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From SNPedia

Geno Mag Summary
(A;A) 5.1 Two copies of C282Y, likely affected by hemochromatosis which may be serious if male or post-menopausal.
(A;G) 3 One copy of C282Y, carrier of hemochromatosis, likely unaffected unless also H63D carrier.
(G;G) 0 Not a C282Y hemochromatosis carrier.
ReferenceGRCh38 38.1/141
GeneHFE, LOC108783645
is asnp
is mentioned by
dbSNP (classic)rs1800562
1000 genomesrs1800562
GWAS Ctlgrs1800562
Max Magnitude5.1
? (A;A) (A;G) (G;G) 28

CPMC Logo.png

This SNP has been recognized by the Coriell Personalized Medicine Collaborative ICOB.
Additional information is available here

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. 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 or Cys282Tyr 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 15591282OA-icon.png]

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 17847004OA-icon.png]

So what percent of rs1800562(A;A) individuals actually develop clinical signs of hemochromatosis? At least in the UK (Caucasian) population, a 2019 survey reported that of 2890 participants homozygous for p.C282Y (0.6%, or 1 in 156), hemochromatosis was diagnosed in 21.7% of men and 9.8% of women over an average follow up (~7 years). p.C282Y homozygous men aged 40 to 70 had a higher prevalence of diagnosed hemochromatosis (OR 411.1, CI: 299-565, p<0.001), liver disease (4.30, 2.97-6.18, p<0.001), rheumatoid arthritis (2.23, 1.51-3.31, p<0.001), osteoarthritis (2.01, 1.71-2.36, p<0.001), and diabetes mellitus (1.53, 1.16-1.98, p=0.002), versus 175,000+ controls (people with no p.C282Y mutations). During the seven year follow-up, 15.7% of homozygous men developed at least one incident associated condition versus 5.0% (p<0.001) with no p.C282Y mutations; for women, it was 10.1% vs 3.4%, p<0.001).doi.org/10.1136/bmj.k5222

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

According to 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
GWAS snp
PMID [PMID 19084217OA-icon.png]
Trait Serum markers of iron status
Title Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels
Risk Allele
P-val 4E-15
Odds Ratio NR NR
GWAS snp
PMID [PMID 19820697OA-icon.png]
Trait Hematological parameters
Title A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium
Risk Allele A
P-val 1E-23
Odds Ratio 1.41 [1.13-1.69] fl increase
GWAS snp
PMID [PMID 19820699OA-icon.png]
Trait Serum markers of iron status
Title Common variants in TMPRSS6 are associated with iron status and erythrocyte volume
Risk Allele A
P-val 5E-7
Odds Ratio 0.20 [0.12-0.28] SD increase
GWAS snp
PMID [PMID 19862010OA-icon.png]
Trait Hematocrit
Title Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium
Risk Allele A
P-val 2E-9
Odds Ratio 0.31 [0.21-0.41] % increase

[PMID 20029940OA-icon.png] Suggestive synergy between genetic variants in TF and HFE as risk factors for Alzheimer's disease

[PMID 20858683OA-icon.png] Common variants at ten genomic loci influence hemoglobin A1C levels via glycemic and non-glycemic pathways

GWAS snp
PMID [PMID 20927387OA-icon.png]
Title A genome-wide association study of red blood cell traits using the electronic medical record
Risk Allele A
P-val 3E-9
Odds Ratio 0.49 [0.33-0.65] unit increase

GWAS snp
PMID [PMID 21665994OA-icon.png]
Title Genome-wide association study identifies two loci strongly affecting transferrin glycosylation.
Risk Allele A
P-val 2E-32
Odds Ratio 0.6290 [0.53-0.73] unit decrease
GWAS snp
PMID [PMID 21785125]
Title Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations.
Risk Allele
P-val 3E-7
Odds Ratio 0.3890 [0.24-0.54] ng/ml increase
GWAS snp
PMID [PMID 21943158OA-icon.png]
Title Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits.
Risk Allele A
P-val 5E-12
Odds Ratio 0.1770 [0.13-0.23] mg/l increase
GWAS snp
PMID [PMID 20686565OA-icon.png]
Title Biological, clinical and population relevance of 95 loci for blood lipids.
Risk Allele A
P-val 6E-10
Odds Ratio 2.2200 None

