The H63D mutation of the hemochromatosis gene is associated with sustained virological response in chronic hepatitis C patients treated with interferon-based therapy: a meta-analysis

The hemochromatosis (HFE) gene encodes the HFE protein that regulates iron absorption. HFE mutations lead to the hemochromatosis disease of excessive iron absorption. HFE mutations may also influence the sustained virologic response (SVR, long-term virus suppression) in chronic hepatitis C patients treated with interferon-based antiviral therapy. We performed a meta-analysis of all English and Chinese language studies of HFE mutations and SVR in interferon-treated chronic hepatitis C patients indexed in the Medline, PubMed, Embase, and China National Knowledge Infrastructure databases to November 2011. Seven studies involving 605 patients with HFE mutations (homozygous or heterozygous mutation of C282Y, H63D or S65C) and 1279 with wild-type HFE (no mutation of C282Y, H63D or S65C for both alleles) were analyzed. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with the fixed- or random-effect models. HFE mutations were associated with significantly higher SVR rate (vs. wild-type: OR = 1.56, 95% CI: 1.23-1.97, P < 0.001), indicating that mutation carriers were likely to achieve SVR in response to interferon-based antiviral therapy. Stratification analysis by HFE mutation type revealed that the H63D mutation was associated with a significantly higher SVR rate (OR = 1.60, 95% CI: 1.09-2.34, P = 0.020), while the C282Y mutation was not (OR = 1.19, 95% CI: 0.71-1.98, P = 0.510). Our meta-analysis results indicate that the H63D mutation in HFE is associated with a higher SVR rate in chronic hepatitis C patients treated with interferon-based antiviral therapy.     

Identification of new mutations of the HFE, hepcidin, and transferrin receptor 2 genes by denaturing HPLC analysis of individuals with biochemical indications of iron overload

BACKGROUND: Hereditary hemochromatosis is a recessive disorder characterized by iron accumulation in parenchymal cells, followed by organ damage and failure. The disorder is mainly attributable to the C282Y and H63D mutations in the HFE gene, but additional mutations in the HFE, transferrin receptor 2 (TfR2), and hepcidin genes have been reported. The copresence of mutations in different genes may explain the phenotypic heterogeneity of the disorder and its variable penetrance. METHODS: We used denaturing HPLC (DHPLC) for rapid DNA scanning of the HFE (exons 2, 3, and 4), hepcidin, and TfR2 (exons 2, 4 and 6) genes in a cohort of 657 individuals with altered indicators of iron status. RESULTS: DHPLC identification of C282Y and H63D HFE alleles was in perfect agreement with the restriction endonuclease assay. Fourteen DNA samples were heterozygous for the HFE S65C mutation. In addition, we found novel mutations: two in HFE (R66C in exon 2 and R224G in exon 4), one in the hepcidin gene (G71D), and one in TfR2 (V22I), plus several intronic or silent substitutions. Six of the seven individuals with hepcidin or TfR2 coding mutations carried also HFE C282Y or S65C mutations. CONCLUSION: DHPLC is an efficient method for mutational screening for the genes involved in hereditary hemochromatosis and for the study of their copresence.     

The prevalence of hereditary hemochromatosis in some men from the Eastern part of Turkey and the effects of H63D mutations on iron studies

Abstract Background: Hereditary hemochromatosis (HH) is characterized by an increased intestinal absorption of iron due to mutations in iron-related genes. The C282Y and H63D mutations of the HFE gene are principally responsible for HFE-related hemochromatosis. The majority of HH cases are reported in Western countries where HFE-related mutations are common. The prevalence of HFE-related mutations is not yet clear in eastern Turkey. We aim to clarify the frequency of HFE gene mutations in men who live in eastern Turkey and also assess the biochemical effects of the H63D mutation. Methods: Using the reverse hybridization Hemochromatosis Strip Assay A (ViennaLab, Profiblot T-48, Tecan), DNA extracted from the blood samples of 159 healthy men was analyzed for different mutations in the HFE gene. Results: The H63D mutation was found with an overall carrier frequency of 5.6% (7% heterozygous and 2% homozygous). We also noted that the C282Y gene mutation was not detected in the study. In subjects with the H63D mutation, there were significantly elevated levels both of serum iron and transferrin saturation (p<0.05). Other hematologic and biochemical tests were in the normal ranges in H63D-positive subjects. Conclusions: A lack of C282Y mutations has been reported as a basic finding for non-Western countries and Turkey. H63D mutations in the HFE gene may cause higher levels of serum iron and transferrin saturation. Both may be useful as simple screening tools for HH.     

