID: PMC3368075  PMID: 22147673
gene-gene interactions; gene-environment interactions; rare variants; next generation sequencing; complex phenotypes; simulations; computational resources
6.  Quality control and quality assurance in genotypic data for genome-wide association studies 
Genetic epidemiology  2010;34(6):591-602.
Genome-wide scans of nucleotide variation in human subjects are providing an increasing number of replicated associations with complex disease traits. Most of the variants detected have small effects and, collectively, they account for a small fraction of the total genetic variance. Very large sample sizes are required to identify and validate findings. In this situation, even small sources of systematic or random error can cause spurious results or obscure real effects. The need for careful attention to data quality has been appreciated for some time in this field, and a number of strategies for quality control and quality assurance (QC/QA) have been developed. Here we extend these methods and describe a system of QC/QA for genotypic data in genome-wide association studies. This system includes some new approaches that (1) combine analysis of allelic probe intensities and called genotypes to distinguish gender misidentification from sex chromosome aberrations, (2) detect autosomal chromosome aberrations that may affect genotype calling accuracy, (3) infer DNA sample quality from relatedness and allelic intensities, (4) use duplicate concordance to infer SNP quality, (5) detect genotyping artifacts from dependence of Hardy-Weinberg equilibrium (HWE) test p-values on allelic frequency, and (6) demonstrate sensitivity of principal components analysis (PCA) to SNP selection. The methods are illustrated with examples from the ‘Gene Environment Association Studies’ (GENEVA) program. The results suggest several recommendations for QC/QA in the design and execution of genome-wide association studies.
doi:10.1002/gepi.20516
PMCID: PMC3061487  PMID: 20718045
GWAS; DNA sample quality; genotyping artifact; Hardy-Weinberg equilibrium; chromosome aberration
7.  Modulation of the BP Response to Diet by Genes in the Renin–Angiotensin System and the Adrenergic Nervous System 
American journal of hypertension  2010;24(2):209-217.
BACKGROUND
Essential hypertension results from the interaction of several genetic and environmental factors. Identification of genetic factors that modulate blood pressure (BP) response to interventions can lead to improved strategies for prevention and control. The purpose of this study was to identify genes that modulate BP response to dietary interventions.
METHODS
We used data and samples collected in two randomized feeding studies to determine the extent to which genetic architecture is associated with the effect on BP of sodium intake and the Dietary approaches to Stop Hypertension (DASH) dietary pattern. Participants in both trials were adults with above-optimal BP or unmedicated stage 1 hypertension. Genomic DNa was typed for several candidate genes.
RESULTS
The effect of sodium intake on BP differed by genotype at the angiotensinogen, β2-adrenergic receptor, and kallikrein loci. The effect of DASH dietary pattern on BP differed by genotype at the β2-adrenergic receptor locus.
CONCLUSIONS
These findings have implications for understanding the mechanism(s) through which diet affects BP, the heterogeneity of these effects, and the extent to which dietary interventions can modulate genetic predisposition.
doi:10.1038/ajh.2010.223
PMCID: PMC3106290  PMID: 21088669
blood pressure; DASH; diet; genetics; hypertension; sodium
8.  Potential Nonresponse Bias in a Clinical Examination After Initial Screening Using Iron Phenotyping and HFE Genotyping in the Hemochromatosis and Iron Overload Screening Study 
Background: Little is known about the factors affecting participation in clinical assessments after HEmochromatosis and IRon Overload Screening. Methods: Initial screening of 101,168 primary care patients in the HEmochromatosis and IRon Overload Screening study was performed using serum iron measures and hemochromatosis gene (HFE) genotyping. Using iron phenotypes and HFE genotypes, we identified 2256 cases and 1232 controls eligible to participate in a clinical examination. To assess the potential for nonresponse bias, we compared the sociodemographic, health status, and attitudinal characteristics of participants and nonparticipants using adjusted odds ratios (ORs) and 95% confidence interval (CI). Results: Overall participation was 74% in cases and 52% in controls; in both groups, participation was highest at a health maintenance organization and lowest among those under 45 years of age (cases: OR = 0.68; 95% CI 0.53, 0.87; controls: OR = 0.59; 95% CI 0.44, 0.78). In controls only, participation was also lower among those over 65 years of age than the reference group aged 46–64 (OR = 0.64; 95% CI 0.47, 0.88). Among cases, participation was higher in HFE C282Y homozygotes (OR = 3.98; 95% CI 2.60, 6.09), H63D homozygotes (OR = 2.79; 95% CI 1.23, 6.32), and C282Y/H63D compound heterozygotes (OR = 1.82; 95% CI 1.03, 3.22) than in other genotypes, and lower among non-Caucasians and those who preferred a non-English language than in Caucasians and those who preferred English (p < 0.0001). Conclusions: Subjects with greatest risk to have iron overload (C282Y homozygotes; cases ≥45 years; Caucasians) were more likely to participate in a postscreening clinical examination than other subjects. We detected no evidence of strong selection bias.
