{{Rsnum
|rsid=1800562
|Gene=HFE
|Chromosome=6
|position=26092913
|Orientation=plus
|GMAF=0.01974
|Assembly=GRCh38
|GenomeBuild=38.1
|dbSNPBuild=141
|Summary=hemochromatosis
|geno1=(A;A)
|geno2=(A;G)
|geno3=(G;G)
|Gene_s=HFE
}}{{ population diversity
| geno1=(A;A)
| geno2=(A;G)
| geno3=(G;G)
| CEU | 0.0 | 10.6 | 89.4
| HCB | 0.0 | 0.0 | 100.0
| JPT | 0.0 | 0.0 | 100.0
| YRI | 0.0 | 0.0 | 100.0
| ASW | 0.0 | 3.5 | 96.5
| CHB | 0.0 | 0.0 | 100.0
| CHD | 0.0 | 0.9 | 99.1
| GIH | 0.0 | 1.0 | 99.0
| LWK | 0.0 | 0.0 | 0.0
| MEX | 0.0 | 1.8 | 98.2
| MKK | 0.0 | 0.0 | 0.0
| TSI | 0.0 | 5.0 | 95.0
| HapMapRevision=28
}}{{CPMC SNP
|link=http://cpmc.coriell.org/Sections/Genes/Hemochromatosis.aspx?PgId=102
}}

[[rs1800562]] represents a SNP that accounts for ~85% of all cases of [[hemochromatosis]], a disorder whose symptoms include cirrhosis of the liver, [[diabetes]], hypermelanotic pigmentation of the skin, and heart failure. [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=235200 OMIM] indicates that [[liver cancer]] is responsible for about one-third of deaths of [[rs1800562]](A;A) homozygotes, and since hemochromatosis is a relatively easily treated disorder if diagnosed, this is a form of preventable [[cancer]].

The [[rs1800562]](A) allele is known as the C282Y mutation, and it is found at a frequency of around 5-10% in many Caucasian populations, leading to an incidence of (A;A) homozygotes around 1 in 200. Early identification of [[rs1800562]](A;A) homozygotes can prevent complications of [[hemochromatosis]]; however, the percentage of all (A;A) homozygotes who actually develop clinical signs of [[hemochromatosis]] may be relatively low, may depend on sex (see below), and appears to be influenced by other SNPs yet to all be discovered as well as (unidentified) environmental factors, possibly including the amount of iron in the diet.

In [[rs1800562]](A;A) patients who do develop [[hemochromatosis]], a SNP has been identified which increases the risk of cardiomyopathy (a form of [[heart disease]]). [[rs4880]](T;T) homozygotes are at ~10 fold increased risk for dilated- or non-dilated cardiopathy based on a study of 217 patients.{{PMID|15591282|OA=1
}}

[[rs235756]], a SNP in the [[BMP2]] gene, is another SNP that may influence the development of [[hemochromatosis]] in [[rs1800562]](A;A) individuals, at least if serum transferrin levels are a good indication. Transferrin levels increased with increasing copies of the [[rs235756]](T) allele.{{PMID|17847004|OA=1
}}  

So which [[rs1800562]](A;A) individuals actually develop clinical signs of [[hemochromatosis]]? In a recent study of ~200 [[rs1800562]](A;A) homozygotes, ~30% of the males had iron-overload related diseases versus 1% of the females. Male C282Y homozygotes with a serum ferritin level of 1,000 mcg per liter or more were more likely to report fatigue, use of [[arthritis]] medicine, and a history of liver disease than were men who lacked a [[rs1800562]](A) allele.{{PMID|18199861}}

Women who are [[rs1800562]](A) homozygotes are less affected by [[hemochromatosis]] due to elimination of excess iron during menstruation, but may become affected after menopause.

Carriers of [[rs1800562]](A) may be affected by a mild form of [[hemochromatosis]] if also a carrier of [[rs1799945]](G) H63D.

