title: Iron overload is rare in patients homozygous for the H63D mutation.
abstract: BACKGROUND
  Previous research has suggested that the H63D HFE mutation is associated with elevated iron indexes. However, the true penetrance of this mutation remains unclear.
  
  
  OBJECTIVE
  To assess the proportion of H63D homozygotes with laboratory abnormalities consistent with iron overload.
  
  
  METHODS
  The present study was a retrospective analysis of all individuals referred for HFE genotyping in Newfoundland and Labrador between 1999 and 2009, who were found to be homozygous for the H63D mutation. Using electronic health records, results of ferritin, transferrin saturation, aspartate aminotransferase and alanine aminotransferase testing performed closest to the time of genetic testing were recorded for each patient. Iron overload was classified using previously published definitions from the HealthIron study. SPSS version 17.0 (IBM Corporation, USA) was used for descriptive statistics and to compare means using one-way ANOVA.
  
  
  RESULTS
  Between 1999 and 2009, 170 individuals tested positive for H63D⁄H63D. At the time of genotyping, 28.8% had an elevated mean (± SD) ferritin level of 501±829 μg⁄L and 15.9% had an elevated transferrin saturation of 0.45±0.18. At genotyping, 94 individuals had sufficient data available to classify iron overload status. Only three (3.2%) had documented iron overload while the majority (85.1%) had no evidence of iron overload. Sixty individuals had follow-up data available and, of these, only four (6.7%) had documented iron overload, while 45 (75.0%) had no evidence of iron overload. Only one individual had evidence of iron overload-related disease at genotyping and at follow-up.
  
  
  CONCLUSIONS
  H63D homozygosity was associated with an elevated mean ferritin level, but only 6.7% had documented iron overload at follow-up. The penetrance of the H63D mutation appeared to be low.
authors.forename: Melissa
authors.initials: M
authors.lastname: Kelley
authors.forename: Nikhil
authors.initials: N
authors.lastname: Joshi
authors.forename: Yagang
authors.initials: Y
authors.lastname: Xie
authors.forename: Mark
authors.initials: M
authors.lastname: Borgaonkar
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D005260:Female; D005293:Ferritins / Q000097:blood; D005820:Genetic Testing; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000097:blood; D019190:Iron Overload / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D019683:Penetrance; D017354:Point Mutation; D012189:Retrospective Studies; D014168:Transferrin / Q000378:metabolism
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D005293:Ferritins; D007501:Iron; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
references.citation: Br J Haematol. 2001 Aug;114(2):474-84
references.pmid: 11529872
references.citation: Gastroenterology. 2001 Feb;120(3):718-25
references.pmid: 11179246
references.citation: N Engl J Med. 2005 Apr 28;352(17):1769-78
references.pmid: 15858186
references.citation: Gut. 1998 Sep;43(3):441-2
references.pmid: 9863493
references.citation: Blood. 2004 Apr 15;103(8):2914-9
references.pmid: 15070663
references.citation: Blood Cells Mol Dis. 1997 Aug;23(2):314-20
references.pmid: 9410475
references.citation: Ann Hematol. 2010 Aug;89(8):767-73
references.pmid: 20107990
references.citation: Ann Epidemiol. 2011 Jan;21(1):1-14
references.pmid: 20800508
references.citation: J Hepatol. 1999 Apr;30(4):588-93
references.pmid: 10207799
references.citation: Am J Hum Genet. 1997 Sep;61(3):762-4
references.pmid: 9326341
references.citation: Gut. 2001 Jun;48(6):836-42
references.pmid: 11358905
references.citation: Genet Med. 2000 Sep-Oct;2(5):271-7
references.pmid: 11399207
references.citation: Blood Cells Mol Dis. 2002 Jul-Aug;29(1):41-7
references.pmid: 12482402
references.citation: Nat Genet. 1996 Aug;13(4):399-408
references.pmid: 8696333
references.citation: Ann Intern Med. 1999 Jun 15;130(12):953-62
references.pmid: 10383365
references.citation: Eur J Haematol. 2007 Jan;78(1):66-71
references.pmid: 17042772
references.citation: Dig Dis Sci. 2006 Apr;51(4):803-7
references.pmid: 16615007
references.citation: Ann Hematol. 2009 Aug;88(8):775-84
references.pmid: 19159930
references.citation: N Engl J Med. 2008 Jan 17;358(3):221-30
references.pmid: 18199861
references.citation: Gastroenterology. 2002 Mar;122(3):646-51
references.pmid: 11874997
references.citation: Clin Genet. 2006 Feb;69(2):155-62
references.pmid: 16433696