Prevalence of HFE (hemochromatosis gene) mutations in unselected male patients with type 2 diabetes

To assess the prevalence of mutations in the HFE (hemochromatosis) gene in unselected male patients with type 2 diabetes, we examined 220 white men without known diabetes and 220 age-matched white men with type 2 diabetes for mutations in the HFE gene. Nucleotide 845 (C282Y) and 187(H63D) alleles were amplified by polymerase chain reaction (PCR) with lymphocyte DNA. The PCR products were analyzed by restriction enzyme digestion. One of the 220 patients (0.45%) with diabetes was homozygous for the HFE 845A (C282Y) mutation and 25 (11.3%) were heterozygous for the same mutation, of whom 3 (1.3%) were compound heterozygotes also carrying the HFE 187G (H63D) mutation. These frequencies did not differ significantly from the control population without diabetes. There is no evidence that HFE mutations are found in excess in unselected male patients with type 2 diabetes, and there is no indication for a population-based search for an excess of these alleles in type 2 diabetes.     

Frequencies of C282Y and H63D mutations and transferrin saturation indices in the Korean population.

Hereditary hemochromatosis (HHC) is an autosomal recessive disorder that damages various organs because of the deposition of excess iron. At the human hemochromatosis (HFE) gene, two mutations of C282Y and H63D have been reported. The frequencies of C282Y and H63D mutations vary among ethnic groups. At present, the most suitable screening test for HHC is the assessment of transferrin saturation (TS). We investigated the distribution of TS and the frequencies of C282Y and H63D mutations among Koreans. TS was measured in 2152 subjects who visited the health promotion center for a checkup. The mean (+/-SD) of TS was 41.7+/-15.4%. We randomly selected 240 subjects and tested them for C282Y and H63D mutations using PCR-restriction fragment length polymorphism (RFLP). All 240 randomly selected samples were found to be G/G homozygous non-mutated for C282Y. Of the 240 subjects, 18 (7.5%) were found to be C/G heterozygous and 222 subjects were C/C homozygous non-mutated for H63D. In this study, the C282Y mutation was not found in the Korean population, and the H63D mutation showed allele frequency of 3.8%. The mean TS in this study was higher than that of Caucasians.     

Reference centiles for serum ferritin and percentage of transferrin saturation, with application to mutations of the HFE gene

BACKGROUND: The gene that causes most cases of hereditary hemochromatosis is designated HFE. Individuals with mutations in the HFE gene may have increased serum iron, transferrin saturation, and ferritin concentrations relative to individuals with the wild-type genotype. METHODS: We generated reference centiles for percentage of transferrin saturation and serum ferritin concentrations in normal (wild-type), healthy Caucasian adults. We then examined transferrin and ferritin concentrations relative to these centiles in 81 individuals homozygous for the major hemochromatosis mutation C282Y and 438 individuals with the compound heterozygous HFE genotype C282Y/H63D. RESULTS: Serum ferritin concentrations, but not percentage of transferrin saturation, in normal, healthy women tended to increase sharply as they progressed through menopause. Transferrin and serum ferritin centiles for normal, healthy females were lower than the corresponding centiles in normal, healthy males. C282Y homozygotes had abnormally high transferrin saturation and serum ferritin values relative to the wild types. Compound heterozygotes appeared to be a mixture of individuals with unexceptional transferrin and ferritin values and those with abnormally large values similar to the homozygotes, with equal proportions of each. CONCLUSIONS: There are age- and sex-related differences in reference centiles for the percentage of transferrin saturation and serum ferritin concentrations in normal, healthy adults. Individuals homozygous for the C282Y mutation in the HFE gene have abnormal transferrin saturation and serum ferritin values relative to the reference population; penetrance with the compound heterozygotes, as reflected by abnormal transferrin and ferritin values, is less than with the homozygotes.     

