Search

We compared initial screening data of 44,082 white and 27,124 black Hemochromatosis and Iron Overload Screening (HEIRS) Study participants. Each underwent serum transferrin saturation (TfSat) and ferritin (SF) measurements without regard to fasting, and HFE C282Y and H63D genotyping. Elevated measurements were defined as: TfSat more than 50% (men), more than 45% (women); and SF more than 300 ng/ml (men), more than 200 ng/ml (women). Mean TfSat and percentages of participants with elevated TfSat were significantly greater in whites than in blacks. Mean SF and percentages of participants with elevated SF were significantly greater in blacks than in whites. TfSat and SF varied by gender and age in whites and blacks. Prevalences of genotypes that included either C282Y or H63D were significantly greater in whites than in blacks. The prevalence of elevated TfSat and SF plus genotypes C282Y/C282Y, C282Y/H63D, or H63D/H63D was 0.006 in whites and 0.0003 in blacks. Among whites with HFE C282Y homozygosity, 76.8% of men and 46.9% of women had elevated TfSat and SF values. Three black participants had HFE C282Y homozygosity; one had elevated TfSat and SF values. Possible explanations for differences in TfSat and SF in whites and blacks and pertinence to the detection of hemochromatosis, iron overload, and other disorders with similar phenotypes are discussed.

Objective:To evaluate familial and genetic influences on carotid artery plaque, a qualitative marker of the systemic burden of atherosclerosis. Methods:The design was a cross-sectional study of 2,223 members of 525 randomly-ascertained families and 2,514 members of 589 high coronary heart disease (CHD) risk families from 4 U.S. communities. Results:The prevalence of plaque was 33, 36, and 47%, respectively, among probands with 0, 1, and 2 or more first-degree relatives with a history of CHD. There was evidence of sibling aggregation of plaque in random families (OR = 1.89; 95% CI: 1.44, 2.48), but associations were substantially attenuated when adjusted for major cardiovascular disease risk factors. A genome scan with 420 microsatellite markers revealed no regions of significant or suggestive linkage for plaque in 342 affected sibling pairs, although suggestive linkage (LOD score: 2.43) was found on chromosome 2p11.2 (D2S1790) in pairs aged 55 years or younger. Other markers with nominal evidence for linkage (p < 0.05) were found on chromosomes 2p25, 2q24-q32, 6q21-q23, 7p12-p21, 7q11-q21, 8q24, 12q12-q13, 18p11, 21q21 and Xp11, Xq12, and Xq24. Conclusions:There was modest familial aggregation of carotid artery plaque, but a genome-wide scan indicated no regions of significant or suggestive linkage.

To assess the genetic contribution to electrocardiographic (ECG) measurements, heritability analysis was performed on ECG data collected on 251 pairs of adult male twins during the second examination of the National Heart, Lung and Blood Institute twin study, a multicenter study of cardiovascular risk factors. Resting 12-lead ECGs were obatained on each twin, pair and, the R-R, QRS, QT, and JT intervals were measured. Both the R-R and QT intervals demonstrated significant heritable components, accounting for 77% and 36%, respectively, of the variability. No significant heritable component of the QRS complex could be identified. Although the MZ intraclass correlation was higher than the DZ intraclass correlation, the JT interval did not demonstrate significant heritability. Therefore, in adult males both heart rate and the duration of ventricular repolarization have significant heritable components. These heritable components may need to be considered when using ECG measurements to screen for patients at risk for cardiovascular disorders or sudden cardiac death.