Risk Rs1800562(A;A)
Alt Rs1800562(A;A)
Reference Rs1800562(G;G)
Significance Other
Disease Hemochromatosis type 1 Porphyria cutanea tarda Porphyria variegata Hemochromatosis Alzheimer disease Transferrin serum level quantitative trait locus 2 Microvascular complications of diabetes 7 not specified not provided Hereditary cancer-predisposing syndrome Hereditary hemochromatosis Cutaneous photosensitivity Porphyrinuria
Variation info
Gene HFE
CLNDBN Hemochromatosis type 1 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 not specified not provided Hereditary cancer-predisposing syndrome Hereditary hemochromatosis Cutaneous photosensitivity Porphyrinuria
Reversed 0
HGVS NC_000006.11:g.26093141G>A
CLNSRC OMIM Allelic Variant UniProtKB (protein)
CLNACC RCV000000019.13, RCV000000020.6, RCV000000021.6, RCV000000022.6, RCV000000023.6, RCV000000024.6, RCV000000025.6, RCV000117222.1, RCV000178096.3, RCV000210820.1, RCV000308358.1, RCV000414811.1,

[PMID 18603647OA-icon.png] Functional genetic polymorphisms and female reproductive disorders: Part I: Polycystic ovary syndrome and ovarian response.

[PMID 18795173OA-icon.png] Variants in iron metabolism genes predict higher blood lead levels in young children.

[PMID 19165391OA-icon.png] Iron metabolism genes, low-level lead exposure, and QT interval.

[PMID 19401444OA-icon.png] 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.

[PMID 19474294OA-icon.png] Potential etiologic and functional implications of genome-wide association loci for human diseases and traits.

[PMID 19673882OA-icon.png] A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis.

[PMID 20659343OA-icon.png] HFE gene variants modify the association between maternal lead burden and infant birthweight: a prospective birth cohort study in Mexico City, Mexico.

[PMID 21240526] Evaluation of the association studies of single nucleotide polymorphisms and hepatocellular carcinoma: a systematic review.

[PMID 21679129] Genotyping of the hemochromatosis HFE p.H63D and p.C282Y mutations by high-resolution melting with the Rotor-Gene 6000(R) instrument.

[PMID 22611049OA-icon.png] Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations.

[PMID 18246059OA-icon.png] 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.

[PMID 23389292OA-icon.png] Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

GWAS snp
PMID [PMID 23263863OA-icon.png]
Trait Hematology traits
Title GWAS of blood cell traits identifies novel associated loci and epistatic interactions in Caucasian and African-American children.
Risk Allele A
P-val 2E-6
Odds Ratio .19 [0.11-0.27] unit increase
GWAS snp
PMID [PMID 23446634OA-icon.png]
Trait Red blood cell traits
Title Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network.
Risk Allele A
P-val 4E-6
Odds Ratio .24 [0.14-0.34] g/dL increase

[PMID 23792061] Meta-analyses of HFE variants in coronary heart disease

[PMID 22735619] 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 23468552OA-icon.png] Genetic variants influencing biomarkers of nutrition are not associated with cognitive capability in middle-aged and older adults.

[PMID 23794717OA-icon.png] Associations of common variants in HFE and TMPRSS6 with iron parameters are independent of serum hepcidin in a general population: a replication study.

[PMID 25085015] Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes

GWAS snp
PMID [PMID 24097068OA-icon.png]
Trait Cholesterol, total
Title Discovery and refinement of loci associated with lipid levels.
Risk Allele A
P-val 2E-12
Odds Ratio .06 [NR] unit decrease
GWAS snp
PMID [PMID 21483845OA-icon.png]
Trait Iron status biomarkers
Title Genome-wide association study identifies genetic loci associated with iron deficiency.
Risk Allele A
P-val 3E-8
Odds Ratio 35.36 [NR] ug/dL decrease

[PMID 24663082OA-icon.png] Influence of diet, menstruation and genetic factors on iron status: a cross-sectional study in Spanish women of childbearing age

[PMID 26460247] Genetic contribution to iron status: SNPs related to iron deficiency anaemia and fine mapping of CACNA2D3 calcium channel subunit

[PMID 26597663] Genetic factors influencing ferritin levels in 14,126 blood donors: results from the Danish Blood Donor Study

[PMID 26690219OA-icon.png] Association Studies of HFE C282Y and H63D Variants with Oral Cancer Risk and Iron Homeostasis Among Whites and Blacks.