doi:10.1089/gtmb.2009.0003
PMCID: PMC2935839  PMID: 19860558
9.  Screening for iron overload: Lessons from the HEmochromatosis and IRon Overload Screening (HEIRS) Study 
BACKGROUND:
The HEmochromatosis and IRon Overload Screening (HEIRS) Study provided data on a racially, ethnically and geographically diverse cohort of participants in North America screened from primary care populations.
METHODS:
A total of 101,168 participants were screened by testing for HFE C282Y and H63D mutations, and measuring serum ferritin concentration and transferrin saturation. In the present review, lessons from the HEIRS Study are highlighted in the context of the principles of screening for a medical disease as previously outlined by the World Health Organization.
RESULTS:
Genetic testing is well accepted, with minimal risk of discrimination. Transferrin saturation has high biological variability and relatively low sensitivity to detect HFE C282Y homozygotes, which limits its role as a screening test. Symptoms attributable to HFE C282Y homozygosity are no more common in individuals identified by population screening than in control subjects.
CONCLUSIONS:
Generalized population screening in a primary care population as performed in the HEIRS Study is not recommended. There may be a role for focused screening in Caucasian men, with some debate regarding genotyping followed by phenotyping, or phenotyping followed by genotyping.
PMCID: PMC2777090  PMID: 19893773
Haemochromatosis; Hemochromatosis; HFE; Iron overload
10.  The Gene, Environment Association Studies Consortium (GENEVA): Maximizing the Knowledge Obtained from GWAS by Collaboration Across Studies of Multiple Conditions 
Genetic epidemiology  2010;34(4):364-372.
Genome-wide association studies (GWAS) have emerged as powerful means for identifying genetic loci related to complex diseases. However, the role of environment and its potential to interact with key loci has not been adequately addressed in most GWAS. Networks of collaborative studies involving different study populations and multiple phenotypes provide a powerful approach for addressing the challenges in analysis and interpretation shared across studies. The Gene, Environment Association Studies (GENEVA) consortium was initiated to: identify genetic variants related to complex diseases; identify variations in gene-trait associations related to environmental exposures; and ensure rapid sharing of data through the database of Genotypes and Phenotypes. GENEVA consists of several academic institutions, including a coordinating center, two genotyping centers and 14 independently designed studies of various phenotypes, as well as several Institutes and Centers of the National Institutes of Health led by the National Human Genome Research Institute. Minimum detectable effect sizes include relative risks ranging from 1.24 to 1.57 and proportions of variance explained ranging from 0.0097 to 0.02. Given the large number of research participants (N > 80,000), an important feature of GENEVA is harmonization of common variables, which allow analyses of additional traits. Environmental exposure information available from most studies also enables testing of gene-environment interactions. Facilitated by its sizeable infrastructure for promoting collaboration, GENEVA has established a unified framework for genotyping, data quality control, analysis and interpretation. By maximizing knowledge obtained through collaborative GWAS incorporating environmental exposure information, GENEVA aims to enhance our understanding of disease etiology, potentially identifying opportunities for intervention.
doi:10.1002/gepi.20492
PMCID: PMC2860056  PMID: 20091798
genome-wide association; complex disease; quantitative traits; gene-environment interaction; phenotype harmonization
11.  Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening 
BACKGROUND:
Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences.
OBJECTIVE:
To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE) mutation (C282Y) identified by screening.
METHODS:
Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without the HFE C282Y or H63D alleles (ie, wild type/wild type; n=364).
RESULTS:
Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects.
CONCLUSIONS:
Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study.