中国健康正常人、骨髓增生异常综合征及再生障碍性贫血患者HFE基因突变的研究

目的 分析健康正常人、骨髓增生异常综合征(MDS)和再生障碍件贫血(AA)患者HFE基因突变的频率并探讨其与铁代谢和铁过载脏器功能受损相关指标的关系.方法 采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)联合测序分析的方法检测271例MDS患者、402例从患者和1615名健康正常对照的HFE基因H63D和C282Y突变,并比较未输注红细胞的MDS和AA患者HFE基因突变组与未突变组的铁代谢指标和铁过载脏器功能受损相关指标.结果 271例MDS患者、402例AA患者及1615名正常对照中均未发现HFE基因C282Y突变及C282Y和H63D复合突变.MDS患者H63D突变率为4.1%(271例中11例),且均为杂合型.从患者H63D杂合型突变率为9.7%(402例中39例),纯合型突变率0.25%(402例中1例).正常对照H63D杂合型突变率为10.2%(164例),纯合型突变率0.24%(4例).MDS患者H63D突变率明显低于正常对照(P:0.002),而AA患者与正常对照比较差异无统计学意义(P=0.988).未输注红细胞的MDS及AA患者的血清铁蛋白(SF)值、血清铁(SI)值、铁饱和度(TS)值均接近或高于正常高限,血清未饱和铁(UIBC)值明显低于正常.未输注红细胞的MDS患者H63D突变组与未突变组的SF、SI、UIBC、总铁结合力(TIBC)、TS值差异无统计学意义(P值均＞0.05);未输注红细胞的AA患者H63D突变绀的SI值明显高于未突变组[42.6(24.6～60.4)μmol/L和32.0(8.4～63.3)μmol/L(P=0.011)],而两组的其他铁代谢参数差异均无统计学意义(P值均＞0.05).MDS及AA患者或就诊前未输注红细胞的MDS及AA患者H63D突变组与未突变组的肝酶值、卒腹血糖(FBS)值、心电图(ECG)异常率、外周血指标差异均无统计学意义(P值均＞0.05).结论 HFE基因H63D和C282Y突变在人群的分布有种族和遗传的差异,中国人HFE基因的突变率明显低于白种人.MDS与AA患者本身均可致铁过载,HFE基因H63D和C282Y突变并不是导致其铁过载的主要原因.     

High prevalence of non-HFE gene-associated haemochromatosis in patients from southern Italy.

Hereditary haemochromatosis is an autosomal recessive disorder of iron regulation that results in abnormal intestinal iron absorption with progressive iron overloading of parenchymal cells. Two specific, single point mutations of the HFE gene (C282Y and H63D) have been described in haemochromatosis patients. Epidemiological studies have revealed a strict association between hereditary haemochromatosis and C282Y homozygosis or C282Y/H63D compound heterozygosis, suggesting that these mutations may provide a useful tool for diagnosis. However, recent investigations from southern Europe have reported lower allelic frequencies of the C282Y mutation among haemochromatosis patients, apparently depending on the geographical area of the population analysed. To assess the predictive value of the detection of the C282Y and H63D HFE mutations in our geographical area, we have evaluated their occurrence in 46 haemochromatosis patients from southern Italy. We found that only 19.6% of our patients were homozygous for the C282Y mutation and 21.7% were compound C282Y/H63D heterozygotes. Among the remaining 59%, approximately 40% did not display any of the known HFE mutations. We conclude that, in southern Italy, another genetic determinant/s must be responsible for many haemochromatosis cases and that a genetic screening for the C282Y and H63D HFE mutations is not sufficient for hereditary haemochromatosis diagnosis.     

HFE mutations do not account for transfusional iron overload in patients with acute myeloid leukemia

BACKGROUND: Hereditary hemochromatosis (HH) is a HFE gene-linked disorder affecting 1 of 200 to 400 persons in white populations. It has been proposed that patients with a hematologic malignancy who are receiving frequent RBC transfusions should be screened for HFE mutations. This would identify C282Y homozygotes, who have a high risk of developing severe iron overload. STUDY DESIGN AND METHODS: DNA samples from 128 controls and 23 adult long-term survivors of acute myeloid leukemia (AML) treated at the Oulu University Hospital (Oulu, Finland) from 1987 to 2000 were examined for the presence of the C282Y and H63D mutations in HFE. All the patients were severely iron-overloaded, as determined from high serum ferritin values and/or increased storage iron in bone marrow. Phlebotomies were performed in five patients because of the symptoms of iron overload. DNA extracted from the blood was used to amplify HFE gene fragments by the PCR method, after which the amplification products were digested with restriction endonucleases SnaB I and Bcl I, and the restriction fragments were analyzed on agarose gels. RESULTS: No chromosomes with the C282Y mutation were found among the AML patients, and 5 patients (21.7%) were heterozygous for the H63D mutation. In the control group, 13 persons (10.2%) were heterozygous for the C282Y mutation and 26 (20.3%) for the H63D mutation, including 3 C282Y/H63D double heterozygotes. CONCLUSION: HFE mutations do not account for the harmful iron overload that develops in AML patients who receive large quantities of RBC concentrates after intensive chemotherapy.     

