Gordon McLaren - Academia.edu (original) (raw)

Papers by Gordon McLaren

Blood, Nov 16, 2004

Designing an optimal screening approach for hemochromatosis and iron overload requires knowledge ... more 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.

Genetic Testing, Sep 1, 2005

We compared initial screening data of 44,082 white and 27,124 black Hemochromatosis and Iron Over... more 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.

Blood, Nov 16, 2008

Hereditary hemochromatosis (HH) is a common iron overload (IO) disorder of people of western Euro... more Hereditary hemochromatosis (HH) is a common iron overload (IO) disorder of people of western European descent. HH, defined using biochemical criteria, occurs in 0.2%–0.5% of US whites. Some HH patients absorb excessive dietary iron and develop consequent liver fibrosis and cirrhosis, hepatocellular carcinoma, diabetes mellitus, cardiomyopathy, and hypogonadotrophic hypogonadism. Most whites with HH have common mutations (C282Y and H63D) in HFE; this gene encodes HFE, which regulates iron absorption by modulating hepatic expression of hepcidin. The spectrum of HH phenotypes is broad, and mutations in known iron-related genes do not account for most phenotype variability. Thus, it is assumed that HH phenotypes are affected by other genetic and environmental factors. Gender and age are two important factors known to affect HH phenotypes. Putative genetic factors may influence dietary choices or modulate iron absorption or loss via mechanisms presently undefined. The Hemochromatosis and Iron Overload Screening (HEIRS) Study is a multi-center, multi-ethnic study in which transferrin saturation (TS), serum ferritin (SF), and HFE mutations were determined in 101,168 adults. We examined familial aggregation and genetic contributions to iron- and HH-related phenotypes in the HEIRS Family Study and hypothesized that both genetic and environmental factors influence serum iron measures after adjustment for gender, age, HFE C282Y and H63D genotype, and other clinical and demographic characteristics. Heritability (h2), defined as the proportion of total variation due to variability in genetic values, measures the fraction of variation between individuals in a population attributable to additive effects of their genotypes. We estimated heritability of TS, SF, and unbound iron-binding capacity (UIBC) in participants from the HEIRS Family Study (N=180 families, mean size 5.5). Eligible probands (aged >24 y) had both TS and SF values above gender-specific thresholds (TS>50% and SF >300 μg/L in men; TS >45% and SF >200 μg/L in women), or were C282Y homozygotes. Family members, 19 years of age or older, were eligible. There were 77% Caucasians, 3% African Americans, 8% Hispanics, and 10% Asians; average age (SD) was 49 (16) y; 56% were female. The distribution of HFE genotypes was 22% C282Y/C282Y, 7% C282Y/H63D, 2% H63D/H63D, 34% C282Y/+, 8% H63D/+, and 26% +/+. A variance component approach using SOLAR software estimated residual heritability, adjusting for age, gender, their interaction (age × gender), race/ethnicity, and HFE genotype (model 1). In another model, study site, body mass index, menopausal status, phlebotomy treatment, hepatitis, average daily intake of alcohol, and level of C-reactive protein were added to the core set of covariates (model 2). Log transformation of serum ferritin was performed prior to analysis. In model 1 (N=938 individuals), h2 was 0.40 (SE 0.060) for UIBC, 0.26 (0.055) for log SF, and 0.25 (0.056) for TS; P < 0.0001 for each test of h2=0. Age, gender, race/ethnicity, and HFE genotype accounted for 38%, 38%, and 36% of the variability in UIBC, log SF, and TS, respectively. In model 2, based on complete data from N=828 individuals, adjusted for the full set of covariates, h2 was 0.31 (0.067) for UIBC, 0.26 (0.067) for log SF, and 0.16 (0.061) for TS; P < 0.0013 for each. The proportion of variance due to age, gender, HFE gene and all measured environmental factors was 0.43 for UIBC, 0.44 for log SF, and 0.41 for TS. We conclude that quantitative serum iron measures in HEIRS Family Study participants have significant heritability components, even after accounting for effects of HFE C282Y and H63D genotypes. This suggests that other genetic variants contribute to the variability in TS, SF, and UIBC, and indicates the need for gene discovery studies to provide insight into clinical disorders in which morbidity and mortality are affected by perturbations of iron metabolism.

