30 results on '"McLaren, Christine E."'
Search Results
2. Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload.
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McLaren CE, Emond MJ, Subramaniam VN, Phatak PD, Barton JC, Adams PC, Goh JB, McDonald CJ, Powell LW, Gurrin LC, Allen KJ, Nickerson DA, Louie T, Ramm GA, Anderson GJ, and McLaren GD
- Subjects
- Alleles, Analysis of Variance, Blotting, Western, Case-Control Studies, Exome genetics, Exome physiology, Ferritins blood, Hemochromatosis physiopathology, Hemochromatosis Protein, Hep G2 Cells, Homozygote, Humans, Iron Overload physiopathology, Liver Cirrhosis genetics, Liver Cirrhosis physiopathology, Male, Phenotype, Point Mutation, RNA, Small Interfering genetics, Real-Time Polymerase Chain Reaction methods, Sequence Analysis, Protein, Severity of Illness Index, Acyltransferases genetics, Genetic Variation, Hemochromatosis genetics, Histocompatibility Antigens Class I genetics, Iron Overload genetics, Membrane Proteins genetics
- Abstract
Unlabelled: To identify polymorphisms associated with variability of iron overload severity in HFE-associated hemochromatosis, we performed exome sequencing of DNA from 35 male HFE C282Y homozygotes with either markedly increased iron stores (n = 22; cases) or with normal or mildly increased iron stores (n = 13; controls). The 35 participants, residents of the United States, Canada, and Australia, reported no or light alcohol consumption. Sequencing data included 82,068 single-nucleotide variants, and 10,337 genes were tested for a difference between cases and controls. A variant in the GNPAT gene showed the most significant association with severe iron overload (P = 3 × 10(-6) ; P = 0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of twenty-two participants with severe iron overload had glyceronephosphate O-acyltransferase (GNPAT) polymorphism p.D519G (rs11558492; 15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of GNPAT deficiency, we performed small interfering RNA-based knockdown of GNPAT in the human liver-derived cell line, HepG2/C3A. This knockdown resulted in a >17-fold decrease in expression of the messenger RNA encoding the iron-regulatory hormone, hepcidin., Conclusion: GNPAT p.D519G is associated with a high-iron phenotype in HFE C282Y homozygotes and may participate in hepcidin regulation., (© 2015 by the American Association for the Study of Liver Diseases.)
- Published
- 2015
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3. HFE mutations in Caucasian participants of the Hemochromatosis and Iron Overload Screening study with serum ferritin level <1000 µg/L.
- Author
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Adams PC, McLaren CE, Speechley M, McLaren GD, Barton JC, and Eckfeldt JH
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- Adult, Female, Genetic Testing, Hemochromatosis diagnosis, Hemochromatosis Protein, Homozygote, Humans, Iron Overload diagnosis, Likelihood Functions, Male, Mass Screening methods, Mutation, Prevalence, Sex Factors, Transferrin metabolism, White People genetics, Ferritins blood, Hemochromatosis genetics, Histocompatibility Antigens Class I genetics, Iron Overload genetics, Membrane Proteins genetics
- Abstract
Background: Many patients referred for an elevated serum ferritin level <1000 µg⁄L are advised that they likely have iron overload and hemochromatosis., Aims: To determine the prevalence of HFE mutations in the hemochromatosis gene for 11 serum ferritin concentration intervals from 200 µg⁄L to 1000 µg⁄L in Caucasian participants in a primary care, population-based study., Methods: The Hemochromatosis and Iron Overload Screening study screened 99,711 participants for serum ferritin levels, transferrin saturation and genetic testing for the C282Y and H63D mutations of the HFE gene. This analysis was confined to 17,160 male and 27,465 female Caucasian participants because the HFE C282Y mutation is rare in other races. Post-test likelihood was calculated for prediction of C282Y homozygosity from a ferritin interval. A subgroup analysis was performed in participants with both an elevated serum ferritin level and transferrin saturation., Results: There were 3359 male and 2416 female participants with an elevated serum ferritin level (200 µg⁄L to 1000 µg⁄L for women, 300 µg⁄L to 1000 µg⁄L for men). There were 69 male (2.1%) and 87 female (3.6%) C282Y homozygotes, and the probability of being a homozygote increased as the ferritin level increased. Post-test likelihood values were 0.3% to 16% in men and 0.3% to 30.4% in women., Conclusions: Iron loading HFE mutations are unlikely to be the most common cause of an elevated serum ferritin level in patients with mild hyperferritinemia. Patients should be advised that there are many causes of an elevated serum ferritin level including iron overload.
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- 2013
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4. Probability of C282Y homozygosity decreases as liver transaminase activities increase in participants with hyperferritinemia in the hemochromatosis and iron overload screening study.
- Author
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Adams PC, Speechley M, Barton JC, McLaren CE, McLaren GD, and Eckfeldt JH
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- Female, Hemochromatosis blood, Hemochromatosis Protein, Homozygote, Humans, Iron Overload blood, Male, Probability, Alanine Transaminase blood, Aspartate Aminotransferases blood, Ferritins blood, Hemochromatosis genetics, Histocompatibility Antigens Class I genetics, Iron Overload genetics, Membrane Proteins genetics
- Abstract
Unlabelled: Hemochromatosis is considered by many to be an uncommon disorder, although the prevalence of HFE (High Iron) 282 Cys → Tyr (C282Y) homozygosity is relatively high in Caucasians. Liver disease is one of the most consistent findings in advanced iron overload resulting from hemochromatosis. Liver clinics are often thought to be ideal venues for diagnosis of hemochromatosis, but diagnosis rates are often low. The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 99,711 primary care participants in North America for iron overload using serum ferritin and transferrin saturation measurements and HFE genotyping. In this HEIRS substudy, serum hepatic transaminases activities (e.g., alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) were compared between 162 C282Y homozygotes and 1,367 nonhomozygotes with serum ferritin levels >300 μg/L in men and >200 μg/L in women and transferrin saturation >45% in women and 50% in men. The probability of being a C282Y homozygote was determined for AST and ALT ranges. Mean ALT and AST activities were significantly lower in C282Y homozygotes than nonhomozygotes. The probability of being a C282Y homozygote increased as the ALT and AST activities decreased., Conclusion: Patients with hyperferritinemia are more likely to be C282Y homozygotes if they have normal liver transaminase activities. This paradox could explain the low yields of hemochromatosis screening reported by some liver clinics., (Copyright © 2012 American Association for the Study of Liver Diseases.)
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- 2012
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5. Associations between single nucleotide polymorphisms in iron-related genes and iron status in multiethnic populations.
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McLaren CE, McLachlan S, Garner CP, Vulpe CD, Gordeuk VR, Eckfeldt JH, Adams PC, Acton RT, Murray JA, Leiendecker-Foster C, Snively BM, Barcellos LF, Cook JD, and McLaren GD
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- Adult, Black or African American genetics, Black or African American statistics & numerical data, Asian People genetics, Asian People statistics & numerical data, Biomarkers analysis, California epidemiology, Female, Follow-Up Studies, Genotype, Hemochromatosis blood, Hemochromatosis epidemiology, Hispanic or Latino genetics, Hispanic or Latino statistics & numerical data, Humans, Iron Overload blood, Iron Overload epidemiology, Male, Membrane Proteins genetics, Middle Aged, Prognosis, Receptors, Cell Surface genetics, Serine Endopeptidases genetics, White People genetics, White People statistics & numerical data, Ethnicity genetics, Hemochromatosis genetics, Iron blood, Iron Overload genetics, Polymorphism, Single Nucleotide genetics
- Abstract
The existence of multiple inherited disorders of iron metabolism suggests genetic contributions to iron deficiency. We previously performed a genome-wide association study of iron-related single nucleotide polymorphisms (SNPs) using DNA from white men aged ≥ 25 y and women ≥ 50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤ 12 µg/L (cases) and controls (SF >100 µg/L in men, SF >50 µg/L in women). We report a follow-up study of white, African-American, Hispanic, and Asian HEIRS participants, analyzed for association between SNPs and eight iron-related outcomes. Three chromosomal regions showed association across multiple populations, including SNPs in the TF and TMPRSS6 genes, and on chromosome 18q21. A novel SNP rs1421312 in TMPRSS6 was associated with serum iron in whites (p = 3.7 × 10(-6)) and replicated in African Americans (p = 0.0012).Twenty SNPs in the TF gene region were associated with total iron-binding capacity in whites (p<4.4 × 10(-5)); six SNPs replicated in other ethnicities (p<0.01). SNP rs10904850 in the CUBN gene on 10p13 was associated with serum iron in African Americans (P = 1.0 × 10(-5)). These results confirm known associations with iron measures and give unique evidence of their role in different ethnicities, suggesting origins in a common founder.