According to [https://cpmc.coriell.org/Sections/Results/rs1800562.aspx?PgId=184 Coriell], in Caucasian populations:
*(A;A) - 0.4% of individuals, carrying 2 copies of the risk variant (33-57% of such males will have quite elevated iron levels; 3-16% if female)
*(G;A) - 12% carry 1 copy of the risk variant and 1 copy of the non-risk variant
*(G;G) - 87.6% carry (only) the non-risk variant

{{PMID Auto GWAS
|PMID=19084217
|Trait=Serum markers of iron status
|Title=Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels
|RiskAllele=
|Pval=4E-15
|OR=NR
|ORtxt=NR
|OA=1
}}
{{PMID Auto GWAS
|PMID=19820697
|Trait=Hematological parameters
|Title=A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium
|RiskAllele=A
|Pval=1E-23
|OR=1.41
|ORtxt=[1.13-1.69] fl increase
|OA=1
}}
{{PMID Auto GWAS
|PMID=19820699
|Trait=Serum markers of iron status
|Title=Common variants in TMPRSS6 are associated with iron status and erythrocyte volume
|RiskAllele=A
|Pval=5E-7
|OR=0.20
|ORtxt=[0.12-0.28] SD increase
|OA=1
}}
{{PMID Auto GWAS
|PMID=19862010
|Trait=Hematocrit
|Title=Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium
|RiskAllele=A
|Pval=2E-9
|OR=0.31
|ORtxt=[0.21-0.41] % increase
|OA=1
}}

{{PharmGKB
|RSID=rs1800562
|Name_s=
|Gene_s=HFE
|Feature=
|Evidence=PubMed ID:19084217
|Annotation=In a GWAS performed on 459 female monozygotic twin pairs, all Australians of European descent, this SNP was found to be associated with serum iron (p=3.5 x 10 (-11)), serum transferrin (p = 1.1 x 10 (-10)), transferrin saturation (p=4.3 x 10 (-15)) and serum ferritin (p=4.5 x 10(-5)).
|Drugs=
|Drug Classes=
|Diseases=
|Curation Level=Curated
|PharmGKB Accession ID=PA164920576
}}

{{PMID Auto
|PMID=20029940
|Title=Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease
|OA=1
}}
{{PMID Auto
|PMID=20858683
|Title=Common variants at ten genomic loci influence hemoglobin A1C levels via glycemic and non-glycemic pathways
|OA=1
}}
{{PMID Auto GWAS
|PMID=20927387
|Trait=None
|Title=A genome-wide association study of red blood cell traits using the electronic medical record
|RiskAllele=A
|Pval=3E-9
|OR=0.49
|ORtxt=[0.33-0.65] unit increase
|OA=1
}}

{{omim
|desc=HFE GENE; HFE
|id=613609
|rsnum=1800562
}}

{{PharmGKB
|RSID=rs1800562
|Name_s=HFE:C282Y; HFE: Cys282Tyr
|Gene_s=HFE
|Feature=
|Evidence=PubMed ID:18025780
|Annotation=HFE variants, HFE: His63Asp and HFE: Cys282Tyr, reduce the amount of r-HuEPO and iron necessary to support erythropoiesis in hemodialysis patients.
|Drugs=epoetin alfa
|Drug Classes=
|Diseases=
|Curation Level=Curated
|PharmGKB Accession ID=PA162652703
}}

{{PharmGKB
|RSID=rs1800562
|Name_s=
|Gene_s=HFE
|Feature=
|Evidence=PubMed ID:19084217; Web Resource:http://www.genome.gov/gwastudies/
|Annotation=GWAS results: Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. (Initial Sample Size: 459 twin pairs; Replication Sample Size: NR); (Region: 6p22.1; Reported Gene(s): HFE; Risk Allele: rs1800562-?); (p-value= 0.0000000001).This variant is associated with Serum markers of iron status(serum transferrin).
|Drugs=
|Drug Classes=
|Diseases=
|Curation Level=Non-Curated
|PharmGKB Accession ID=PA164740110
}}

{{PharmGKB
|RSID=rs1800562
|Name_s=
|Gene_s=HFE
|Feature=
|Evidence=PubMed ID:19084217; Web Resource:http://www.genome.gov/gwastudies/
|Annotation=GWAS results: Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. (Initial Sample Size: 459 twin pairs; Replication Sample Size: NR); (Region: 6p22.1; Reported Gene(s): HFE; Risk Allele: rs1800562-?); (p-value= 0.00000000004).This variant is associated with Serum markers of iron status(serum iron).
|Drugs=
|Drug Classes=
|Diseases=
|Curation Level=Non-Curated
|PharmGKB Accession ID=PA164740112
}}