HFE mutations and hemochromatosis in Danish patients admitted for HFE genotyping

Analysis of the common C282Y and H63D mutations in the HFE gene is widely used to diagnose hereditary hemochromatosis (HH). The aim of this study was to evaluate the efficiency with which different hospitals and general practitioners select patients for HH genotype and to determine the distribution of HFE mutations in such patients. Nine hundred unrelated patients from Danish hospitals and general practitioners (group A) and 69 consecutive patients from a specialized liver unit (group B) were examined for HFE substitutions using multiplex real-time polymerase chain reaction. In group A we found 13.0% (0%) C282Y homozygotes, 5.8% (2.6%) H63D/C282Y compound heterozygotes and 1.9% (3.1%) S65C heterozygotes. The values for 420 Danish blood donors are shown in parentheses. The distribution of genotypes in group B was similar to that of the blood donors. Serum ferritin, transferrin iron saturation and pathological data were collected from 38 randomly selected C282Y homozygotes, 36 H63D/C282Y compound heterozygotes, 19 H63D heterozygotes, 17 S65C heterozygotes and 144 wild-types. All of the C282Y homozygotes and 28% of the compound heterozygotes were diagnosed as HH patients. There was no evidence of HH in the H63D homozygotes or S65C heterozygotes. Moreover, 7 wild-type patients, 2 C282Y heterozygote patients and one H63D heterozygote patient fulfilled the criteria for HH. The significant enrichment of HH among associated genotype samples submitted for HFE testing indicates that the clinical selection is generally adequate. However, the study showed substantial deviation in the selection efficiency among the various hospitals and general practitioners.     

HFE mutations and hemochromatosis in Danish patients admitted for HFE genotyping

Analysis of the common C282Y and H63D mutations in the HFE gene is widely used to diagnose hereditary hemochromatosis (HH). The aim of this study was to evaluate the efficiency with which different hospitals and general practitioners select patients for HH genotype and to determine the distribution of HFE mutations in such patients. Nine hundred unrelated patients from Danish hospitals and general practitioners (group A) and 69 consecutive patients from a specialized liver unit (group B) were examined for HFE substitutions using multiplex real-time polymerase chain reaction. In group A we found 13.0% (0%) C282Y homozygotes, 5.8% (2.6%) H63D/C282Y compound heterozygotes and 1.9% (3.1%) S65C heterozygotes. The values for 420 Danish blood donors are shown in parentheses. The distribution of genotypes in group B was similar to that of the blood donors. Serum ferritin, transferrin iron saturation and pathological data were collected from 38 randomly selected C282Y homozygotes, 36 H63D/C282Y compound heterozygotes, 19 H63D heterozygotes, 17 S65C heterozygotes and 144 wild-types. All of the C282Y homozygotes and 28% of the compound heterozygotes were diagnosed as HH patients. There was no evidence of HH in the H63D homozygotes or S65C heterozygotes. Moreover, 7 wild-type patients, 2 C282Y heterozygote patients and one H63D heterozygote patient fulfilled the criteria for HH. The significant enrichment of HH among associated genotype samples submitted for HFE testing indicates that the clinical selection is generally adequate. However, the study showed substantial deviation in the selection efficiency among the various hospitals and general practitioners.     

An unusual melting curve profile in LightCycler multiplex genotyping of the hemochromatosis H63D/C282Y gene mutations.

OBJECTIVES: Real time polymerase chain reaction followed by melting curve analysis using hybridization probes has become an important tool in routine diagnosis of the HFE mutations, which are associated with hereditary hemochromatosis. DESIGN AND METHODS: We used the LightCycler technology for simultaneous detection of the H63D and C282Y mutations of the HFE gene in patients with a higher prevalence for hemochromatosis. RESULTS: In our cohort we identified two siblings with a variant pattern of the HFE-LightCycler melting profiles preventing allelic discrimination. CONCLUSIONS: As a consequence, in these patients DNA sequencing or RFLP analysis is necessary to unequivocally assign the correct HFE genotype.     