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- 2012
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6. IRon Overload screeNing tool (IRON): development of a tool to guide screening in primary care.
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Mainous AG 3rd, Diaz VA, Everett CJ, Knoll ME, Hulihan MM, Grant AM, McLaren CE, and McLaren GD
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- Adult, Aged, Aged, 80 and over, Female, Ferritins blood, Hemochromatosis blood, Hemochromatosis diagnosis, Hemochromatosis epidemiology, Humans, Iron blood, Iron metabolism, Iron Overload blood, Iron Overload epidemiology, Male, Mass Screening methods, Middle Aged, Models, Biological, Nutrition Surveys, Risk Factors, Sensitivity and Specificity, Transferrin analysis, Transferrin metabolism, United States epidemiology, Young Adult, Iron Overload diagnosis, Primary Health Care methods
- Abstract
Iron overload is associated with significant morbidity and mortality yet is easily treated. The objective of this study was to create a tool that could be easily adapted to clinical practice that indicates the likelihood of a patient having undetected iron overload. We used the National Health and Nutrition Examination Survey (NHANES) 1999-2002 for US adults aged 20 years and older to build a model (unweighted n=8,779). We chose potential variables for inclusion that could be gathered by self-report or measured without laboratory data and were suggested by past literature on hemochromatosis and iron overload. We computed logistic regressions to create the scores by initially evaluating the variables' relationship with elevated ferritin and elevated transferrin saturation and then using odds ratios to correspond to scores. The resulting score on the IRon Overload ScreeNing Tool (IRON) was then validated with data on 13,844 adults in the NHANES III, 1988-94. Predictors in the final tool were age, gender, previous diagnoses of liver condition, osteoporosis or thyroid disease. The IRON score yielded an area under the curve (AUC) in the NHANES 1999-02 of 0.720 and an AUC of 0.685 in the NHANES III validation sample. The IRON score is a tool to assist in identification of patients with iron overload that has several qualities that make it attractive for use in clinical practice with an undifferentiated patient population including brevity, easily collected information and predictive ability comparable to other tools that help in directing screening., (Copyright © 2011 Wiley-Liss, Inc.)
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- 2011
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7. Tumor necrosis factor-alpha promoter variants and iron phenotypes in 785 hemochromatosis and iron overload screening (HEIRS) study participants.
- Author
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Acton RT, Barton JC, Leiendecker-Foster C, Zaun C, McLaren CE, and Eckfeldt JH
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- Adult, Chromatography, High Pressure Liquid, Ethnicity genetics, Female, Genetic Testing, Genetic Variation, Genotype, Hemochromatosis blood, Hemochromatosis Protein, Histocompatibility Antigens Class I genetics, Humans, Iron Overload blood, Male, Membrane Proteins genetics, Middle Aged, Mutation, Missense, Phenotype, Point Mutation, Ferritins blood, Hemochromatosis genetics, Iron blood, Iron Overload genetics, Promoter Regions, Genetic genetics, Transferrin analysis, Tumor Necrosis Factor-alpha genetics
- Abstract
We sought to determine if TNF promoter variants could explain iron phenotype heterogeneity in adults with previous HFE genotyping. HEIRS Study participants genotyped for C282Y and H63D were designated as high transferrin saturation (TS) and/or serum ferritin (SF) (high TS/SF), low TS/SF, or controls. We grouped 191 C282Y homozygotes as high TS/SF, low TS/SF, or controls, and 594 other participants by race/ethnicity as high TS/SF or controls. Using denaturing high-performance liquid chromatography (DHPLC), we screened the TNF promoter region in each participant. We performed multiple regression analyses in C282Y homozygotes using age, sex, HEIRS Study Field Center, and positivity for TNF -308G-->A and -238G-->A to determine if these attributes predicted ln TS or ln SF. DHPLC analyses were successful in 99.3% of 791 participants and detected 9 different variants; TNF -308G-->A and -238G-->A were the most prevalent. Most subjects positive for variants were heterozygous. The phenotype frequencies of each variant did not differ significantly (p<0.05) across subgroups of C282Y homozygotes, or across white, black, Hispanic, and Asian non-C282Y homozygotes subgrouped as high TS/SF phenotypes and controls. TNF -308G-->A positivity was a significant predictor of initial screening ln TS but not ln SF; TNF -238G-->A predicted neither ln TS nor ln SF. We conclude that TNF promoter variants have little, if any, effect on initial screening SF values in adults with or without C282Y homozygosity. We cannot exclude a possible association of homozygosity for TNF promoter variants on TS and SF values.
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- 2010
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8. Heritability of serum iron measures in the hemochromatosis and iron overload screening (HEIRS) family study.
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McLaren CE, Barton JC, Eckfeldt JH, McLaren GD, Acton RT, Adams PC, Henkin LF, Gordeuk VR, Vulpe CD, Harris EL, Harrison BW, Reiss JA, and Snively BM
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- Adult, Aged, Family, Female, Ferritins genetics, Hemochromatosis Protein, Histocompatibility Antigens Class I blood, Homozygote, Humans, Male, Membrane Proteins blood, Middle Aged, Mutation, Missense, Ferritins blood, Hemochromatosis blood, Hemochromatosis genetics, Histocompatibility Antigens Class I genetics, Iron blood, Iron Overload blood, Iron Overload genetics, Membrane Proteins genetics
- Abstract
Heritability is the proportion of observed variation in a trait among individuals in a population that is attributable to hereditary factors. The Hemochromatosis and Iron Overload Screening family study estimated heritability of serum iron measures. Probands were HFE C282Y homozygotes or non-C282Y homozygotes with elevated transferrin saturation (TS > 50%, men; TS > 45%, women) and serum ferritin concentration (SF > 300 microg/L, men; SF > 200 microg/L, women). Heritability (h(2)) was estimated by variance component analysis of TS, natural logarithm (ln) of SF, and unsaturated iron-binding capacity (UIBC). Participants (N = 942) were 77% Caucasians, 10% Asians, 8% Hispanics, and 5% other race/ethnicities. Average age (SD) was 49 (16) years; 57% were female. For HFE C282Y homozygote probands and their family members, excluding variation due to HFE C282Y and H63D genotype and measured demographic and environmental factors, the residual h(2) (SE) was 0.21 (0.07) for TS, 0.37 (0.08) for ln SF, and 0.34 (0.08) for UIBC (all P < 0.0004 for comparisons with zero). For the non-C282Y homozygote proband group, residual h(2) was significant with a value of 0.64 (0.26) for ln SF (P = 0.0096). In conclusion, serum iron measures have significant heritability components, after excluding known genetic and nongenetic sources of variation.
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- 2010
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9. Heme carrier protein 1 (HCP1) genetic variants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study participants.