The Canadian journal of gastroenterology, 2013

American Journal of Hematology, 2017

Blood Cells, Molecules, and Diseases, 2020

Blood, 2007

In previous investigations, we modeled the distribution of transferrin saturation (TS) in Caucasi... more In previous investigations, we modeled the distribution of transferrin saturation (TS) in Caucasians and demonstrated a strong association between HFE genotype and TS subpopulations. Extending this approach, we now have analyzed joint population distributions of TS and serum ferritin concentration (SF) measured in the multi-ethnic Hemochromatosis and Iron Overload Screening (HEIRS) Study and examined the association of these distributions with the presence of HFE C282Y and H63D mutations, self-reported liver disease, and iron deficiency (defined as SF <15 μg/L). Based on separate models for each race/ethnicity by gender, four components with successively increasing age-adjusted means for TS and SF were identified in data from 26,832 African Americans, 12,620 Asians, 12,264 Hispanics, and 43,254 Whites. Fig. 1 illustrates age-adjusted values from 16,662 White men. Superimposed 95% confidence ellipses reflect component probability densities and show separation of the 1st and 4th co...

Blood, 2015

Symptoms of porphyria cutanea tarda (PCT) resolve when iron stores are depleted by phlebotomy, an... more Symptoms of porphyria cutanea tarda (PCT) resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y) that increases iron absorption by reducing hepcidin expression is a risk factor for PCT. These observations suggest that PCT is an iron dependent disease and that factors that affect iron homeostasis influence the risk of developing the PCT. Recently, a polymorphic variant (D519G) of GNPAT was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homozygotes) who presented with a high iron phenotype [McLaren CE, et al. Hepatology Aug;62(2):429-39 2015]. Available evidence suggests that like HFE C282Y, GNPAT D519G increases iron absorption by reducing expression of hepcidin. Therefore, we investigated the prevalence GNPAT D519G in patients with PCT. The study population consisted of 247 patients with PCT. High-resolution DNA melting analysis and Taqman SNP assays were used to identify HFE (C282Y) and GNPAT (D519G) allel...

Blood, 2012

2095 Celiac disease (CD) is an increasingly recognized disorder in Caucasian populations of Europ... more 2095 Celiac disease (CD) is an increasingly recognized disorder in Caucasian populations of European origin. Little is known about its prevalence in non-Caucasians. While CD is thought to be a cause of iron deficiency anemia, the extent to which CD contributes to iron deficiency in Caucasians and especially non-Caucasians is unknown. Iron deficiency is one of the most common nutritional deficiencies in both the developed world and in developing countries. Thus, it is important to know the prevalence of CD in different populations and in iron-deficient and iron-replete persons. To answer these questions, we tested serum collected from Caucasian and non-Caucasian men aged ≥ 25 y and women ≥ 50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. In the HEIRS Study, 101,168 participants were screened with serum biochemical tests of iron status, which not only detected participants with iron overload but also identified a unique multiethnic population of participants with...

Statistics in Medicine, 2000

Blood, Nov 16, 2004

We compared initial screening data of 44,149 whites (17,043 men; 27,106 women) and 26,947 blacks ... more 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50% and SF &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;300 ng/mL, men; TfSat &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;45% and SF &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001). The prevalence of elevated TfSat and SF plus genotype C282Y/C282Y was 0.003 in whites and 0.00004 in blacks (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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.