PMCID: PMC2661195  PMID: 19018338
Complications; Cross-sectional study; Hemochromatosis; HFE; Iron overload; Prevalence
12.  Specificity of Clinical Breast Examination in Community Practice 
Background
Millions of women receive clinical breast examination (CBE) each year, as either a breast cancer screening test or a diagnostic test for breast symptoms. While screening CBE had moderately high specificity (∼94%) in clinical trials, community clinicians may be comparatively inexperienced and may conduct relatively brief examinations, resulting in even higher specificity but lower sensitivity.
Objective
To estimate the specificity of screening and diagnostic CBE in clinical practice and identify patient factors associated with specificity.
Design
Retrospective cohort study.
Subjects
Breast-cancer-free female health plan enrollees in 5 states (WA, OR, CA, MA, and MN) who received CBE (N = 1,484).
Measurements
Medical charts were abstracted to ascertain breast cancer risk factors, examination purpose (screening vs diagnostic), and results (true-negative vs false-positive). Women were considered “average-risk” if they had neither a family history of breast cancer nor a prior breast biopsy and “increased-risk” otherwise.
Results
Among average- and increased-risk women, respectively, the specificity (true-negative proportion) of screening CBE was 99.4% [95% confidence interval (CI): 98.8–99.7%] and 97.1% (95% CI: 95.7–98.0%), and the specificity of diagnostic CBE was 68.7% (95% CI: 59.7–76.5%) and 57.1% (95% CI: 51.1–63.0%). The odds of a true-negative screening CBE (specificity) were significantly lower among women at increased risk of breast cancer (adjusted odds ratio 0.21; 95% CI: 0.10–0.46).
Conclusions
Screening CBE likely has higher specificity among community clinicians compared to examiners in clinical trials of breast cancer screening, even among women at increased breast cancer risk. Highly specific examinations, however, may have relatively low sensitivity for breast cancer. Diagnostic CBE, meanwhile, is relatively nonspecific.
doi:10.1007/s11606-006-0062-7
PMCID: PMC1824753  PMID: 17356964
breast cancer; sensitivity and specificity; screening; physical examination
13.  Performance of the U.S. Office of Management and Budget’s Revised Race and Ethnicity Categories in Asian Populations* 
Objectives
The U.S. Office of Management and Budget (OMB) guidelines for collecting and reporting race and ethnicity information recently divided the “Asian or Pacific Islander” category into “Asian” and “Native Hawaiian or Other Pacific Islander”. The OMB’s decision to disaggregate the “Asian or Pacific Islander” category was the first step toward providing these communities with information to better serve their needs. However, whether individuals who formerly made up the combined group categorize themselves as the new guidelines intend is a question analyzed in this report.
Methods
A subset of adults participating in the Hemochromatosis and Iron Overload Screening Study completed both the OMB-minimum and the expanded race and ethnicity measure used in the National Health Interview Survey. We compared responses on the expanded measure contained within the OMB “Asian” definition (Filipino, Korean, Vietnamese, Japanese, Asian Indian, Chinese, and/or Other Asian) to “Asian” responses on the OMB-minimum measure.
Results
Mixed heritage Asians less often marked “Asian”. Among mixed heritage Japanese, Chinese, and Filipinos, 27%, 49%, and 52% did not mark “Asian” on the OMB measure, respectively. Eleven percent of single-heritage Filipinos did not mark “Asian.”
Conclusions
Many individuals formerly making up the combined “Asian or Pacific Islander” group do not categorize themselves as the revised OMB guidelines intend. This is particularly evident among Filipinos and among Asians of mixed heritage. This research illuminates the reliability and utility of the broad “Asian” category and points to possible consequences of collapsing groups into a single category, i.e., missed information and/or erroneous generalization.
doi:10.1016/j.ijintrel.2007.02.001
PMCID: PMC2084211  PMID: 18037976
14.  Specificity of Clinical Breast Examination in Community Practice 
Background
Millions of women receive clinical breast examination (CBE) each year, as either a breast cancer screening test or a diagnostic test for breast symptoms. While screening CBE had moderately high specificity (∼94%) in clinical trials, community clinicians may be comparatively inexperienced and may conduct relatively brief examinations, resulting in even higher specificity but lower sensitivity.
Objective
To estimate the specificity of screening and diagnostic CBE in clinical practice and identify patient factors associated with specificity.
Design
Retrospective cohort study.
