title: Hereditary hemochromatosis type 1 phenotype modifiers in Italian patients. The controversial role of variants in HAMP, BMP2, FTL and SLC40A1 genes.
abstract: Hereditary hemochromatosis (HH) is a heterogeneous disorder of iron metabolism. The most common form of the disease is Classic or type 1 HH, mainly caused by a biallelic missense p.Cys282Tyr (c.845G>A) mutation in the HFE gene. However, the penetrance of p.Cys282Tyr/p.Cys282Tyr genotype is incomplete in terms of both biochemical and clinical expressivity. Lack of penetrance is thought to be caused by several genetic and environmental factors. Recently, a lot of evidences on HH genetic modifiers were produced, often without conclusive results. We investigated 6 polymorphisms (rs10421768 in HAMP gene, rs235756 in BMP2 gene, rs2230267 in FTL gene, rs1439816 in SLC40A1 gene, rs41295942 in TFR2 gene and rs2111833 in TMPRSS6 gene) with uncertain function in order to further evaluate their role in an independent cohort of 109 HH type 1 patients. Our results make it likely the role of rs10421768, rs235756, rs2230267 and rs1439816 polymorphisms, respectively in HAMP, BMP2, FTL and SLC40A1 genes in HH expressivity. In addition, previous and our findings support a hypothetical multifactorial model of HH, characterized by a principal gene (HFE in HH type 1) and minor genetic and environmental factors that still have to be fully elucidated.
authors.affiliation: Medical Genetics, Molecular Medicine Department, Sapienza University of Rome, San Camillo-Forlanini Hospital, Rome, Italy. Electronic address: francescaclementina.radio@uniroma1.it.
authors.forename: Francesca Clementina
authors.initials: FC
authors.lastname: Radio
authors.affiliation: Medical Genetics, Molecular Medicine Department, Sapienza University of Rome, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Majore
authors.affiliation: Porphyria Centre San Gallicano Institute IRCCS IFO, Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Aurizi
authors.affiliation: Porphyria Centre San Gallicano Institute IRCCS IFO, Rome, Italy.
authors.forename: Fiammetta
authors.initials: F
authors.lastname: Sorge
authors.affiliation: Porphyria Centre San Gallicano Institute IRCCS IFO, Rome, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Biolcati
authors.affiliation: Department of Genetic Diagnosis, Careggi Hospital, Florence, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bernabini
authors.affiliation: Department of Genetic Diagnosis, Careggi Hospital, Florence, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Giotti
authors.affiliation: Department of Genetic Diagnosis, Careggi Hospital, Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Torricelli
authors.affiliation: Biostatistical Unit, Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Giannarelli
authors.affiliation: Medical Genetics, Molecular Medicine Department, Sapienza University of Rome, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Carmelilia
authors.initials: C
authors.lastname: De Bernardo
authors.affiliation: Medical Genetics, Molecular Medicine Department, Sapienza University of Rome, San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Grammatico
mesh_terms: D000483:Alleles; D001052:Apoferritins / Q000235:genetics*; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D005260:Female; D005293:Ferritins / Q000097:blood; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D005838:Genotype; D006432:Hemochromatosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D000071020:Hemochromatosis Protein; D064451:Hepcidins / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D019683:Penetrance; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011990:Receptors, Transferrin / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D014168:Transferrin / Q000378:metabolism; D000098742:Ferroportin
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D027682:Cation Transport Proteins; C507433:FTL protein, human; C578702:HAMP protein, human; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; C503640:TFR2 protein, human; D014168:Transferrin; D000098742:Ferroportin; D005293:Ferritins; D001052:Apoferritins; D007501:Iron; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human
keywords: BMP2; FTL; HAMP; Hereditary hemochromatosis; Iron overload; Penetrance defect; SLC40A1; TFR2; TMPRSS6; p.Cys282Tyr