The Vietnam Era Twin (VET) Registry includes 14 800 male twins born 1939–55 and in military service in 1964–75. A mailed health survey including the Jenkins Sleep Questionnaire was sent to 11 959 members and 8870 (74.2%) provided responses on the frequency of sleep problems in the previous month. Prevalence of those experiencing conditions at least 1 day per month was 67.2% for waking often, 61.5% for waking tired/worn out, 48.1% for trouble falling asleep and 48.6% for awakening early. Ordinal logistic regression analysis was used to estimate sleep problems from demographic, behaviour and lifestyle characteristics, and morbid conditions. Black (vs. white) race, older age, church/religious group participation, social support, employment, cigarette smoking, light physical activity, and strenuous physical activity were associated with lower risk of one or more sleep problems. Eleven morbid conditions with a prevalence of 1% or more, coffee consumption, heavy alcohol consumption, and Framingham Type A behaviour pattern were associated with a higher risk of sleep problems. These analyses suggest that sleep problems may be one of the mechanisms relating reduced quality of life to many physical and behavioural characteristics. Fortunately, a number of the risk factors associated with sleep problems are lifestyle characteristics which, if modified, may reduce sleep problems.

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.

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.

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.

Some patients with hemochromatosis (HC) experience fatigue, heart failure or arrhythmias, diabetes mellitus, liver damage, impotence, or arthritis. We examined self-reported symptoms and clinical conditions in persons homozygous for HFE C282Y, the major HC-associated gene mutation, identified in the Hemochromatosis and Iron Overload Screening (HEIRS) Study, a multi-center, multi-ethnic study in which 101,168 adults were recruited from primary care settings. Non-Hispanic Caucasian C282Y homozygotes were compared to participants without HFE C282Y or H63D alleles (controls) with transferrin saturation (TfS) and serum ferritin (SF) levels in the middle half of gender-specific distributions. Evaluation included a medical history, focused physical examination, and repeat SF. Among 44,082 non-Hispanic Caucasian participants screened at five Field Centers in the United States and Canada, 282 persons homozygous for C282Y were identified, comprising three groups: newly-diagnosed cases with normal (N=64) or elevated (N=131) SF (>200 μg/L in women, >300 μg/L in men), and previously-diagnosed cases (N=87). There were 364 non-Hispanic Caucasian controls. Significant differences were observed for six of 38 outcomes. Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated SF reported significantly more chronic fatigue than controls (p=0.002). All groups of C282Y homozygotes reported weight loss more often than controls (p<0.001). Excessive thirst was reported more often than controls by newly diagnosed C282Y homozygotes, regardless of SF level (p=0.004), but there was no difference in self-reported history of diabetes. Joint stiffness was more common among newly diagnosed C282Y homozygotes with elevated SF than among control subjects (p<0.001). Swelling or tenderness of the second and third metacarpophalangeal joints and increased pigmentation were also more common among previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated SF than among controls (p=0.001 and p=0.002, respectively). The prevalences of manifestations related to liver or heart disease among C282Y homozygotes were not significantly different from controls. There were no differences among the three groups of C282Y homozygotes in the prevalences of any symptoms or clinical conditions. In summary, some symptoms and conditions associated with HC were more prevalent among C282Y homozygotes than among controls. However, C282Y homozygotes identified by screening in primary care settings did not have a higher prevalence of most symptoms and signs associated with HC than control subjects.

Some patients with hemochromatosis (HC) experience fatigue, heart failure or arrhythmias, diabetes mellitus, liver damage, impotence, or arthritis. We examined self-reported symptoms and clinical conditions in persons homozygous for HFEC282Y, the major HC-associated gene mutation, identified in the Hemochromatosis and Iron Overload Screening (HEIRS) Study, a multi-center, multi-ethnic study in which 101,168 adults were recruited from primary care settings. Non-Hispanic Caucasian C282Y homozygotes were compared to participants without HFEC282Y or H63D alleles (controls) with transferrin saturation (TfS) and serum ferritin (SF) levels in the middle half of gender-specific distributions. Evaluation included a medical history, focused physical examination, and repeat SF. Among 44,082 non-Hispanic Caucasian participants screened at five Field Centers in the United States and Canada, 282 persons homozygous for C282Y were identified, comprising three groups: newly-diagnosed cases with normal (N=64) or elevated (N=131) SF (>200 μg/L in women, >300 μg/L in men), and previously-diagnosed cases (N=87). There were 364 non-Hispanic Caucasian controls. Significant differences were observed for six of 38 outcomes. Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated SF reported significantly more chronic fatigue than controls (p=0.002). All groups of C282Y homozygotes reported weight loss more often than controls (p<0.001). Excessive thirst was reported more often than controls by newly diagnosed C282Y homozygotes, regardless of SF level (p=0.004), but there was no difference in self-reported history of diabetes. Joint stiffness was more common among newly diagnosed C282Y homozygotes with elevated SF than among control subjects (p<0.001). Swelling or tenderness of the second and third metacarpophalangeal joints and increased pigmentation were also more common among previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated SF than among controls (p=0.001 and p=0.002, respectively). The prevalences of manifestations related to liver or heart disease among C282Y homozygotes were not significantly different from controls. There were no differences among the three groups of C282Y homozygotes in the prevalences of any symptoms or clinical conditions. In summary, some symptoms and conditions associated with HC were more prevalent among C282Y homozygotes than among controls. However, C282Y homozygotes identified by screening in primary care settings did not have a higher prevalence of most symptoms and signs associated with HC than control subjects.