Humana Press eBooks, 2012

Blood, Nov 16, 2006

Some patients with hemochromatosis (HC) experience fatigue, heart failure or arrhythmias, diabete... more 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 (&amp;amp;amp;amp;amp;amp;amp;amp;gt;200 μg/L in women, &amp;amp;amp;amp;amp;amp;amp;amp;gt;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&amp;amp;amp;amp;amp;amp;amp;amp;lt;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&amp;amp;amp;amp;amp;amp;amp;amp;lt;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.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Oct 9, 2009

Blood, Nov 19, 2010

Abstract 4257 Iron in the plasma is bound to transferrin. The total iron binding capacity (TIBC) ... more Abstract 4257 Iron in the plasma is bound to transferrin. The total iron binding capacity (TIBC) represents the maximum amount of iron that can be bound and is directly related to transferrin concentration. TIBC and serum transferrin concentration are increased in iron deficiency and decreased in iron overload. Recently, an association was reported between single nucleotide polymorphisms (SNPs) in the transferrin gene, TF, on chromosome 3q22.1, and serum transferrin levels (Benyamin et al. Am J Hum Genet. 2009;84:60-65). In the current study, we investigated whether the association between SNP rs3811647 in TF and transferrin levels (assessed by measurement of TIBC) is attributable to an effect on regulation of body iron status. The Personalized Medicine Research Project (PMRP) is the largest population-based biobank in the US containing genetic, phenotypic and environmental information on approximately 20,000 people. PMRP is part of the NHGRI-funded eMERGE (www.gwas.net) network. Previously, genotyping was performed on selected PMRP samples with the Illumina Human660W-Quad BeadChip platform. Eligible participants in the current study were 491 white men age ≥ 25 y and 747 white women ≥ 50 y with serum ferritin (SF) values collected between 1985 and 2010. Exclusion criteria included a diagnosis of celiac disease and previous phlebotomy treatment for hemochromatosis. Using TIBC as a marker of serum transferrin for eligible participants having multiple measurements, mean TIBC and median serum ferritin were considered in analyses. Subsets of participants included cases of iron deficiency with multiple measurements of SF ≤ 12 μg/L and iron-replete controls (all measurements of SF…

Blood, Nov 16, 2004

Designing an optimal screening approach for hemochromatosis and iron overload requires knowledge ... more 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50% and ferritin &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;300 ng/mL, men; &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;45% and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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.

Genetic Testing, Sep 1, 2005

We compared initial screening data of 44,082 white and 27,124 black Hemochromatosis and Iron Over... more 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.