{{PharmGKB
|RSID=rs1800562
|Name_s=
|Gene_s=HFE
|Feature=
|Evidence=PubMed ID:19084217; Web Resource:http://www.genome.gov/gwastudies/
|Annotation=GWAS results: Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. (Initial Sample Size: 459 twin pairs; Replication Sample Size: NR); (Region: 6p22.1; Reported Gene(s): HFE; Risk Allele: rs1800562-?); (p-value= 0.000000000000004).This variant is associated with Serum markers of iron status(transferrin saturation).
|Drugs=
|Drug Classes=
|Diseases=
|Curation Level=Non-Curated
|PharmGKB Accession ID=PA164740104
}}

{{PMID Auto GWAS
|PMID=21665994
|Trait=None
|Title=Genome-wide association study identifies two loci strongly affecting transferrin glycosylation.
|RiskAllele=A
|Pval=2E-32
|OR=0.6290
|ORtxt=[0.53-0.73] unit decrease
|OA=1
}}

{{PMID Auto GWAS
|PMID=21785125
|Trait=None
|Title=Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations.
|RiskAllele=
|Pval=3E-7
|OR=0.3890
|ORtxt=[0.24-0.54] ng/ml increase
}}

{{PMID Auto GWAS
|PMID=21943158
|Trait=None
|Title=Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits.
|RiskAllele=A
|Pval=5E-12
|OR=0.1770
|ORtxt=[0.13-0.23] mg/l increase
|OA=1
}}

{{PMID Auto GWAS
|PMID=20686565
|Trait=None
|Title=Biological, clinical and population relevance of 95 loci for blood lipids.
|RiskAllele=A
|Pval=6E-10
|OR=2.2200
|ORtxt=None
|OA=1
}}

{{ClinVar
|rsid=1800562
|Reversed=0
|FwdREF=G
|FwdALT=A
|REF=G
|ALT=A
|RSPOS=26093141
|CHROM=6
|GMAF=0.0197
|dbSNPBuildID=89
|SSR=0
|SAO=1
|VP=0x050368000000150517130100
|GENEINFO=HFE:3077
|GENE_NAME=HFE
|GENE_ID=3077
|WGT=0
|VC=SNV
|CLNALLE=1
|CLNHGVS=NC_000006.11:g.26093141G>A
|CLNSRC=GTR; OMIM Allelic Variant
|CLNORIGIN=1
|CLNSRCID=GTR000219921; 613609.0001
|CLNSIG=255
|CLNCUI=C0392514; CN068375; CN034317
|CLNDBN=Hereditary hemochromatosis; Porphyria cutanea tarda, susceptibility to; Porphyria variegata, susceptibility to; Hemochromatosis, juvenile, digenic; Alzheimer disease, susceptibility to; Transferrin serum level quantitative trait locus 2; Microvascular complications of diabetes 7
|Disease=Hereditary hemochromatosis; Porphyria cutanea tarda; Porphyria variegata; Hemochromatosis; Alzheimer disease; Transferrin serum level quantitative trait locus 2; Microvascular complications of diabetes 7
|CLNACC=RCV000000019.3; RCV000000020.3; RCV000000021.3; RCV000000022.3; RCV000000023.3; RCV000000024.3; RCV000000025.3
|Tags=PM;PMC;S3D;SLO;VLD;G5;HD;GNO;KGPhase1;KGPROD;OTHERKG;PH3;LSD;MTP;OM
|CAF=0.9803; 0.01974
|CLNDSDB=GeneReviews:MedGen:OMIM:SNOMED_CT; MedGen:OMIM
|CLNDSDBID=NBK1440:C0392514:235200:35400008; C3280096:614193; CN034317:612635
|COMMON=1
}}

{{PMID Auto
|PMID=18603647
|Title=Functional genetic polymorphisms and female reproductive disorders: Part I: Polycystic ovary syndrome and ovarian response.
|OA=1
}}

{{PMID Auto
|PMID=18795173
|Title=Variants in iron metabolism genes predict higher blood lead levels in young children.
|OA=1
}}

{{PMID Auto
|PMID=19165391
|Title=Iron metabolism genes, low-level lead exposure, and QT interval.
|OA=1
}}

{{PMID Auto
|PMID=19401444
|Title=Body iron stores and glucose intolerance in premenopausal women: role of hyperandrogenism, insulin resistance, and genomic variants related to inflammation, oxidative stress, and iron metabolism.
|OA=1
}}

{{PMID Auto
|PMID=19474294
|Title=Potential etiologic and functional implications of genome-wide association loci for human diseases and traits.
|OA=1
}}

{{PMID Auto
|PMID=19673882
|Title=A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis.
|OA=1
}}