Mean serum ferritin concentration (SF) has been positively associated with diabetes mellitus in some racial/ethnic groups. We evaluated the associations of self-reported diabetes mellitus with SF, serum transferrin saturation (TfSat), and HFE C282Y and H63D mutations in six racial/ethnic groups recruited at five Field Centers in the multi-center, primary care-based HEIRS Study. Analyses were conducted on the 97,470 participants for whom pertinent data were available. Participants who reported that they had been previously diagnosed with diabetes mellitus and/or hemochromatosis or iron overload were compared to participants who did not report a previous diagnosis. The overall prevalence of diabetes mellitus was 13.8%; the highest prevalence was observed in Native Hawaiian/Pacific Islanders (20.1%). 2.0% of all participants with diabetes mellitus and 2.2% of whites with diabetes mellitus reported that they also had hemochromatosis or iron overload. Mean SF was elevated in women with diabetes mellitus in all racial/ethnic groups and in American Indian/Alaska Native men with diabetes mellitus. Mean SF was significantly lower in Asian men with diabetes mellitus. Mean TfSat was lower (or not increased) in participants with diabetes mellitus than in those without diabetes mellitus. There was no significant association of diabetes mellitus with HFE genotype. Mean SF was greater (p <0.0001) in women with diabetes mellitus than in those without diabetes mellitus for HFE genotypes except C282Y/C282Y and C282Y/H63D. There was a significant positive association of log SF and diabetes mellitus in a logistic regression analysis after adjusting for age, gender, racial/ethnic group, HFE genotype, and Field Center. We conclude that SF is significantly associated with diabetes mellitus, even at levels of SF below those typically associated with hemochromatosis or iron overload.

Mean serum ferritin concentration (SF) has been positively associated with diabetes mellitus in some racial/ethnic groups. We evaluated the associations of self-reported diabetes mellitus with SF, serum transferrin saturation (TfSat), and HFEC282Y and H63D mutations in six racial/ethnic groups recruited at five Field Centers in the multi-center, primary care-based HEIRS Study. Analyses were conducted on the 97,470 participants for whom pertinent data were available. Participants who reported that they had been previously diagnosed with diabetes mellitus and/or hemochromatosis or iron overload were compared to participants who did not report a previous diagnosis. The overall prevalence of diabetes mellitus was 13.8%; the highest prevalence was observed in Native Hawaiian/Pacific Islanders (20.1%). 2.0% of all participants with diabetes mellitus and 2.2% of whites with diabetes mellitus reported that they also had hemochromatosis or iron overload. Mean SF was elevated in women with diabetes mellitus in all racial/ethnic groups and in American Indian/Alaska Native men with diabetes mellitus. Mean SF was significantly lower in Asian men with diabetes mellitus. Mean TfSat was lower (or not increased) in participants with diabetes mellitus than in those without diabetes mellitus. There was no significant association of diabetes mellitus with HFEgenotype. Mean SF was greater (p <0.0001) in women with diabetes mellitus than in those without diabetes mellitus for HFEgenotypes except C282Y/C282Y and C282Y/H63D. There was a significant positive association of log SF and diabetes mellitus in a logistic regression analysis after adjusting for age, gender, racial/ethnic group, HFEgenotype, and Field Center. We conclude that SF is significantly associated with diabetes mellitus, even at levels of SF below those typically associated with hemochromatosis or iron overload.