Blood, Nov 16, 2008

Hereditary hemochromatosis (HH) is a common iron overload (IO) disorder of people of western Euro... more Hereditary hemochromatosis (HH) is a common iron overload (IO) disorder of people of western European descent. HH, defined using biochemical criteria, occurs in 0.2%–0.5% of US whites. Some HH patients absorb excessive dietary iron and develop consequent liver fibrosis and cirrhosis, hepatocellular carcinoma, diabetes mellitus, cardiomyopathy, and hypogonadotrophic hypogonadism. Most whites with HH have common mutations (C282Y and H63D) in HFE; this gene encodes HFE, which regulates iron absorption by modulating hepatic expression of hepcidin. The spectrum of HH phenotypes is broad, and mutations in known iron-related genes do not account for most phenotype variability. Thus, it is assumed that HH phenotypes are affected by other genetic and environmental factors. Gender and age are two important factors known to affect HH phenotypes. Putative genetic factors may influence dietary choices or modulate iron absorption or loss via mechanisms presently undefined. The Hemochromatosis and Iron Overload Screening (HEIRS) Study is a multi-center, multi-ethnic study in which transferrin saturation (TS), serum ferritin (SF), and HFE mutations were determined in 101,168 adults. We examined familial aggregation and genetic contributions to iron- and HH-related phenotypes in the HEIRS Family Study and hypothesized that both genetic and environmental factors influence serum iron measures after adjustment for gender, age, HFE C282Y and H63D genotype, and other clinical and demographic characteristics. Heritability (h2), defined as the proportion of total variation due to variability in genetic values, measures the fraction of variation between individuals in a population attributable to additive effects of their genotypes. We estimated heritability of TS, SF, and unbound iron-binding capacity (UIBC) in participants from the HEIRS Family Study (N=180 families, mean size 5.5). Eligible probands (aged &amp;amp;amp;amp;amp;amp;amp;amp;gt;24 y) had both TS and SF values above gender-specific thresholds (TS&amp;amp;amp;amp;amp;amp;amp;amp;gt;50% and SF &amp;amp;amp;amp;amp;amp;amp;amp;gt;300 μg/L in men; TS &amp;amp;amp;amp;amp;amp;amp;amp;gt;45% and SF &amp;amp;amp;amp;amp;amp;amp;amp;gt;200 μg/L in women), or were C282Y homozygotes. Family members, 19 years of age or older, were eligible. There were 77% Caucasians, 3% African Americans, 8% Hispanics, and 10% Asians; average age (SD) was 49 (16) y; 56% were female. The distribution of HFE genotypes was 22% C282Y/C282Y, 7% C282Y/H63D, 2% H63D/H63D, 34% C282Y/+, 8% H63D/+, and 26% +/+. A variance component approach using SOLAR software estimated residual heritability, adjusting for age, gender, their interaction (age × gender), race/ethnicity, and HFE genotype (model 1). In another model, study site, body mass index, menopausal status, phlebotomy treatment, hepatitis, average daily intake of alcohol, and level of C-reactive protein were added to the core set of covariates (model 2). Log transformation of serum ferritin was performed prior to analysis. In model 1 (N=938 individuals), h2 was 0.40 (SE 0.060) for UIBC, 0.26 (0.055) for log SF, and 0.25 (0.056) for TS; P &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001 for each test of h2=0. Age, gender, race/ethnicity, and HFE genotype accounted for 38%, 38%, and 36% of the variability in UIBC, log SF, and TS, respectively. In model 2, based on complete data from N=828 individuals, adjusted for the full set of covariates, h2 was 0.31 (0.067) for UIBC, 0.26 (0.067) for log SF, and 0.16 (0.061) for TS; P &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0013 for each. The proportion of variance due to age, gender, HFE gene and all measured environmental factors was 0.43 for UIBC, 0.44 for log SF, and 0.41 for TS. We conclude that quantitative serum iron measures in HEIRS Family Study participants have significant heritability components, even after accounting for effects of HFE C282Y and H63D genotypes. This suggests that other genetic variants contribute to the variability in TS, SF, and UIBC, and indicates the need for gene discovery studies to provide insight into clinical disorders in which morbidity and mortality are affected by perturbations of iron metabolism.

The Canadian journal of gastroenterology, 2013

American Journal of Hematology, 2017

Blood Cells, Molecules, and Diseases, 2020

Blood, 2007

In previous investigations, we modeled the distribution of transferrin saturation (TS) in Caucasi... more In previous investigations, we modeled the distribution of transferrin saturation (TS) in Caucasians and demonstrated a strong association between HFE genotype and TS subpopulations. Extending this approach, we now have analyzed joint population distributions of TS and serum ferritin concentration (SF) measured in the multi-ethnic Hemochromatosis and Iron Overload Screening (HEIRS) Study and examined the association of these distributions with the presence of HFE C282Y and H63D mutations, self-reported liver disease, and iron deficiency (defined as SF <15 μg/L). Based on separate models for each race/ethnicity by gender, four components with successively increasing age-adjusted means for TS and SF were identified in data from 26,832 African Americans, 12,620 Asians, 12,264 Hispanics, and 43,254 Whites. Fig. 1 illustrates age-adjusted values from 16,662 White men. Superimposed 95% confidence ellipses reflect component probability densities and show separation of the 1st and 4th co...