Rapid single-tube screening of the C282Y hemochromatosis mutation by real-time multiplex allele-specific PCR without fluorescent probes

BACKGROUND: An accurate determination of the major HFE mutation (C282Y), which is associated with hereditary hemochromatosis, is important in diagnosis and risk assessment for this disease. We report a single-tube high-throughput PCR method for the detection of C282Y. METHODS: We combined three previously described principles: allele-specific PCR, mutagenically separated PCR, and amplicon identification by specific dissociation curves. PCR amplification was performed with fluorescence detection or conventional thermocycler using the same primers, reactant constituents, and cycling protocol. Primer cross-reactions were prevented by deliberate primer:primer and primer:template mismatches. RESULTS: PCR products were identified by their characteristic melting temperatures based on SYBR Green I fluorescence. For each of the 256 random and 17 known HFE C282Y samples, mutant homozygous, wild-type, and heterozygous samples were unequivocally distinguished. CONCLUSIONS: This homogeneous assay is rapid, reproducible, does not require fluorescent oligonucleotide probes, and correctly identifies HFE genotypes.     

Clinical utility and outcome of HFE-genotyping in the search for hereditary hemochromatosis

BACKGROUND: Hereditary hemochromatosis (HH), a disease involving iron accumulation in internal organs, occurs in about 1 in 200-400 Caucasians. The gene mutated in this disorder is termed HFE. The present study was designed to evaluate the diagnostic utility and outcome of genetic testing for HH in the service of public health care. METHODS: 137 subjects were referred by health clinics and general hospitals for HFE genotyping from various parts of Finland during the period 1999-2001. Two major mutations (C282Y and H63D) were determined for each patient. Reasons contributing to referrals and sets of values for serum transferrin saturation (s-TS) and iron and ferritin concentrations were also determined. RESULTS: 16.8% of the subjects were homozygous for the C282Y mutation, together with seven C282Y/H63D compound heterozygotes (5.1%). The rate of positive findings for the most typical mutations responsible for HH was found to have increased steadily during the period 1999-2001. CONCLUSIONS: Our data support a role for active testing for the C282Y and H63D mutations in health care. The fairly low number of genotyping requests nevertheless suggests that a large number of patients even with typical clinical signs or symptoms continue to escape detection.     

Complete scanning of the hereditary hemochromatosis gene (HFE) by use of denaturing HPLC

BACKGROUND: Between 4% and 35% of hereditary hemochromatosis (HC) probands are C282Y or H63D heterozygotes or lack both of these two common HFE mutations, and 15 novel HFE mutations have been described recently. We evaluated denaturing HPLC (DHPLC) for screening of the whole HFE coding region and further defined whether HC probands with an incomplete HFE genotype carry uncommon mutations. METHODS: Analytical conditions for each coding exon were determined by a combination of computer melting profile predictions and experimental melting curves. To test accuracy for scanning the complete HFE coding region and optimize DHPLC running conditions, each melting domain was investigated with at least one mutation or one polymorphism as reference. We tested 100 DNA samples harboring the C282Y, H63D, or S65C mutations and 17 artificially created positive controls that carried either 1 of the 14 other known HFE mutations or 3 selected polymorphisms. RESULTS: Investigations on each of the coding exons 1, 2, 4, 5, and 6 could be performed at one analysis temperature. Coding exon 3 displayed a more complex melting profile and required two analysis temperatures. DHPLC detected all known HFE mutations as well as the three selected polymorphisms. CONCLUSIONS: DHPLC can be used to scan the HFE gene in HC probands in whom at least one chromosome lacks an assigned mutation.     

Role of hemochromatosis C282Y and H63D mutations in HFE gene in development of type 2 diabetes and diabetic nephropathy.

OBJECTIVE: In patients with clinical hemochromatosis, the frequency of diabetes ranges from 20 to 50%, and the heterozygosity for the C282Y mutation in the HFE gene might be associated with an increased risk for diabetes. There are also some reports that suggest that iron overload might cause diabetic nephropathy. RESEARCH DESIGN AND METHODS: We performed an association study to assess the role of the C282Y and H63D mutations in the HFE gene as a risk factor for type 2 diabetes and diabetic nephropathy. Altogether, 563 patients with type 2 diabetes were included in the study. In the analyzed group, 108 patients had overt proteinuria, 154 had microalbuminuria, and 301 had normoalbuminuria. Among the patients with normoalbuminuria, only those with known diabetes duration > or = 10 years were considered normoalbuminuric (n = 162). A total of 196 unrelated healthy subjects were used as a control group. All subjects were genotyped for C282Y and H63D using the polymerase chain reaction-based protocol. RESULTS: There was an increased frequency of 282Y allele carriers among patients with type 2 diabetes versus healthy control subjects (OR 5.3, 95% CI 1.6-17.3). We observed an increased frequency of the 63D allele carriers among patients with diabetic nephropathy (1.8, 1.2-2.8). CONCLUSIONS: In conclusion, our study is the first to indicate that being a carrier of the H63D hemochromatosis mutation is a risk factor for nephropathy in type 2 diabetic patients. We also confirmed previous observations that the frequency of the 282Y mutation was higher in patients with type 2 diabetes than it was in the general population of healthy subjects.     