Subjects
Breast-cancer-free female health plan enrollees in 5 states (WA, OR, CA, MA, and MN) who received CBE (N = 1,484).
Measurements
Medical charts were abstracted to ascertain breast cancer risk factors, examination purpose (screening vs diagnostic), and results (true-negative vs false-positive). Women were considered “average-risk” if they had neither a family history of breast cancer nor a prior breast biopsy and “increased-risk” otherwise.
Results
Among average- and increased-risk women, respectively, the specificity (true-negative proportion) of screening CBE was 99.4% [95% confidence interval (CI): 98.8–99.7%] and 97.1% (95% CI: 95.7–98.0%), and the specificity of diagnostic CBE was 68.7% (95% CI: 59.7–76.5%) and 57.1% (95% CI: 51.1–63.0%). The odds of a true-negative screening CBE (specificity) were significantly lower among women at increased risk of breast cancer (adjusted odds ratio 0.21; 95% CI: 0.10–0.46).
Conclusions
Screening CBE likely has higher specificity among community clinicians compared to examiners in clinical trials of breast cancer screening, even among women at increased breast cancer risk. Highly specific examinations, however, may have relatively low sensitivity for breast cancer. Diagnostic CBE, meanwhile, is relatively nonspecific.
doi:10.1007/s11606-006-0062-7
PMCID: PMC1824753  PMID: 17356964
breast cancer; sensitivity and specificity; screening; physical examination
15.  Cyclin D1 Repression of Peroxisome Proliferator-Activated Receptor γ Expression and Transactivation 
Molecular and Cellular Biology  2003;23(17):6159-6173.
The cyclin D1 gene is overexpressed in human breast cancers and is required for oncogene-induced tumorigenesis. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPARγ induces hepatic steatosis, and liganded PPARγ promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPARγ function, transactivation, expression, and promoter activity. PPARγ transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB- and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix (HLH) structure. The cyclin D1 HLH region was also required for repression of the PPARγ ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPARγ-specific ligands (BRL49653, troglitazone) was enhanced in cyclin D1−/− fibroblasts and reversed by retroviral expression of cyclin D1. Homozygous deletion of the cyclin D1 gene, enhanced expression by PPARγ ligands of PPARγ and PPARγ-responsive genes, and cyclin D1−/− mice exhibit hepatic steatosis. Finally, reduction of cyclin D1 abundance in vivo using ponasterone-inducible cyclin D1 antisense transgenic mice, increased expression of PPARγ in vivo. The inhibition of PPARγ function by cyclin D1 is a new mechanism of signal transduction cross talk between PPARγ ligands and mitogenic signals that induce cyclin D1.
doi:10.1128/MCB.23.17.6159-6173.2003
PMCID: PMC180960  PMID: 12917338
16.  Heritability of Serum Iron Measures in the Hemochromatosis and Iron Overload Screening (HEIRS) Family Study 
American journal of hematology  2010;85(2):10.1002/ajh.21585.
Heritability is the proportion of observed variation in a trait among individuals in a population that is attributable to hereditary factors. The HEIRS Family Study estimated heritability of serum iron measures. Probands were HFE C282Y homozygotes or non-C282Y homozygotes with elevated transferrin saturation (TS > 50%, men; TS > 45%, women) and serum ferritin concentration (SF > 300 μg/L, men; SF > 200 μg/L, women). Heritability (h2) was estimated by variance component analysis of TS, natural logarithm (ln) of SF, and unsaturated iron-binding capacity (UIBC). Participants (N=942) were 77% Caucasians, 10% Asians, 8% Hispanics, and 5% other race/ethnicities. Average age (SD) was 49 (16) y; 57% were female. For HFE C282Y homozygote probands and their family members, excluding variation due to HFE C282Y and H63D genotype and measured demographic and environmental factors, the residual h2 (SE) was 0.21 (0.07) for TS, 0.37 (0.08) for ln SF, and 0.34 (0.08) for UIBC (all P < 0.0004 for comparisons with zero). For the non-C282Y homozygote proband group, residual h2 was significant with a value of 0.64 (0.26) for ln SF (p=0.0096). In conclusion, serum iron measures have significant heritability components, after excluding known genetic and non-genetic sources of variation.
doi:10.1002/ajh.21585
PMCID: PMC3816512  PMID: 20095037
HFE; familial aggregation; transferrin saturation; serum ferritin concentration

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