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Wang X, Leiendecker-Foster C, Acton RT, Barton JC, McLaren CE, McLaren GD, Gordeuk VR, and Eckfeldt JH
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- Canada epidemiology, Case-Control Studies, Chromatography, High Pressure Liquid, Cohort Studies, DNA Mutational Analysis, Ethnicity genetics, Exons genetics, Hemochromatosis blood, Hemochromatosis ethnology, Hemochromatosis Protein, Heterozygote, Histocompatibility Antigens Class I genetics, Humans, Introns genetics, Iron blood, Iron Overload blood, Iron Overload ethnology, Membrane Proteins genetics, Membrane Transport Proteins physiology, Mutation, Missense, Nucleic Acid Denaturation, Point Mutation, Proton-Coupled Folate Transporter, Racial Groups genetics, Sampling Studies, Transferrin analysis, United States epidemiology, Hemochromatosis genetics, Iron Overload genetics, Membrane Transport Proteins genetics
- Abstract
Heme carrier protein 1 (HCP1) has been identified as a possible heme carrier by in vitro analysis. To determine the association of mutations within the HCP1 gene with iron phenotypes, we examined the entire coding region of the HCP1 gene in 788 US and Canadian participants selected from the Hemochromatosis and Iron Overload Screening (HEIRS) Study using denaturing high-performance liquid chromatography. We sequenced the exon and flanking intronic regions if variants were detected. We tested 298 non-C282Y homozygotes from four racial/ethnic backgrounds (White, Black, Asian, and Hispanic) selected because they had high serum ferritin (SF) and transferrin saturations (TS). As controls, we chose 300 other random participants of the same racial/ethnic backgrounds from the same geographic locations. From the 333 HEIRS Study C282Y homozygotes, we selected 75 based on high SF and TS, 75 based on low SF and TS; and 75 were selected randomly as controls. Thirty-five of the randomly selected C282Y homozygotes were also included in the high and the low SF and TS groups due to numerical limitations. We identified eight different HCP1 genetic variants; each occurred in a heterozygous state. Except one, each was found in a single HEIRS Study participant. Thus, HCP1 variants are infrequent in the populations that we tested. Five HEIRS Study participants had non-synonymous, coding region HCP1 variants. Each of these five had TS above the 84th gender- and ethnic/racial group-specific percentile (TS percentiles: 84.7, 91.3, 97.9, 99.5, and 99.9).
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- 2009
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10. Accuracy of family history of hemochromatosis or iron overload: the hemochromatosis and iron overload screening study.
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Acton RT, Barton JC, Passmore LV, Adams PC, McLaren GD, Leiendecker-Foster C, Speechley MR, Harris EL, Castro O, Reiss JA, Snively BM, Harrison BW, and McLaren CE
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- Adult, Aged, Aged, 80 and over, Arthritis diagnosis, Case-Control Studies, Diabetes Mellitus diagnosis, Female, Genotype, Heart Diseases diagnosis, Hemochromatosis Protein, Histocompatibility Antigens Class I genetics, Humans, Liver Diseases diagnosis, Male, Membrane Proteins genetics, Middle Aged, Reproducibility of Results, Sensitivity and Specificity, Surveys and Questionnaires, Hemochromatosis diagnosis, Iron Overload diagnosis, Medical History Taking statistics & numerical data
- Abstract
Background & Aims: The aim of this study was to assess the analytic validity of self-reported family history of hemochromatosis or iron overload., Methods: A total of 141 probands, 549 family members, and 641 controls participated in the primary care Hemochromatosis and Iron Overload Screening Study. Participants received a postscreening clinical examination and completed questionnaires about personal and family histories of hemochromatosis or iron overload, arthritis, diabetes, liver disease, and heart disease. We evaluated sensitivities and specificities of proband-reported family history, and concordance of HFE genotype C282Y/C282Y in probands and siblings who reported having hemochromatosis or iron overload., Results: The sensitivities of proband-reported family history ranged from 81.4% for hemochromatosis or iron overload to 18.4% for liver disease; specificities for diabetes, liver disease, and heart disease were greater than 94%. Hemochromatosis or iron overload was associated with a positive family history across all racial/ethnic groups in the study (odds ratio, 14.53; 95% confidence intervals, 7.41-28.49; P < .0001) and among Caucasians (odds ratio, 16.98; 95% confidence intervals, 7.53-38.32; P < .0001). There was 100% concordance of HFE genotype C282Y/C282Y in 6 probands and 8 of their siblings who reported having hemochromatosis or iron overload., Conclusions: Self-reported family history of hemochromatosis or iron overload can be used to identify individuals whose risk of hemochromatosis or iron overload and associated conditions is increased. These individuals could benefit from further evaluation with iron phenotyping and HFE mutation analysis.
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- 2008
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11. Serum ferritin concentrations and body iron stores in a multicenter, multiethnic primary-care population.
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Gordeuk VR, Reboussin DM, McLaren CE, Barton JC, Acton RT, McLaren GD, Harris EL, Reiss JA, Adams PC, Speechley M, Phatak PD, Sholinsky P, Eckfeldt JH, Chen WP, Passmore L, and Dawkins FW
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- Epidemiologic Measurements, Ethnicity, Female, Genotype, Hemochromatosis Protein, Histocompatibility Antigens Class I genetics, Humans, Iron Overload ethnology, Male, Membrane Proteins genetics, Mutation, Missense, Phlebotomy, Predictive Value of Tests, Prevalence, Ferritins blood, Iron metabolism, Iron Overload diagnosis, Iron Overload epidemiology
- Abstract
How often elevated serum ferritin in primary-care patients reflects increased iron stores (normally 0.8 g in men, 0.4 g in women) is not known. The Hereditary Hemochromatosis and Iron Overload Screening (HEIRS) study screened 101,168 primary-care participants (44% Caucasians, 27% African-Americans, 14% Asians/Pacific Islanders, 13% Hispanics, 2% others). Follow-up clinical evaluation was performed in 302 of 333 HFE C282Y homozygotes regardless of iron measures and 1,375 of 1,920 nonhomozygotes with serum ferritin >300 microg/L (men), >200 microg/L (women) and transferrin saturation >50% (men), >45% (women). Quantitative phlebotomy was conducted in 122 of 175 C282Y homozygotes and 122 of 1,102 nonhomozygotes with non-transfusional serum ferritin elevation at evaluation. The estimated prevalence in the Caucasian population of C282Y homozygotes with serum ferritin >900 microg/L at evaluation was 20 per 10,000 men and 4 per 10,000 women; this constellation was predictive of iron stores >4 g in men and >2 g in women. The estimated prevalence per 10,000 of non-C282Y homozygotes with serum ferritin >900 microg/L at evaluation was 7 among Caucasians, 13 among Hispanics, 20 among African Americans, and 38 among Asians and Pacific Islanders, and this constellation was predictive of iron stores >2 g but <4 g. In conclusion, serum ferritin >900 microg/L after initial elevations of both serum ferritin and transferrin saturation is predictive of mildly increased iron stores in multiple ethnic populations regardless of HFE genotype. Serum ferritin >900 microg/L in male C282Y homozygotes is predictive of moderately increased iron stores., (Copyright 2008 Wiley-Liss, Inc.)
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- 2008
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12. Bivariate mixture modeling of transferrin saturation and serum ferritin concentration in Asians, African Americans, Hispanics, and whites in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.
