title: Toll-like receptor 4 gene polymorphism modulates phenotypic expression in patients with hereditary hemochromatosis.
abstract: BACKGROUND
  Clinical penetrance of hereditary hemochromatosis is highly variable. We hypothesized that it might be modified by factors involved in the cellular immune response, such as toll-like receptors (TLRs) or nucleotide oligomerization domain proteins (NODs).
  
  
  METHODS
  Clinical expression of hemochromatosis was assessed as a function of TLR4, TLR9, and NOD2 polymorphisms in 99 homozygous carriers of the HFE C282Y mutation with mild-to-severe iron overload.
  
  
  RESULTS
  Thirteen (13%) of the 99 hemochromatosis patients were heterozygous for a TLR4 Asp299Gly polymorphism and 86 (87%) were TLR4 wild-type-only carriers. Clinical expression of hemochromatosis was observed more frequently in carriers of the TLR4 polymorphism (100%) than in TLR4 wild-type carriers (56%, P = 0.002). This was based on higher prevalences of liver disease (92 vs. 45%, P = 0.002) and arthropathy of metacarpophalangeal joints (69 vs. 35%, P = 0.018) in TLR4 polymorphism carriers. The finding was strengthened by the strong association of TLR4 polymorphism with liver fibrosis in the subgroup of 52 patients who underwent a liver biopsy (P = 0.011). The TLR4 polymorphism did, however, not correlate with body iron overload. The study results remained significant in multiple regression analyses after excluding possible confounding effects, such as age, sex, alcohol, or meat intake, and in the subgroup of 84 patients presenting as the first members of their families.
  
  
  CONCLUSIONS
  TLR4 Asp299Gly polymorphism modulates clinical expression in patients with hereditary hemochromatosis. The polymorphism does not correlate with iron overload suggesting that TLR4 plays a role in an inflammatory process arising from toxic effects of iron accumulation.
authors.affiliation: Division of Internal Medicine, Medical Clinic and Policlinic, University Hospital of Zurich, Zurich, Switzerland. pierrea.krayenbuehl@usz.ch
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Krayenbuehl
authors.forename: Martin
authors.initials: M
authors.lastname: Hersberger
authors.forename: Kaspar
authors.initials: K
authors.lastname: Truninger
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.forename: Friedrich E
authors.initials: FE
authors.lastname: Maly
authors.forename: Mario
authors.initials: M
authors.lastname: Bargetzi
authors.forename: Georg
authors.initials: G
authors.lastname: Schulthess
mesh_terms: D000328:Adult; D001177:Arthropathy, Neurogenic / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies / Q000706:statistics & numerical data; D020022:Genetic Predisposition to Disease; D006432:Hemochromatosis / Q000150:complications* / Q000473:pathology*; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D008662:Metacarpophalangeal Joint / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D019683:Penetrance; D010641:Phenotype; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D051217:Toll-Like Receptor 9 / Q000235:genetics
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495371:TLR9 protein, human; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9