We compared initial screening data of 44,149 whites (17,043 men; 27,106 women) and 26,947 blacks (9,788 men; 17,159 women) who reported no previous diagnosis of hemochromatosis or iron overload from a primary care-based sample of ~100,000 adults ≥25 years recruited from 5 Field Centers. Each underwent transferrin saturation (TfSat) and serum ferritin (SF) measurements without regard to fasting, and HFEC282Y and H63D genotyping. We observed these mean TfSat and SF values and percentages of participants with elevated biochemical measurements (TfSat >50% and SF >300 ng/mL, men; TfSat >45% and SF >200 ng/mL, women):

Designing an optimal screening approach for hemochromatosis and iron overload requires knowledge of racial/ethnic subpopulations and frequencies of HFEmutations and phenotypes in geographic areas. In the HEIRS Study, HFEC282Y and H63D genotypes and prevalences of participants who met biochemical criteria for further evaluation (transferrin saturation >50% and ferritin >300 ng/mL, men; >45% and >200 ng/mL, women) were compared in a primary care-based sample of ~100,000 adults ≥25 years from 5 Field Centers. There were different respective HFEC282Y and H63D genotype frequencies in Whites, Blacks, Asians, and Hispanics across geographic areas (all p<0.0001), but not in Native Americans or Pacific Islanders. In Whites, the C282Y/C282Y proportion was significantly higher in AL than in CA or OR/HI. AL also had a significantly higher proportion of C282Y/wt than CA or OR/HI. In Blacks, D.C. had a significantly higher proportion of C282Y and H63D genotypes than AL. ONT had a significantly higher H63D genotype proportion than AL. In Asians, CA had a significantly higher proportion of H63D genotypes than OR/HI or ONT. In Hispanics, there were significant differences between: AL and CA; AL and D.C.; CA and D.C.; CA and OR/HI; D.C. and OR/HI; and D.C. and ONT. We also observed:

Designing an optimal screening approach for hemochromatosis and iron overload requires knowledge of racial/ethnic subpopulations and frequencies of HFE mutations and phenotypes in geographic areas. In the HEIRS Study, HFE C282Y and H63D genotypes and prevalences of participants who met biochemical criteria for further evaluation (transferrin saturation >50% and ferritin >300 ng/mL, men; >45% and >200 ng/mL, women) were compared in a primary care-based sample of ~100,000 adults ≥25 years from 5 Field Centers. There were different respective HFE C282Y and H63D genotype frequencies in Whites, Blacks, Asians, and Hispanics across geographic areas (all p<0.0001), but not in Native Americans or Pacific Islanders. In Whites, the C282Y/C282Y proportion was significantly higher in AL than in CA or OR/HI. AL also had a significantly higher proportion of C282Y/wt than CA or OR/HI. In Blacks, D.C. had a significantly higher proportion of C282Y and H63D genotypes than AL. ONT had a significantly higher H63D genotype proportion than AL. In Asians, CA had a significantly higher proportion of H63D genotypes than OR/HI or ONT. In Hispanics, there were significant differences between: AL and CA; AL and D.C.; CA and D.C.; CA and OR/HI; D.C. and OR/HI; and D.C. and ONT. We also observed: Prevalences of Participants Who Met Biochemical Criteria for Further Evaluation Race/Ethnicity Geographic Area Prevalence (%) 95% CI Asians California 5.54 4.98, 6.16 Oregon/Hawaii 5.06 4.29, 5.95 Ontario 4.25 3.69, 4.88 Alabama 1.41 0.25, 7.56 D.C. 0.96 0.26, 3.42 Pacific Islanders California 3.66 1.25, 10.21 Oregon/Hawaii 3.47 2.23, 5.36 Native Americans Alabama 2.65 0.91, 7.52 Oregon/Hawaii 2.50 0.69, 8.66 D.C. 0.99 0.17, 5.40 Ontario 0.75 0.21, 2.71 Whites Ontario 2.31 2.08, 2.56 California 1.93 1.56, 2.37 Oregon/Hawaii 1.52 1.34, 1.73 Alabama 1.48 1.26, 1.74 D.C. 1.40 0.80, 2.43 Hispanics Ontario 1.92 0.82, 4.41 California 1.52 1.28, 1.79 Oregon/Hawaii 1.34 0.73, 2.4 Alabama 0.84 0.23, 3.01 D.C. 0.74 0.48, 1.16 Blacks D.C. 1.75 1.56, 1.96 Ontario 1.55 0.52, 4.45 Alabama 1.09 0.90, 1.32 Oregon/Hawaii 0.92 0.31, 2.66 California 0.86 0.29, 2.51 The percentage of men who met biochemical criteria for further evaluation was greater than that of women. We conclude that 1) C282Y and H63D genotype frequencies vary significantly within a single racial/ethnic group across geographic regions; and 2) the percentage of participants who met biochemical criteria for further evaluation varies by racial/ethnic group.

We compared initial screening data of 44,149 whites (17,043 men; 27,106 women) and 26,947 blacks (9,788 men; 17,159 women) who reported no previous diagnosis of hemochromatosis or iron overload from a primary care-based sample of ~100,000 adults ≥25 years recruited from 5 Field Centers. Each underwent transferrin saturation (TfSat) and serum ferritin (SF) measurements without regard to fasting, and HFE C282Y and H63D genotyping. We observed these mean TfSat and SF values and percentages of participants with elevated biochemical measurements (TfSat >50% and SF >300 ng/mL, men; TfSat >45% and SF >200 ng/mL, women): Participants Mean % TfSat (95% CI) Elevated TfSat, % Participants Mean SF, ng/mL (95% CI) Elevated SF, % Participants White men 32.4 (32.3, 32.6) 7.05 150.9 (149.1, 152.8) 19.49 Black men 29.3 (29.1, 29.5) 4.03 178.4 (175.5, 181.3) 25.95 p Value <0.0001 <0.0001 <0.0001 <0.0001 White women 27.5 (27.3, 27.6) 6.62 63.0 (62.3, 63.7) 8.74 Black women 23.3 (23.1, 23.4) 3.04 68.3 (67.2, 69.4) 15.43 p Value <0.0001 <0.0001 <0.0001 <0.0001 In participants grouped by decade, mean TfSat was greater in white men than in black men, and in white women than in black women (all p<0.0001). Mean SF was greater in black men than in white men in all decades except 25–34 years, and in black women than in white women in decades ≥45 years. SF increased with age to ~45 years in white men and ~50 years in black men, and then decreased. In white women, SF rose with age until ~62 years and less rapidly to age ≥80. In black women, SF rose with age until ~62 years and then decreased. C282Y allele frequency was 0.0700 (95% CI: 0.0683, 0.0717) in whites and 0.0119 (0.0110, 0.0129) in blacks. H63D allele frequency was 0.1532 (0.1509, 0.1556) in whites and 0.0299 (0.0284, 0.0313) in blacks. Frequencies of genotypes with C282Y or H63D were greater in whites than in blacks (all p<0.0001). The prevalence of elevated TfSat and SF plus genotype C282Y/C282Y was 0.003 in whites and 0.00004 in blacks (p<0.0001). The prevalence of elevated TfSat and SF plus genotype C282Y/C282Y, C282Y/H63D, or H63D/H63D was 0.006 in whites and 0.0003 in blacks (p<0.0001). We conclude that: 1) the prevalence of elevated TfSat is higher in whites and the prevalence of elevated SF is higher in blacks; 2) SF levels increase with age; 3) HFE C282Y and H63D alleles occur more frequently in whites than in blacks; and 4) the prevalence of elevated TfSat and SF plus genotypes with two common HFE mutations is greater in whites than in blacks.