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McLaren CE, Gordeuk VR, Chen WP, Barton JC, Acton RT, Speechley M, Castro O, Adams PC, Snively BM, Harris EL, Reboussin DM, McLachlan GJ, and Bean R
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- Canada epidemiology, Comorbidity, Female, Gene Frequency, Genotype, Hemochromatosis blood, Humans, Iron Overload blood, Male, Models, Genetic, Odds Ratio, United States epidemiology, Ferritins blood, Genetic Predisposition to Disease, Hemochromatosis genetics, Iron Overload genetics, Racial Groups genetics, Transferrin metabolism
- Abstract
Bivariate mixture modeling was used to analyze joint population distributions of transferrin saturation (TS) and serum ferritin concentration (SF) measured in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Four components (C1, C2, C3, and C4) with successively age-adjusted increasing means for TS and SF were identified in data from 26,832 African Americans, 12,620 Asians, 12,264 Hispanics, and 43,254 whites. The largest component, C2, had normal mean TS (21% to 26% for women, 29% to 30% for men) and SF (43-82 microg/L for women, 165-242 microg/L for men), which consisted of component proportions greater than 0.59 for women and greater than 0.68 for men. C3 and C4 had progressively greater mean values for TS and SF with progressively lesser component proportions. C1 had mean TS values less than 16% for women (<20% for men) and SF values less than 28 microg/L for women (<47 microg/L for men). Compared with C2, adjusted odds of iron deficiency were significantly greater in C1 (14.9-47.5 for women, 60.6-3530 for men), adjusted odds of liver disease were significantly greater in C3 and C4 for African-American women and all men, and adjusted odds of any HFE mutation were increased in C3 (1.4-1.8 for women, 1.2-1.9 for men) and in C4 for Hispanic and white women (1.5 and 5.2, respectively) and men (2.8 and 4.7, respectively). Joint mixture modeling identifies a component with lesser SF and TS at risk for iron deficiency and 2 components with greater SF and TS at risk for liver disease or HFE mutations. This approach can identify populations in which hereditary or acquired factors influence metabolism measurement.
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- 2008
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13. Characteristics of participants with self-reported hemochromatosis or iron overload at HEIRS study initial screening.
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Barton JC, Acton RT, Leiendecker-Foster C, Lovato L, Adams PC, Eckfeldt JH, McLaren CE, Reiss JA, McLaren GD, Reboussin DM, Gordeuk VR, Speechley MR, Press RD, and Dawkins FW
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- Adult, Antimicrobial Cationic Peptides genetics, Female, Genotype, Hemochromatosis complications, Hemochromatosis diagnosis, Hemochromatosis Protein, Hepcidins, Histocompatibility Antigens Class I genetics, Homozygote, Humans, Iron Overload complications, Iron Overload diagnosis, Male, Membrane Proteins genetics, Phenotype, Promoter Regions, Genetic, Receptors, Transferrin genetics, Sequence Deletion, Hemochromatosis genetics, Iron Overload genetics, Mutation
- Abstract
There are few descriptions of young adults with self-reported hemochromatosis or iron overload (H/IO). We analyzed initial screening data in 7,343 HEmochromatosis and IRon Overload Screening (HEIRS) Study participants ages 25-29 years, including race/ethnicity and health information; transferrin saturation (TS) and ferritin (SF) measurements; and HFE C282Y and H63D genotypes. We used denaturing high-pressure liquid chromatography and sequencing to detect mutations in HJV, TFR2, HAMP, SLC40A1, and FTL. Fifty-one participants reported previous H/IO; 23 (45%) reported medical conditions associated with H/IO. Prevalences of reports of arthritis, diabetes, liver disease or liver cancer, heart failure, fertility problems or impotence, and blood relatives with H/IO were significantly greater in participants with previous H/IO reports than in those without. Only 7.8% of the 51 participants with previous H/IO reports had elevated TS; 13.7% had elevated SF. Only one participant had C282Y homozygosity. Three participants aged 25-29 years were heterozygous for potentially deleterious mutations in HFE2, TFR2, and HAMP promoter, respectively. Prevalences of self-reported conditions, screening iron phenotypes, and C282Y homozygosity were similar in 1,165 participants aged 30 years or greater who reported previous H/IO. We conclude that persons who report previous H/IO diagnoses in screening programs are unlikely to have H/IO phenotypes or genotypes. Previous H/IO reports in some participants could be explained by treatment that induced iron depletion before initial screening, misdiagnosis, or participant misunderstanding of their physician or the initial screening questionnaire.
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- 2008
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14. Iron-overload-related disease in HFE hereditary hemochromatosis.
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Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, McLaren CE, Bahlo M, Nisselle AE, Vulpe CD, Anderson GJ, Southey MC, Giles GG, English DR, Hopper JL, Olynyk JK, Powell LW, and Gertig DM
- Subjects
- Adult, Aged, Aspartate Aminotransferases blood, Female, Ferritins blood, Hemochromatosis complications, Hemochromatosis Protein, Heterozygote, Homozygote, Humans, Iron Overload complications, Iron Overload mortality, Liver Diseases etiology, Male, Middle Aged, Penetrance, Proportional Hazards Models, Prospective Studies, Hemochromatosis genetics, Histocompatibility Antigens Class I genetics, Iron Overload epidemiology, Liver Diseases epidemiology, Membrane Proteins genetics
- Abstract
Background: Most persons who are homozygous for C282Y, the HFE allele most commonly asssociated with hereditary hemochromatosis, have elevated levels of serum ferritin and transferrin saturation. Diseases related to iron overload develop in some C282Y homozygotes, but the extent of the risk is controversial., Methods: We assessed HFE mutations in 31,192 persons of northern European descent between the ages of 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), we obtained clinical and biochemical data, including two sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints., Results: The proportion of C282Y homozygotes with documented iron-overload-related disease was 28.4% (95% confidence interval [CI], 18.8 to 40.2) for men and 1.2% (95% CI, 0.03 to 6.5) for women. Only one non-C282Y homozygote (a compound heterozygote) had documented iron-overload-related disease. Male C282Y homozygotes with a serum ferritin level of 1000 mug per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wild-type gene., Conclusions: In persons who are homozygous for the C282Y mutation, iron-overload-related disease developed in a substantial proportion of men but in a small proportion of women., (Copyright 2008 Massachusetts Medical Society.)
- Published
- 2008
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15. Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study.
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McLaren CE, Barton JC, Gordeuk VR, Wu L, Adams PC, Reboussin DM, Speechley M, Chang H, Acton RT, Harris EL, Ruggiero AM, and Castro O
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- Adult, Aged, Female, Ferritins blood, Hemochromatosis genetics, Hemochromatosis Protein, Homozygote, Humans, Iron Overload etiology, Iron Overload genetics, Liver Function Tests, Male, Middle Aged, Mutation, Missense, Sex Factors, Transferrin analysis, White People, Erythrocyte Indices, Hemochromatosis blood, Hemoglobins analysis, Histocompatibility Antigens Class I genetics, Iron Overload blood, Mass Screening, Membrane Proteins genetics
- Abstract
Elevated mean corpuscular volume (MCV) is common in persons with hemochromatosis associated with HFE C282Y homozygosity. We evaluated data from the subset of non-Hispanic white participants in the Hemochromatosis and Iron Overload Screening Study to determine if elevated MCV in C282Y homozygotes is related to this genotype or to serum iron measures. Regression analysis was used to model MCV and Hb from transferrin saturation (TfSat), serum ferritin (SF), mean corpuscular hemoglobin concentration, red blood cell count, age, HFE genotype, Field Center, and presence of liver-related abnormalities in C282Y homozygotes and control subjects without HFE mutations (wt/wt genotype). Mean MCV was higher in C282Y homozygotes than in HFE wt/wt controls (94.4 vs. 89.7 fL in women; 95.3 vs. 91.2 fL in men; P < 0.0001 for both). These differences were largely associated with increased mean TfSat and SF in C282Y homozygotes. Adjusted mean MCV was 92.0 fL (95% confidence interval, 91.1, 92.9) in female C282Y homozygotes and 90.9 fL (90.3, 91.5) in controls. Among women with SF in the reference range 20-200 microg/L, adjusted mean MCV was 92.9 fL, (91.7, 94.2) in C282Y homozygotes, 1.8 fL higher than in controls (P = 0.013). The adjusted mean MCV of male C282Y homozygotes and controls was similar (P = 0.30). Adjusted mean Hb was 0.2 g/dL higher in women with C282Y/C282Y than in controls. Greater mean MCV in C282Y homozygosity reflects increased mean TfSat and mean SF in men and women; an additional effect of genotype on MCV and Hb was detected in women.
