title: The role of hemochromatosis susceptibility gene mutations in protecting against iron deficiency in celiac disease.
abstract: OBJECTIVE
  Celiac disease and hereditary hemochromatosis are common HLA-defined conditions in northwestern Europe. We sought to determine whether there is a genetic relationship between the 2 diseases and if hemochromatosis susceptibility gene (HFE) mutations are protective against iron deficiency in celiac disease.
  
  
  METHODS
  Polymerase chain reaction amplification using sequence-specific primers capable of identifying the 2 HFE gene mutations (H63D and C282Y) and the HLA class I and II alleles was used to type 145 white patients with celiac disease and 187 matched controls. Hemoglobin and fasting serum iron levels in celiac patients were measured at diagnosis.
  
  
  RESULTS
  HFE gene mutations, H63D or C282Y, were identified in 70 celiac patients (48.3%) and 61 controls (32.6%) (P = 0.004). The C282Y mutation was associated with HLA-A*03 and B*07 alleles in controls and with A*01, A*03, B*08, and DRB1*0301 alleles in celiac patients; the H63D mutation was associated with HLA-A*25 and DRB1*03 alleles in controls and A*29 and DRB1*03 alleles in celiac patients. At diagnosis, celiac patients with the C282Y mutation had higher mean hemoglobin and fasting serum iron levels compared with the HFE wild type (P = 0.0002 and 0.006, respectively). This was not observed with the H63D mutation.
  
  
  CONCLUSIONS
  In celiac disease, HFE gene mutations are common and are in linkage disequilibrium with different HLA alleles compared with controls. A disease-specific haplotype that carries C282Y and DQB1*02 is suggested. We propose that HFE gene mutations provide a survival advantage by ameliorating the iron deficiency seen in celiac patients.
authors.affiliation: Gastroenterology Unit, City Hospital, Birmingham, England. j.r.butterworth@btinternet.com
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Butterworth
authors.forename: Brian T
authors.initials: BT
authors.lastname: Cooper
authors.forename: William M C
authors.initials: WM
authors.lastname: Rosenberg
authors.forename: Michael
authors.initials: M
authors.lastname: Purkiss
authors.forename: Shirley
authors.initials: S
authors.lastname: Jobson
authors.forename: Mark
authors.initials: M
authors.lastname: Hathaway
authors.forename: David
authors.initials: D
authors.lastname: Briggs
authors.forename: W Martin
authors.initials: WM
authors.lastname: Howell
authors.forename: Gordon M
authors.initials: GM
authors.lastname: Wood
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.forename: Tariq H
authors.initials: TH
authors.lastname: Iqbal
mesh_terms: D000328:Adult; D002446:Celiac Disease / Q000097:blood / Q000150:complications / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics*; D015234:HLA-A Antigens / Q000235:genetics; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006432:Hemochromatosis / Q000235:genetics*; D000071020:Hemochromatosis Protein; D006454:Hemoglobins / Q000032:analysis; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D000090463:Iron Deficiencies; D015810:Linkage Disequilibrium; D008565:Membrane Proteins; D009154:Mutation
chemical_list: C103673:HFE protein, human; D006680:HLA Antigens; D015234:HLA-A Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D000071020:Hemochromatosis Protein; D006454:Hemoglobins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins