title: GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes.
abstract: 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.
  
  
  
  We 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 <674.1pmol/L (<300μg/L) or either age≥40y with iron ≤2.5g iron by induction phlebotomy or age≥50y with ≤3.0g 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).
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Southern Iron Disorders Center, Birmingham, AL, 35209, USA; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: ironmd@isp.com.
authors.forename: James C
authors.initials: JC
authors.lastname: Barton
authors.affiliation: Chao Family Comprehensive Cancer Center, Irvine, CA 92697, USA.
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Emond
authors.affiliation: Rochester General Hospital, Rochester, NY 14621, USA.
authors.forename: Pradyumna D
authors.initials: PD
authors.lastname: Phatak
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4006, Australia; Faculty of Medicine and Biomedical Sciences, The University of Queensland, Herston, QLD, 4006, Australia.
authors.forename: V Nathan
authors.initials: VN
authors.lastname: Subramaniam
authors.affiliation: Department of Medicine, London Health Sciences Centre, London, Ontario, N6A 5W9, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Adams
authors.affiliation: Centre for MEGA Epidemiology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Lyle C
authors.initials: LC
authors.lastname: Gurrin
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4006, Australia; School of Medicine and School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane, St. Lucia, QLD 4072, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Anderson
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4006, Australia; Faculty of Medicine and Biomedical Sciences, The University of Queensland, Herston, QLD, 4006, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Ramm
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane City, QLD 4006, Australia; Faculty of Medicine and Biomedical Sciences, The University of Queensland, Herston, QLD, 4006, Australia; Royal Brisbane & Women's Hospital, Herston, QLD, 4029, Australia.
authors.forename: Lawrie W
authors.initials: LW
authors.lastname: Powell
authors.affiliation: Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia.
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Allen
authors.affiliation: Departments of Medicine and Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Phillips
authors.affiliation: Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Parker
authors.affiliation: Department of Veterans Affairs Long Beach Healthcare System, Long Beach, CA 90822, USA; Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA 92868, USA.
authors.forename: Gordon D
authors.initials: GD
authors.lastname: McLaren
authors.affiliation: Department of Epidemiology, University of California, Irvine, CA 92697, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: McLaren
mesh_terms: D000217:Acyltransferases / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000367:Age Factors; D000368:Aged; D000428:Alcohol Drinking; D005260:Female; D000071020:Hemochromatosis Protein / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense
chemical_list: D000071020:Hemochromatosis Protein; D007501:Iron; D000217:Acyltransferases; C020051:glycerone-phosphate O-acyltransferase
keywords: Hemochromatosis; Iron overload; rs11558492; rs1800562