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- 2007
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16. HFE C282Y homozygotes aged 25-29 years at HEIRS Study initial screening.
- Author
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Barton JC, Acton RT, Leiendecker-Foster C, Lovato L, Adams PC, McLaren GD, Eckfeldt JH, McLaren CE, Reboussin DM, Gordeuk VR, Speechley MR, Reiss JA, Press RD, and Dawkins FW
- Subjects
- Adult, Antimicrobial Cationic Peptides genetics, Apoferritins, Cation Transport Proteins genetics, DNA Mutational Analysis, Female, Ferritins genetics, Genetic Testing, Genotype, Hemochromatosis blood, Hemochromatosis diagnosis, Hemochromatosis Protein, Hepcidins, Humans, Iron Overload blood, Iron Overload diagnosis, Male, Mutation, Receptors, Transferrin genetics, Hemochromatosis genetics, Histocompatibility Antigens Class I genetics, Homozygote, Iron Overload genetics, Membrane Proteins genetics
- Abstract
We characterized HFE C282Y homozygotes aged 25-29 years in the HEmochromatosis and IRon Overload Screening (HEIRS) Study using health questionnaire responses, transferrin saturation (TfSat), serum ferritin (SF), and HFE genotyping. In eight homozygotes, we used denaturing high-performance liquid chromatography and sequencing to search for HFE2 (= HJV), TFR2, HAMP, SLC40A1 (= FPN1), and FTL mutations. Sixteen of 4,008 White or Hispanic participants aged 25-29 years had C282Y homozygosity (15 White, 1 Hispanic); 15 were previously undiagnosed. Eleven had elevated TfSat; nine had elevated SF. None reported iron overload-associated abnormalities. No deleterious non-HFE mutations were detected. The prevalence of C282Y homozygosity in White or Hispanic HEIRS Study participants aged 25-29 years did not differ significantly from the prevalence of C282Y homozygosity in older White or Hispanic HEIRS Study participants. The prevalences of reports of iron overload-associated abnormalities were not significantly different in these 16 C282Y homozygotes and in HFE wt/wt control participants aged 25-29 years who did not report having hemochromatosis or iron overload. We conclude that C282Y homozygotes aged 25-29 years diagnosed by screening infrequently report having iron overload-associated abnormalities, although some have elevated SF. Screening using an elevated TfSat criterion would fail to detect some C282Y homozygotes aged 25-29 years.
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- 2007
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17. African Americans at risk for increased iron stores or liver disease.
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Dawkins FW, Gordeuk VR, Snively BM, Lovato L, Barton JC, Acton RT, McLaren GD, Leiendecker-Foster C, McLaren CE, Adams PC, Speechley M, Harris EL, Jackson S, and Thomson EJ
- Subjects
- Adult, Cross-Sectional Studies, Female, Ferritins blood, Genotype, Hemochromatosis Protein, Hemosiderosis ethnology, Histocompatibility Antigens Class I genetics, Humans, Male, Membrane Proteins genetics, Prevalence, Transferrin analysis, Black or African American statistics & numerical data, Iron Overload ethnology, Liver Diseases ethnology
- Abstract
Purpose: We sought to determine the prevalence of elevated measures of iron status in African Americans and whether the combination of serum ferritin concentration >200 microg/L for women or >300 microg/L for men and transferrin saturation in the highest quartile represents increased likelihood of mutation of HFE, self-reported iron overload or self-reported liver disease., Subjects and Methods: A cross-sectional observational study of 27,224 African Americans > or =25 years of age recruited in a primary care setting was conducted as part of the multi-center, multi-ethnic Hemochromatosis and Iron Overload Screening (HEIRS) Study. Measurements included serum ferritin concentration, transferrin saturation, testing for HFE C282Y and H63D, and self-reported iron overload and liver disease., Results: Serum ferritin concentration >200 microg/L for women or >300 microg/L for men occurred in 5263 (19.3%) of African Americans, while serum ferritin concentration in this range with highest-quartile transferrin saturation (>29% women; >35% men) occurred in 1837 (6.7%). Adjusted odds of HFE mutation (1.76 women, 1.67 men), self-reported iron overload (1.97 women, 2.88 men), or self-reported liver disease (5.18 women, 3.73 men) were greater with elevated serum ferritin concentration and highest-quartile transferrin saturation than with nonelevated serum ferritin concentration (each P <.05)., Conclusions: Serum ferritin concentration >200 microg/L for women or >300 microg/L for men in combination with transferrin saturation >29% for women or >35% for men occurs in approximately 7% of adult African American primary care patients. Patients with this combination of iron test results should be evaluated for increased body iron stores or liver disease.
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- 2007
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18. Mixture models of serum iron measures in population screening for hemochromatosis and iron overload.
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McLaren CE, Li KT, McLaren GD, Gordeuk VR, Snively BM, Reboussin DM, Barton JC, Acton RT, Dawkins FW, Harris EL, Eckfeldt JH, Moses GC, and Adams PC
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- Adult, Biomarkers blood, Female, Ferritins blood, Ferritins genetics, Genotype, Hemochromatosis genetics, Hemochromatosis Protein, Humans, Iron Overload genetics, Male, Molecular Epidemiology, Mutation, Reproducibility of Results, Sensitivity and Specificity, Transferrin analysis, Transferrin genetics, Hemochromatosis blood, Histocompatibility Antigens Class I genetics, Iron blood, Iron Overload blood, Membrane Proteins genetics, Models, Statistical
- Abstract
Homozygosity for the C282Y mutation of the hemochromatosis gene on chromosome 6p (HFE) is a common genetic trait that increases susceptibility to iron overload. The authors describe and apply methodology developed for the analysis of phenotypic and genotypic data from 46,136 non-Hispanic Caucasians, a subset of the multi-ethnic cohort enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. For analysis of the distribution of transferrin saturation (TS), mixtures of normal distributions were considered and the expectation-maximization (EM) algorithm was applied for parameter estimation. Maximized log-likelihoods were compared, and significance was assessed by resampling. Sensitivity, specificity, and predictive values from the modeled subpopulations were compared with the actual observed genotypes for C282Y and H63D mutations in the HFE gene. A strong association between HFE genotype and TS subpopulations was found in these data collected from different geographic regions, confirming the external validity of the statistical approach when applied to population-based data. It was concluded that mixture modeling of phenotypic data may provide a clinical guide for screening with gender-specific thresholds to identify potential samples for genetic testing.
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- 2006
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19. Geographic and racial/ethnic differences in HFE mutation frequencies in the Hemochromatosis and Iron Overload Screening (HEIRS) Study.
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Acton RT, Barton JC, Snively BM, McLaren CE, Adams PC, Harris EL, Speechley MR, McLaren GD, Dawkins FW, Leiendecker-Foster C, Holup JL, and Balasubramanyam A
- Subjects
- Adult, Asian People genetics, Asian People statistics & numerical data, Black People genetics, Black People statistics & numerical data, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Testing, Genotype, Hemochromatosis ethnology, Hemochromatosis Protein, Hispanic or Latino genetics, Hispanic or Latino statistics & numerical data, Humans, Indians, North American genetics, Indians, North American statistics & numerical data, Iron Overload ethnology, Male, Native Hawaiian or Other Pacific Islander genetics, Native Hawaiian or Other Pacific Islander statistics & numerical data, North America epidemiology, White People genetics, White People statistics & numerical data, Ethnicity genetics, Hemochromatosis epidemiology, Hemochromatosis genetics, Histocompatibility Antigens Class I genetics, Iron Overload epidemiology, Iron Overload genetics, Membrane Proteins genetics, Mutation, Racial Groups genetics
- Abstract
Objective: To assess geographic differences in the frequencies of HFE C282Y and H63D genotypes in six racial/ethnic groups recruited in the Hemochromatosis and Iron Overload Screening (HEIRS) Study., Design: HFE C282Y and H63D genotypes of 97,551 participants, ages > or = 25 years, who reported that they belonged to one of six racial/ethnic groups, were analyzed. HFE genotype frequencies were compared among the racial/ethnic groups and among the HEIRS Study field centers within each racial/ethnic group., Results: The distribution of HFE C282Y and H63D genotypes differed among racial/ethnic groups (P<.0001) and among field centers in Hispanics, Asians, Whites, and Blacks (each P<.05). Genotype frequencies were similar among field centers in Native Americans and Pacific Islanders. Frequencies of C282Y and H63D genotypes were greatest in Whites. The lowest frequencies of C282Y genotypes were observed in Asians; Blacks had the lowest H63D genotype frequencies and the highest frequency of the wild-type genotype. Among racial/ethnic groups, Hispanics had the greatest variation in HFE genotypes across geographic regions., Conclusion: HFE C282Y and H63D genotype frequencies vary significantly between racial/ethnic groups and within some racial/ethnic groups across geographic regions.