{{PMID Auto
|PMID=20659343
|Title=HFE gene variants modify the association between maternal lead burden and infant birthweight: a prospective birth cohort study in Mexico City, Mexico.
|OA=1
}}

{{PMID Auto
|PMID=21240526
|Title=Evaluation of the association studies of single nucleotide polymorphisms and hepatocellular carcinoma: a systematic review.
}}

{{PMID Auto
|PMID=21679129
|Title=Genotyping of the hemochromatosis HFE p.H63D and p.C282Y mutations by high-resolution melting with the Rotor-Gene 6000(R) instrument.
}}

{{PMID Auto
|PMID=22611049
|Title=Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations.
|OA=1
}}

{{PMID|18246059|OA=1
}} Was the C282Y mutation an Irish Gaelic mutation that the Vikings helped disseminate? Conclusion: The C282Y frequency shows a west to east decline from Ireland through the north of Europe. Vikings may have been involved in the spread of C282Y, but the mutation is probably older and may have been spread in Europe by earlier seafarers.

{{GET Evidence
|gene=HFE
|aa_change=Cys282Tyr
|aa_change_short=C282Y
|impact=pathogenic
|qualified_impact=Low clinical importance,  pathogenic
|inheritance=recessive
|quality_scores=Array
|dbsnp_id=rs1800562
|overall_frequency_n=532
|overall_frequency_d=10758
|overall_frequency=0.0494516
|n_genomes=2
|n_genomes_annotated=0
|n_haplomes=1
|n_articles=3
|n_articles_annotated=3
|qualityscore_in_silico=2
|qualitycomment_in_silico=Y
|qualityscore_in_vitro=2
|qualitycomment_in_vitro=Y
|qualityscore_case_control=5
|qualitycomment_case_control=Y
|qualityscore_familial=0
|qualitycomment_familial=Y
|qualityscore_severity=2
|qualitycomment_severity=Y
|qualityscore_treatability=3
|qualitycomment_treatability=Y
|gene_in_genetests=Y
|in_omim=Y
|in_pharmgkb=Y
|pph2_score=1.0
|genetests_testable=Y
|genetests_reviewed=Y
|nblosum100=6
|autoscore=6
|webscore=N
|n_web_uneval=10
|variant_evidence=0
|clinical_importance=2
|summary_short=This variant is associated with hereditary haemochromatosis, 80% of patients with that disease are homozygous for this variant. However, the penetrance is low, in Beutler et al. they note that only 1 of their 158 homozygotes met criteria for diagnosis with the condition.
}}

{{PMID Auto
|PMID=23389292
|Title=Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study
}}

{{PMID Auto GWAS
  |PMID=23263863
  |Trait=Hematology traits
  |Title=GWAS of blood cell traits identifies novel associated loci and epistatic interactions in Caucasian and African-American children.
  |RiskAllele=A
  |Pval=2E-6
  |OR=.19
  |ORtxt=[0.11-0.27] unit increase
  |OA=1
}}

{{PMID Auto GWAS
  |PMID=23446634
  |Trait=Red blood cell traits
  |Title=Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network.
  |RiskAllele=A
  |Pval=4E-6
  |OR=.24
  |ORtxt=[0.14-0.34] g/dL increase
  }}

{{PMID Auto
|PMID=23792061
|Title=Meta-analyses of HFE variants in coronary heart disease
}}

{{PMID Auto
|PMID=22735619
|Title=Sample-to-SNP kit: a reliable, easy and fast tool for the detection of HFE p.H63D and p.C282Y variations associated to hereditary hemochromatosis.
}}

{{PMID Auto
|PMID=23468552
|Title=Genetic variants influencing biomarkers of nutrition are not associated with cognitive capability in middle-aged and older adults.
|OA=1
}}

{{PMID Auto
|PMID=23794717
|Title=Associations of common variants in HFE and TMPRSS6 with iron parameters are independent of serum hepcidin in a general population: a replication study.
}}

{{PMID Auto
|PMID=24922956
|Title=156 Regulation of LDL-cholesterol Associated Gene Expression by Iron Responsive Elements and Iron
}}

{{PMID Auto
|PMID=25085015
|Title=Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes
}}
{{on chip | 23andMe v1}}
{{on chip | 23andMe v2}}
{{on chip | 23andMe v3}}
{{on chip | 23andMe v4}}
{{on chip | Affy GenomeWide 6}}
{{on chip | Illumina Human 1M}}