title: A common SNP near BMP2 is associated with severity of the iron burden in HFE p.C282Y homozygous patients: a follow-up study.
abstract: OBJECTIVE
  It is now generally admitted that penetrance of the common HFE p.C282Y/p.C282Y genotype is incomplete, and identification of modifier genes is the concern of a growing number of research projects. We recently identified a significant association between pretherapeutic serum ferritin level and the common rs235756 single nucleotide polymorphism (SNP) of the BMP2 gene region. Our results further suggested an interactive effect between the BMP2 rs235756 SNP and the rs16827043 SNP in HJV, with a small additive effect of the rs4901474 SNP in BMP4.
  
  
  METHODS
  The present study has been designed as a replication study in an independent cohort of 450 HFE p.C282Y homozygous patients from a nearby French region (Brittany). Information on individual alcohol consumption and amount of iron removed by phlebotomy being available for a substantial part of this cohort, additional analyses were conducted.
  
  
  RESULTS
  Only the use of the Amount of Iron Removed by phlebotomy (AIR) as marker of iron burden has provided positive results. Indeed, a significant association was detected between rs235756 and AIR adjusted for sex and age, with a mean AIR increasing with the number of BMP2 T alleles in the genotype groups. The effect of rs235657 was not strong enough to detect effects of gene combinations. Still, the trend in two-locus genotype risks involving BMP2 and HJV for AIR was concordant with the specific interactive effect described in the initial study.
  
  
  CONCLUSIONS
  Although we failed to replicate results of the initial study, we argue that, altogether, our results help to consider genes involved in the regulation of hepcidin synthesis as potential modifiers of the p.C282Y/pC282Y genotype expression and especially BMP2.
authors.affiliation: IRD - UR010, Paris, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Milet
authors.forename: Gérald
authors.initials: G
authors.lastname: Le Gac
authors.forename: Virginie
authors.initials: V
authors.lastname: Scotet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gourlaouen
authors.forename: Corine
authors.initials: C
authors.lastname: Thèze
authors.forename: Jean
authors.initials: J
authors.lastname: Mosser
authors.forename: Catherine
authors.initials: C
authors.lastname: Bourgain
authors.forename: Yves
authors.initials: Y
authors.lastname: Deugnier
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
mesh_terms: D000328:Adult; D000428:Alcohol Drinking; D019943:Amino Acid Substitution; D015415:Biomarkers / Q000097:blood; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005293:Ferritins / Q000097:blood; D005500:Follow-Up Studies; D005602:France; D005787:Gene Frequency; D056726:Genetic Association Studies; D006432:Hemochromatosis / Q000097:blood / Q000235:genetics* / Q000628:therapy; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D019683:Penetrance; D018962:Phlebotomy; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index
chemical_list: C525718:BMP2 protein, human; D015415:Biomarkers; D055396:Bone Morphogenetic Protein 2; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D005293:Ferritins; D007501:Iron