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- 2006
20. Comparison of the unsaturated iron-binding capacity with transferrin saturation as a screening test to detect C282Y homozygotes for hemochromatosis in 101,168 participants in the hemochromatosis and iron overload screening (HEIRS) study.
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Adams PC, Reboussin DM, Leiendecker-Foster C, Moses GC, McLaren GD, McLaren CE, Dawkins FW, Kasvosve I, Acton RT, Barton JC, Zaccaro D, Harris EL, Press R, Chang H, and Eckfeldt JH
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Hemochromatosis blood, Hemochromatosis genetics, Hemochromatosis Protein, Homozygote, Humans, Male, Middle Aged, Mutation, Protein Binding, ROC Curve, Sensitivity and Specificity, Hemochromatosis diagnosis, Histocompatibility Antigens Class I genetics, Iron blood, Iron Overload diagnosis, Membrane Proteins genetics, Transferrin metabolism
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- 2005
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21. Increased frequency of GNPAT p.D519G in compound HFE p.C282Y/p.H63D heterozygotes with elevated serum ferritin levels
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Secondes, Eriza S, Wallace, Daniel F, Rishi, Gautam, McLaren, Gordon D, McLaren, Christine E, Chen, Wen-Pin, Ramm, Louise E, Powell, Lawrie W, Ramm, Grant A, Barton, James C, and Subramaniam, V Nathan
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Digestive Diseases ,Chronic Liver Disease and Cirrhosis ,Hematology ,Liver Disease ,Genetics ,2.1 Biological and endogenous factors ,Acyltransferases ,Adult ,Female ,Ferritins ,Hemochromatosis ,Hemochromatosis Protein ,Heterozygote ,Humans ,Male ,Middle Aged ,Point Mutation ,GNPAT ,HFE ,Genetic modifiers ,Iron overload ,Clinical Sciences ,Immunology ,Cardiovascular medicine and haematology - Abstract
Glyceronephosphate O-acyltransferase (GNPAT) p.D519G (rs11558492) was identified as a genetic modifier correlated with more severe iron overload in hemochromatosis through whole-exome sequencing of HFE p.C282Y homozygotes with extreme iron phenotypes. We studied the prevalence of p.D519G in HFE p.C282Y/p.H63D compound heterozygotes, a genotype associated with iron overload in some patients. Cases were Australian participants with elevated serum ferritin (SF) levels ≥300μg/L (males) and ≥200μg/L (females); subjects whose SF levels were below these cut-offs were designated as controls. Samples were genotyped for GNPAT p.D519G. We compared the allele frequency of the present subjects, with/without elevated SF, to p.D519G frequency in public datasets. GNPAT p.D519G was more prevalent in our cohort of p.C282Y/p.H63D compound heterozygotes with elevated SF (37%) than European public datasets: 1000G 21%, gnomAD 20% and ESP 21%. We conclude that GNPAT p.D519G is associated with elevated SF in Australian HFE p.C282Y/p.H63D compound heterozygotes.
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- 2020
22. GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes
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Barton, James C, Chen, Wen-pin, Emond, Mary J, Phatak, Pradyumna D, Subramaniam, V Nathan, Adams, Paul C, Gurrin, Lyle C, Anderson, Gregory J, Ramm, Grant A, Powell, Lawrie W, Allen, Katrina J, Phillips, John D, Parker, Charles J, McLaren, Gordon D, and McLaren, Christine E
- Subjects
Biomedical and Clinical Sciences ,Nutrition and Dietetics ,Substance Misuse ,Clinical Research ,Alcoholism ,Alcohol Use and Health ,Cardiovascular ,Good Health and Well Being ,Acyltransferases ,Adult ,Age Factors ,Aged ,Alcohol Drinking ,Female ,Hemochromatosis Protein ,Homozygote ,Humans ,Iron ,Male ,Middle Aged ,Mutation ,Missense ,Hemochromatosis Iron overload ,rs11558492 ,rs1800562 ,Hemochromatosis ,Iron overload ,Clinical Sciences ,Immunology ,Cardiovascular medicine and haematology - Abstract
BackgroundGNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes.MethodsWe defined markedly increased iron stores as serum ferritin >2247pmol/L (>1000μg/L) and either hepatic iron >236μmol/g dry weight or iron >10g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin
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- 2017
23. HFE C282Y and H63D simple heterozygosity
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Zaloumis, Sophie G, Allen, Katrina J, Bertalli, Nadine A, Turkovic, Lidija, Delatycki, Martin B, Nicoll, Amanda J, McLaren, Christine E, English, Dallas R, Hopper, John L, Giles, Graham G, Anderson, Gregory J, Olynyk, John K, Powell, Lawrie W, Gurrin, Lyle C, and Investigators, HealthIron Study
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Biomedical and Clinical Sciences ,Clinical Sciences ,Prevention ,Liver Disease ,Digestive Diseases ,Genetics ,Hematology ,Clinical Research ,Chronic Liver Disease and Cirrhosis ,Adult ,Aged ,Cohort Studies ,Female ,Genotype ,Hemochromatosis ,Hemochromatosis Protein ,Heterozygote ,Histocompatibility Antigens Class I ,Humans ,Iron Overload ,Male ,Membrane Proteins ,Middle Aged ,Morbidity ,Prospective Studies ,Time Factors ,hereditary disease ,iron overload-related disease ,liver disease ,serum ferritin ,transferrin saturation ,HealthIron Study Investigators ,Gastroenterology & Hepatology ,Clinical sciences - Abstract
Background and aimThe risk of hemochromatosis-related morbidity for HFE simple heterozygosity for either the C282Y or H63D substitutions in the HFE protein was assessed using a prospective community-based cohort study.MethodsHFE genotypes were measured for 31,192 persons of northern European descent, aged between 40 and 69 years when recruited to the Melbourne Collaborative Cohort Study, and subjects were followed for an average of 12 years. For a random sample of 1438 participants stratified according to HFE genotype, two sets of biochemical iron indices performed 12 years apart and, at follow-up only, the presence/absence of six disease features associated with hereditary hemochromatosis were obtained. Summary data for 257 (139 female) C282Y simple heterozygotes and 123 (74 female) H63D simple heterozygotes were compared with 330 (181 female) controls with neither HFE mutation.ResultsAt baseline, mean transferrin saturation (TS) (95% confidence interval) and prevalence of TS > 55% were 35.14% (33.25, 37.04) and 3/112 (3%), 33.03% (29.9, 36.15) and 0/39 (0%), and 29.67% (27.93, 31.4) and 3/135 (2%) for C282Y, H63D and wild-type male participants, respectively. At follow-up, mean TS levels remained similar to baseline levels for both men and women irrespective of simple heterozygosity for either mutation. No HFE C282Y or H63D simple heterozygotes had documented iron overload (based on hepatic iron measures or serum ferritin greater than 1000 mg/L at baseline with documented therapeutic venesection).ConclusionNo documented iron overload was observed for HFE simple heterozygotes for either C282Y or H63D, and morbidity for both HFE simple heterozygote groups was similar to that of HFE wild-type participants.
