title: HFE p.C282Y homozygosity predisposes to rapid serum ferritin rise after menopause: A genotype-stratified cohort study of hemochromatosis in Australian women.
abstract: OBJECTIVE
  Women who are homozygous for the p.C282Y mutation in the HFE gene are at much lower risk of iron overload-related disease than p.C282Y homozygous men, presumably because of the iron-depleting effects of menstruation and pregnancy. We used data from a population cohort study to model the impact of menstruation cessation at menopause on serum ferritin (SF) levels in female p.C282Y homozygotes, with p.C282Y/p.H63D simple or compound heterozygotes and those with neither p.C282Y nor p.H63D mutations (HFE wild types) as comparison groups.
  
  
  METHODS
  A sample of the Melbourne Collaborative Cohort Study was selected for the "HealthIron" study (n = 1438) including all HFE p.C282Y homozygotes plus a random sample stratified by HFE-genotype (p.C282Y and p.H63D). The relationship between the natural logarithm of SF and time since menopause was examined using linear mixed models incorporating spline smoothing.
  
  
  RESULTS
  For p.C282Y homozygotes, SF increased by a factor of 3.6 (95% CI (1.8, 7.0), P < 0.001) during the first 10 years postmenopause, after which SF continued to increase but at less than half the previous rate. In contrast, SF profiles for other HFE genotype groups increase more gradually and did not show a distinction between premenopausal and postmenopausal SF levels. Only p.C282Y homozygotes had predicted SF exceeding 200 μg/L postmenopause, but the projected SF did not increase the risk of iron overload-related disease.
  
  
  CONCLUSIONS
  These data provide the first documented evidence that physiological blood loss is a major factor in determining the marked gender difference in expression of p.C282Y homozygosity.
authors: Product Development, Roche Products Ltd, Welwyn Garden City, Hertfordshire, UK.
authors: Charles D
authors: CD
authors: Warne
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
authors: Sophie G
authors: SG
authors: Zaloumis
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.|Population Health, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors: Nadine A
authors: NA
authors: Bertalli
authors: Population Health, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.|Austin Health, Heidelberg, Victoria, Australia.
authors: Martin B
authors: MB
authors: Delatycki
authors: Department of Gastroenterology, Eastern Health and Melbourne Health, Monash University, Melbourne, Victoria, Australia.
authors: Amanda J
authors: AJ
authors: Nicoll
authors: Department of Epidemiology, University of California, Irvine, California, USA.
authors: Christine E
authors: CE
authors: McLaren
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
authors: John L
authors: JL
authors: Hopper
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
authors: Graham G
authors: GG
authors: Giles
authors: QIMR Berghofer Medical Research Institute and The University of Queensland, Brisbane, Queensland, Australia.
authors: Greg J
authors: GJ
authors: Anderson
authors: Department of Gastroenterology, Fiona Stanley and Fremantle Hospitals, Murdoch, Western Australia, Australia.|School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia.|School of Veterinary and Life Sciences, Murdoch University, Perth, Western Australia, Australia.
authors: John K
authors: http://orcid.org/0000-0003-0417-3411
authors: JK
authors: Olynyk
authors: QIMR Berghofer Medical Research Institute and The University of Queensland, Brisbane, Queensland, Australia.|The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors: Lawrie W
authors: LW
authors: Powell
authors: Population Health, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors: Katrina J
authors: KJ
authors: Allen
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
authors: Lyle C
authors: LC
authors: Gurrin
mesh_terms: D000328:Adult; D000368:Aged; D001315:Australia; D015331:Cohort Studies; D005260:Female; D005293:Ferritins / Q000097:blood*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008593:Menopause / Q000097:blood* / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D005293:Ferritins
keywords: HFE p.C282Y homozygosity; hereditary hemochromatosis; iron accumulation; iron overload-related disease; menopause; women's health