Blood, 2015

Symptoms of porphyria cutanea tarda (PCT) resolve when iron stores are depleted by phlebotomy, an... more Symptoms of porphyria cutanea tarda (PCT) resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y) that increases iron absorption by reducing hepcidin expression is a risk factor for PCT. These observations suggest that PCT is an iron dependent disease and that factors that affect iron homeostasis influence the risk of developing the PCT. Recently, a polymorphic variant (D519G) of GNPAT was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homozygotes) who presented with a high iron phenotype [McLaren CE, et al. Hepatology Aug;62(2):429-39 2015]. Available evidence suggests that like HFE C282Y, GNPAT D519G increases iron absorption by reducing expression of hepcidin. Therefore, we investigated the prevalence GNPAT D519G in patients with PCT. The study population consisted of 247 patients with PCT. High-resolution DNA melting analysis and Taqman SNP assays were used to identify HFE (C282Y) and GNPAT (D519G) allel...

Blood, 2012

2095 Celiac disease (CD) is an increasingly recognized disorder in Caucasian populations of Europ... more 2095 Celiac disease (CD) is an increasingly recognized disorder in Caucasian populations of European origin. Little is known about its prevalence in non-Caucasians. While CD is thought to be a cause of iron deficiency anemia, the extent to which CD contributes to iron deficiency in Caucasians and especially non-Caucasians is unknown. Iron deficiency is one of the most common nutritional deficiencies in both the developed world and in developing countries. Thus, it is important to know the prevalence of CD in different populations and in iron-deficient and iron-replete persons. To answer these questions, we tested serum collected from Caucasian and non-Caucasian men aged ≥ 25 y and women ≥ 50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. In the HEIRS Study, 101,168 participants were screened with serum biochemical tests of iron status, which not only detected participants with iron overload but also identified a unique multiethnic population of participants with...

Statistics in Medicine, 2000

Blood, Nov 16, 2004

We compared initial screening data of 44,149 whites (17,043 men; 27,106 women) and 26,947 blacks ... more 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50% and SF &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;300 ng/mL, men; TfSat &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;45% and SF &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001). The prevalence of elevated TfSat and SF plus genotype C282Y/C282Y was 0.003 in whites and 0.00004 in blacks (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;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.

Humana Press eBooks, 2012

Blood, Nov 16, 2006

Some patients with hemochromatosis (HC) experience fatigue, heart failure or arrhythmias, diabete... more 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 (&amp;amp;amp;amp;amp;amp;amp;amp;gt;200 μg/L in women, &amp;amp;amp;amp;amp;amp;amp;amp;gt;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&amp;amp;amp;amp;amp;amp;amp;amp;lt;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&amp;amp;amp;amp;amp;amp;amp;amp;lt;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.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, Oct 9, 2009

Blood, Nov 19, 2010

Abstract 4257 Iron in the plasma is bound to transferrin. The total iron binding capacity (TIBC) ... more Abstract 4257 Iron in the plasma is bound to transferrin. The total iron binding capacity (TIBC) represents the maximum amount of iron that can be bound and is directly related to transferrin concentration. TIBC and serum transferrin concentration are increased in iron deficiency and decreased in iron overload. Recently, an association was reported between single nucleotide polymorphisms (SNPs) in the transferrin gene, TF, on chromosome 3q22.1, and serum transferrin levels (Benyamin et al. Am J Hum Genet. 2009;84:60-65). In the current study, we investigated whether the association between SNP rs3811647 in TF and transferrin levels (assessed by measurement of TIBC) is attributable to an effect on regulation of body iron status. The Personalized Medicine Research Project (PMRP) is the largest population-based biobank in the US containing genetic, phenotypic and environmental information on approximately 20,000 people. PMRP is part of the NHGRI-funded eMERGE (www.gwas.net) network. Previously, genotyping was performed on selected PMRP samples with the Illumina Human660W-Quad BeadChip platform. Eligible participants in the current study were 491 white men age ≥ 25 y and 747 white women ≥ 50 y with serum ferritin (SF) values collected between 1985 and 2010. Exclusion criteria included a diagnosis of celiac disease and previous phlebotomy treatment for hemochromatosis. Using TIBC as a marker of serum transferrin for eligible participants having multiple measurements, mean TIBC and median serum ferritin were considered in analyses. Subsets of participants included cases of iron deficiency with multiple measurements of SF ≤ 12 μg/L and iron-replete controls (all measurements of SF…