- Published
- 2015
24. Hemochromatosis and Iron-Overload Screening in a Racially Diverse Population
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Adams, Paul C, Reboussin, David M, Barton, James C, McLaren, Christine E, Eckfeldt, John H, McLaren, Gordon D, Dawkins, Fitzroy W, Acton, Ronald T, Harris, Emily L, Gordeuk, Victor R, Leiendecker-Foster, Catherine, Speechley, Mark, Snively, Beverly M, Holup, Joan L, Thomson, Elizabeth, and Sholinsky, Phyliss
- Subjects
Prevention ,Digestive Diseases ,Clinical Research ,Genetics ,Chronic Liver Disease and Cirrhosis ,Liver Disease ,Hematology ,Arthritis ,Diabetes Complications ,Female ,Ferritins ,Gene Frequency ,Genotype ,Heart Diseases ,Hemochromatosis ,Hemochromatosis Protein ,Histocompatibility Antigens Class I ,Homozygote ,Humans ,Iron ,Iron Overload ,Liver Diseases ,Logistic Models ,Male ,Membrane Proteins ,Mutation ,Phenotype ,Sex Distribution ,Transferrin ,United States ,Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators ,Medical and Health Sciences ,General & Internal Medicine - Abstract
BackgroundIron overload and hemochromatosis are common, treatable conditions. HFE genotypes, levels of serum ferritin, transferrin saturation values, and self-reported medical history were studied in a multiethnic primary care population.MethodsParticipants were recruited from primary care practices and blood-drawing laboratories. Blood samples were tested for transferrin saturation, serum ferritin, and C282Y and H63D mutations of the HFE gene. Before genetic screening, participants were asked whether they had a history of medical conditions related to iron overload.ResultsOf the 99,711 participants, 299 were homozygous for the C282Y mutation. The estimated prevalence of C282Y homozygotes was higher in non-Hispanic whites (0.44 percent) than in Native Americans (0.11 percent), Hispanics (0.027 percent), blacks (0.014 percent), Pacific Islanders (0.012 percent), or Asians (0.000039 percent). Among participants who were homozygous for the C282Y mutation but in whom iron overload had not been diagnosed (227 participants), serum ferritin levels were greater than 300 mug per liter in 78 of 89 men (88 percent) and greater than 200 microg per liter in 79 of 138 women (57 percent). Pacific Islanders and Asians had the highest geometric mean levels of serum ferritin and mean transferrin saturation despite having the lowest prevalence of C282Y homozygotes. There were 364 participants in whom iron overload had not been diagnosed (29 C282Y homozygotes) who had a serum ferritin level greater than 1000 microg per liter. Among men, C282Y homozygotes and compound heterozygotes were more likely to report a history of liver disease than were participants without HFE mutations.ConclusionsThe C282Y mutation is most common in whites, and most C282Y homozygotes have elevations in serum ferritin levels and transferrin saturation. The C282Y mutation does not account for high mean serum ferritin levels and transferrin saturation values in nonwhites.
- Published
- 2005
25. Natural history of HFE simple heterozygosity for C282Y and H63D: a prospective 12-year study
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Zaloumis, Sophie G, Allen, Katrina J, Bertalli, Nadine A, Turkovic, Lidija, Delatycki, Martin B, Nicoll, Amanda J, McLaren, Christine E, English, Dallas R, Hopper, John L, Giles, Graham G, Anderson, Gregory J, Olynyk, John K, Powell, Lawrie W, Gurrin, Lyle C, and HealthIron Study Investigators
- Subjects
Adult ,Male ,Heterozygote ,Iron Overload ,Time Factors ,Genotype ,Chronic Liver Disease and Cirrhosis ,Clinical Sciences ,HealthIron Study Investigators ,Cohort Studies ,transferrin saturation ,Clinical Research ,Genetics ,Humans ,Prospective Studies ,Hemochromatosis Protein ,Aged ,Gastroenterology & Hepatology ,Prevention ,Liver Disease ,Histocompatibility Antigens Class I ,serum ferritin ,Membrane Proteins ,Hematology ,Middle Aged ,hereditary disease ,iron overload-related disease ,Female ,Hemochromatosis ,Morbidity ,Digestive Diseases - Abstract
Background and aimThe risk of hemochromatosis-related morbidity for HFE simple heterozygosity for either the C282Y or H63D substitutions in the HFE protein was assessed using a prospective community-based cohort study.MethodsHFE genotypes were measured for 31,192 persons of northern European descent, aged between 40 and 69 years when recruited to the Melbourne Collaborative Cohort Study, and subjects were followed for an average of 12 years. For a random sample of 1438 participants stratified according to HFE genotype, two sets of biochemical iron indices performed 12 years apart and, at follow-up only, the presence/absence of six disease features associated with hereditary hemochromatosis were obtained. Summary data for 257 (139 female) C282Y simple heterozygotes and 123 (74 female) H63D simple heterozygotes were compared with 330 (181 female) controls with neither HFE mutation.ResultsAt baseline, mean transferrin saturation (TS) (95% confidence interval) and prevalence of TS > 55% were 35.14% (33.25, 37.04) and 3/112 (3%), 33.03% (29.9, 36.15) and 0/39 (0%), and 29.67% (27.93, 31.4) and 3/135 (2%) for C282Y, H63D and wild-type male participants, respectively. At follow-up, mean TS levels remained similar to baseline levels for both men and women irrespective of simple heterozygosity for either mutation. No HFE C282Y or H63D simple heterozygotes had documented iron overload (based on hepatic iron measures or serum ferritin greater than 1000 mg/L at baseline with documented therapeutic venesection).ConclusionNo documented iron overload was observed for HFE simple heterozygotes for either C282Y or H63D, and morbidity for both HFE simple heterozygote groups was similar to that of HFE wild-type participants.
- Published
- 2015
26. Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes.
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Barton, James C., McLaren, Christine E., Wen-pin Chen, Ramm, Grant A., Anderson, Gregory J., Powell, Lawrie W., Subramaniam, V. Nathan, Adams, Paul C., Phatak, Pradyumna D., Gurrin, Lyle C., Phillips, John D., Parker, Charles J., Emond, Mary J., and McLaren, Gordon D.
- Subjects
CIRRHOSIS of the liver ,HEMOCHROMATOSIS ,TREATMENT of cirrhosis of the liver ,HOMOZYGOSITY ,ASPARTATE aminotransferase ,DISEASE risk factors - Abstract
Introduction and aim. We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study. Material and methods. We evaluated 368 p.C282Y homozygotes who underwent liver biopsy and compared characteristics of those with and without cirrhosis. We performed multivariable logistic regression on cirrhosis with: age; sex; race/ ethnicity; diabetes; blood pints/units donated voluntarily; erythrocyte pints/units received; iron supplement use; alcohol intake, g/d; body mass index, kg/m2; swollen/tender 2nd/3rd metacarpophalangeal joints; elevated alanine aminotransferase; elevated aspartate aminotransferase; steatosis/fatty liver; iron removed by phlebotomy, g; and GNPAT p.D519G positivity. Results. Mean age of 368 participants (73.6% men) was 47 ± 13 (standard deviation) y. Cirrhosis was diagnosed in 86 participants (23.4%). Participants with cirrhosis had significantly greater mean age, proportion of men, diabetes prevalence, mean daily alcohol intake, prevalence of swollen/ tender 2nd/3rd metacarpophalangeal joints, mean serum ferritin, elevated alanine aminotransferase, elevated aspartate aminotransferase, and mean iron removed; and significantly fewer mean blood pints/units donated. GNPAT p.D519G positivity was detected in 82 of 188 participants (43.6%). In a multivariable model for cirrhosis, there were four significant positive associations: age (10-y intervals) (odds ratio 2.2 [95% confidence interval 1.5, 3.3]); diabetes (3.3; [1.1, 9.7]); alcohol intake (14 g alcohol drinks/ d) (1.5 [1.2, 1.8]); and iron removed, g (1.3 [1.2, 1.4]). There was no statistical evidence of two-way interactions between these variables. Conclusion. In conclusion, cirrhosis in HFE p.C282Y homozygotes is significantly associated with age, diabetes, daily alcohol intake, and iron removed by phlebotomy, taking into account the effect of other variables. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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27. Probability of C282Y homozygosity decreases as liver transaminase activities increase in participants with hyperferritinemia in the HEIRS Study
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Adams, Paul C., Speechley, Mark, Barton, James C., McLaren, Christine E., McLaren, Gordon D., and Eckfeldt, John H.