Prevalence of hemochromatosis-related symptoms among individuals with mutations in the HFE gene

OBJECTIVE: To determine the prevalence of hemochromatosis-related symptoms in homozygotes for the HFE mutation C282Y compared with controls without HFE mutations identified through a large screening program of subjects attending a health appraisal center. SUBJECTS AND METHODS: Presence of symptoms commonly associated with clinical hemochromatosis was ascertained by self-report on a written questionnaire among C282Y homozygotes and HFE wild-type subjects of white or Hispanic ethnicity identified from screening 41,599 adult subjects between March 1999 and August 2001. A subset of C282Y homozygotes and wild-type subjects identified from 12,756 subjects attending the center in the final year of the study completed a standardized double-blind interview with a physician regarding the presence, duration, and severity of a larger set of symptoms. Prevalence of symptoms among C282Y homozygotes and wild-type controls ascertained by written questionnaire and interview were compared by chi2 analysis or Fisher exact test. Symptoms among subjects with other combinations of the C282Y and H63D HFE mutations were also assessed by questionnaire. RESULTS: The 124 C282Y homozygotes who filled out the written questionnaire and the 17 C282Y homozygotes who completed the physician double-blind interview reported no significantly higher rates of arthritis or joint pain, abdominal pain, arrhythmias, darkening of skin, or other symptoms traditionally associated with hemochromatosis compared with the 22,429 wild-type controls who filled out the written questionnaire and 29 wild-type controls who completed the double-blind interview. The only symptom reported more frequently by C282Y homozygotes was loss of body hair, reported by 5 C282Y/C282Y female subjects compared with 1 wild-type male subject (P=.02) in the physician interview. Symptoms among subjects with other HFE genotypes were similar to symptoms of wild-type subjects. CONCLUSIONS: Results of this study indicate that many of the symptoms associated with hemochromatosis are common among HFE wild types and that clinical penetrance of the C282Y/C282Y genotype in regard to these symptoms is low.     

Relationships of serum ferritin, transferrin saturation, and HFE mutations and self-reported diabetes in the Hemochromatosis and Iron Overload Screening (HEIRS) study

OBJECTIVE: We evaluated the associations of self-reported diabetes with serum ferritin concentration, transferrin saturation (TfSat), and HFE C282Y and H63D mutations in six racial/ethnic groups recruited at five field centers in the Hemochromatosis and Iron Overload Screening (HEIRS) study. RESEARCH DESIGN AND METHODS: Analyses were conducted on 97,470 participants. Participants who reported a previous diagnosis of diabetes and/or hemochromatosis or iron overload were compared with participants who did not report a previous diagnosis. RESULTS: The overall prevalence of diabetes was 13.8%; the highest prevalence was in Pacific Islanders (20.1%). Of all participants with diabetes, 2.0% reported that they also had hemochromatosis or iron overload. The mean serum ferritin concentration was significantly greater in women with diabetes in all racial/ethnic groups and in Native-American men with diabetes than in those without diabetes. The mean serum ferritin concentration was significantly lower in Asian men with diabetes than in those without diabetes. Mean TfSat was lower in participants with diabetes from all racial/ethnic groups except Native-American women than in those without diabetes. There was no significant association of diabetes with HFE genotype. The mean serum ferritin concentration was greater (P < 0.0001) in women with diabetes than in those without diabetes for HFE genotypes except C282Y/C282Y and C282Y/H63D. Log serum ferritin concentration was significantly associated with diabetes in a logistic regression analysis after adjusting for age, sex, racial/ethnic group, HFE genotype, and field center. CONCLUSIONS: Serum ferritin concentration is associated with diabetes, even at levels below those typically associated with hemochromatosis or iron overload.