- Subjects
Male ,Iron Overload ,Histocompatibility Antigens Class I ,Homozygote ,Membrane Proteins ,Alanine Transaminase ,Article ,Ferritins ,Humans ,Female ,Aspartate Aminotransferases ,Hemochromatosis ,Hemochromatosis Protein ,Probability - Abstract
Hemochromatosis is considered by many to be an uncommon disorder, although the prevalence of HFE (High Iron) 282 Cys → Tyr (C282Y) homozygosity is relatively high in Caucasians. Liver disease is one of the most consistent findings in advanced iron overload resulting from hemochromatosis. Liver clinics are often thought to be ideal venues for diagnosis of hemochromatosis, but diagnosis rates are often low. The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 99,711 primary care participants in North America for iron overload using serum ferritin and transferrin saturation measurements and HFE genotyping. In this HEIRS substudy, serum hepatic transaminases activities (e.g., alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) were compared between 162 C282Y homozygotes and 1,367 nonhomozygotes with serum ferritin levels300 μg/L in men and200 μg/L in women and transferrin saturation45% in women and 50% in men. The probability of being a C282Y homozygote was determined for AST and ALT ranges. Mean ALT and AST activities were significantly lower in C282Y homozygotes than nonhomozygotes. The probability of being a C282Y homozygote increased as the ALT and AST activities decreased.Patients with hyperferritinemia are more likely to be C282Y homozygotes if they have normal liver transaminase activities. This paradox could explain the low yields of hemochromatosis screening reported by some liver clinics.
- Published
- 2012
28. A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis.
- Author
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Constantine, Clare C., Anderson, Greg J., Vulpe, Chris D., McLaren, Christine E., Bahlo, Melanie, Yeap, Heng Lin, Gertig, Dorota M., Osborne, Nicholas J., Bertalli, Nadine A., Beckman, Kenneth B., Chen, Victoria, Matak, Pavel, McKie, Andrew T., Delatycki, Martin B., Olynyk, John K., English, Dallas R., Southey, Melissa C., Giles, Graham G., Hopper, John L., and Allen, Katrina J.
- Subjects
HEMOCHROMATOSIS ,TRANSFERRIN ,FERRITIN ,IRON metabolism ,GENETIC disorders ,GENETIC mutation ,GENETIC polymorphisms ,COHORT analysis - Abstract
There is emerging evidence that there are genetic modifiers of iron indices for HFE gene mutation carriers at risk of hereditary hemochromatosis. A random sample, stratified by HFE genotype, of 863 from a cohort of 31 192 people of northern European descent provided blood samples for genotyping of 476 single nucleotide polymorphisms (SNPs) in 44 genes involved in iron metabolism. Single SNP association testing, using linear regression models adjusted for sex, menopause and HFE genotype, was conducted for four continuously distributed outcomes: serum ferritin (log transformed), transferrin saturation, serum transferrin, and serum iron. The SNP rs884409 in CYBRD1 is a novel modifier specific to HFE C282Y homozygotes. Median unadjusted serum ferritin concentration decreased from 1194 μg/l ( N = 27) to 387 μg/l ( N = 16) for male C282Y homozygotes and from 357 μg/l ( N = 42) to 69 μg/l ( N = 12) for females, comparing those with no copies to those with one copy of rs884409. Functional testing of this CYBRD1 promoter polymorphism using a heterologous expression assay resulted in a 30% decrease in basal promoter activity relative to the common genotype ( P = 0·004). This putative genetic modifier of iron overload expression accounts for 11% (95% CI 0·4%, 22·6%) of the variance in serum ferritin levels of C282Y homozygotes. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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29. GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes.
- Author
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Barton, James C., Chen, Wen-pin, Emond, Mary J., Phatak, Pradyumna D., Subramaniam, V. Nathan, Adams, Paul C., Gurrin, Lyle C., Anderson, Gregory J., Ramm, Grant A., Powell, Lawrie W., Allen, Katrina J., Phillips, John D., Parker, Charles J., McLaren, Gordon D., and McLaren, Christine E.
- Subjects
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HOMOZYGOSITY , *FERRITIN , *BLOOD proteins , *AMINOTRANSFERASES , *RED blood cell transfusion - Abstract
Background GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes. Methods We defined markedly increased iron stores as serum ferritin > 2247 pmol/L (> 1000 μg/L) and either hepatic iron > 236 μmol/g dry weight or iron > 10 g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin < 674.1 pmol/L (< 300 μg/L) or either age ≥ 40 y with iron ≤ 2.5 g iron by induction phlebotomy or age ≥ 50 y with ≤ 3.0 g iron by induction phlebotomy (men only). We compared participant subgroups using univariate methods. Using multivariable logistic regression, we evaluated associations of markedly increased iron stores with these variables: age; iron supplement use (dichotomous); whole blood units donated; erythrocyte units received as transfusion; daily alcohol consumption, g; and p.D519G positivity (heterozygosity or homozygosity). Results The mean age of 56 participants (94.6% men) was 55 ± 10 (SD) y; 41 had markedly increased iron stores. Prevalences of swollen/tender 2nd/3rd metacarpophalangeal joints and elevated aspartate or alanine aminotransferase were significantly greater in participants with markedly increased iron stores. Only participants with markedly increased iron stores had cirrhosis. In multivariable analyses, p.D519G positivity was the only exposure variable significantly associated with markedly increased iron stores (odds ratio 9.9, 95% CI [1.6, 60.3], p = 0.0126). Conclusions GNPAT p.D519G is strongly associated with markedly increased iron stores in p.C282Y homozygotes after correction for age, iron-related variables, and alcohol consumption. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
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30. Increased frequency of GNPAT p.D519G in compound HFE p.C282Y/p.H63D heterozygotes with elevated serum ferritin levels.
- Author
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Secondes, Eriza S., Wallace, Daniel F., Rishi, Gautam, McLaren, Gordon D., McLaren, Christine E., Chen, Wen-Pin, Ramm, Louise E., Powell, Lawrie W., Ramm, Grant A., Barton, James C., and Subramaniam, V. Nathan
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GENETIC carriers , *GENE frequency , *SERUM , *FERRITIN , *IRON - Abstract
Glyceronephosphate O-acyltransferase (GNPAT) p.D519G (rs11558492) was identified as a genetic modifier correlated with more severe iron overload in hemochromatosis through whole-exome sequencing of HFE p.C282Y homozygotes with extreme iron phenotypes. We studied the prevalence of p.D519G in HFE p.C282Y/p.H63D compound heterozygotes, a genotype associated with iron overload in some patients. Cases were Australian participants with elevated serum ferritin (SF) levels ≥300μg/L (males) and ≥200μg/L (females); subjects whose SF levels were below these cut-offs were designated as controls. Samples were genotyped for GNPAT p.D519G. We compared the allele frequency of the present subjects, with/without elevated SF, to p.D519G frequency in public datasets. GNPAT p.D519G was more prevalent in our cohort of p.C282Y/p.H63D compound heterozygotes with elevated SF (37%) than European public datasets: 1000G 21%, gnomAD 20% and ESP 21%. We conclude that GNPAT p.D519G is associated with elevated SF in Australian HFE p.C282Y/p.H63D compound heterozygotes. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
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