rs1799945
mixedMag 6.5This is a variant in the HFE gene that changes a histidine to an aspartate.
Key Literature Trait Associations
Hereditary Hemochromatosis
The HFE H63D variant (G allele) is classified as pathogenic for hereditary hemochromatosis type 1 by ClinVar. H63D homozygotes (GG) and compound heterozygotes (H63D/C282Y) carry elevated risk for iron overload, though penetrance is considerably lower than for C282Y homozygotes. A landmark meta-analysis of 202 studies (66,263 cases and 226,515 controls) confirmed significant associations across multiple hemochromatosis-related endpoints. A UK Biobank GWAS (n=8,289) identified rs1799945 at genome-wide significance for liver iron concentration, with HFE variants collectively accounting for ~85% of hereditary hemochromatosis cases.
Iron biomarkers
The G allele of rs1799945 is robustly associated with elevated serum ferritin, transferrin saturation, and serum iron levels. A large Mendelian randomization phenome-wide study (UK Biobank n=424,439) used rs1799945 as a genetic instrument for iron status and found higher genetically-determined iron status was significantly associated with decreased anemia risk (OR 0.72, 95% CI 0.64–0.81, P=4×10⁻⁸) alongside other pleiotropic effects. The GWAS Catalog reports a beta of approximately 4.95 µg/dl for serum iron (C allele effect) at p=3×10⁻⁹. These iron-raising effects underlie most downstream disease associations attributed to this variant.
Porphyria cutanea tarda
H63D homozygotes (GG) show a 3-fold increased risk of porphyria cutanea tarda (OR 3.0, 95% CI 1.6–5.6) compared to wild-type, with heterozygotes also showing elevated risk (OR 1.7, 95% CI 1.0–3.1), based on a meta-analysis of 202 studies. Porphyria cutanea tarda is the commonest porphyria and is exacerbated by hepatic iron loading; the H63D variant's iron-raising effect provides a plausible mechanistic pathway. This is among the strongest disease-endpoint associations for H63D outside of hemochromatosis itself.
Non-alcoholic fatty liver disease
A systematic review and meta-analysis of 5,758 NAFLD cases and 14,741 controls found HFE H63D significantly associated with increased NAFLD risk under allele, heterozygote, and dominant models. However, a separate meta-analysis of 30 studies (2,610 cases, 7,298 controls) found no significant overall association (pooled OR 1.03), highlighting inconsistency in the literature; the positive signal may be driven by compound heterozygotes (H63D/C282Y). Hepatocellular carcinoma risk showed a modest positive association (OR 1.14–1.28 for CG and GG genotypes respectively) in a 28-study meta-analysis.
Coronary heart disease
Meta-analysis of HFE variants and CHD found the H63D G allele associated with a modest but statistically significant 6% increased risk of coronary heart disease (OR 1.06, 95% CI 1.01–1.11, p=0.02). Conversely, a Mendelian randomization study using rs1799945 as an iron-status instrument found higher transferrin saturation associated with a protective effect on CAD (OR ~0.95 per SD), suggesting a complex relationship between iron status and cardiovascular risk that may be context- or dose-dependent. Overall evidence points to a small elevated risk from carrying the G allele.
Alcoholic liver disease
Among individuals with heavy alcohol consumption, the H63D homozygous genotype (GG) is associated with increased susceptibility to alcoholic liver disease. A meta-analysis of 16 studies (1,933 cases, 9,874 controls) found H63D homozygosity associated with OR 1.52 (95% CI 1.05–2.22, p=0.029) for ALD, with a marginal association also observed for the D allele when comparing ALD patients to alcohol-exposed controls without liver damage. This iron-alcohol interaction is mechanistically plausible, as alcohol promotes hepatic iron accumulation.
Endurance athletic performance
The G allele (H63D) is overrepresented among elite endurance athletes compared to controls. A meta-analysis across five cohorts found OR 1.96 (95% CI 1.58–2.45, p=1.7×10⁻⁹) for CG/GG genotypes in endurance athletes vs. controls. A larger meta-analysis of 43 studies (3,938 athletes, 10,752 controls) found pooled OR 2.85 (95% CI 1.27–6.39), though with high heterogeneity (I²=71%). The effect is thought to relate to increased iron availability for erythropoiesis and higher VO₂max, though the association may be confounded by population stratification.
▶GWAS Catalog Trait Associations (19)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (19)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
Alzheimer disease; Bronze diabetes; Cardiomyopathy (CMYO); Cystic fibrosis (CF); Familial porphyria cutanea tarda (PCT); Hemochromatosis type 1 (HFE1); Hereditary hemochromatosis (HFE); Microvascular complications of diabetes, susceptibility to, 7; See cases; TRANSFERRIN SERUM LEVEL QUANTITATIVE TRAIT LOCUS 2 (TFQTL2); Variegate porphyria (VP); not specified
View on ClinVar →▶Research that mentions this SNP (4)
▶Patatin-like phospholipase domain-containing 3 I148M affects liver steatosis in patients with chronic hepatitis BReviewMauro Viganò et al.(2013)· Hepatology
This comprehensive review examines the genetic background of nonalcoholic fatty liver disease (NAFLD), focusing on variants identified by genome-wide association studies (GWAS) and candidate gene studies. The most significant GWAS-identified variants are PNPLA3 rs738409 (I148M), which strongly associates with increased liver steatosis, fibrosis severity, and HCC risk (12-fold increased risk for homozygous carriers), and TM6SF2 rs58542926 (E167K), which increases NASH progression but reduces cardiovascular risk. The review also discusses numerous candidate genes involved in lipid and glucose metabolism and liver injury mechanisms.
▶Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutationsAssociationN=786James E. Nelson et al.(2012)· Hepatology
This association study examined HFE gene mutations in 786 NAFLD patients from the NASH Clinical Research Network. NAFLD patients with C282Y mutations (rs1800562) had lower median serum hepcidin levels (57 vs 65 ng/ml, p=0.01) and higher mean hepatocellular iron grades (0.59 vs 0.28, p<0.001) compared to wild-type subjects. H63D mutations (rs1799945) were associated with higher steatosis grades and NAFLD activity scores (OR≥1.4, p≤0.041) but not with iron deposition, while C282Y mutations were associated with less ballooning or NASH (OR≤0.62, p≤0.024).
▶Dissociation betweenAPOC3variants, hepatic triglyceride content and insulin resistanceReviewJulia Kozlitina et al.(2011)· Hepatology
Comprehensive review of genetic background in nonalcoholic fatty liver disease (NAFLD). The PNPLA3 I148M variant (rs738409 C>G) is identified as a major genetic player strongly associated with increased liver fat content, NASH development, fibrosis severity, and HCC risk. The TM6SF2 E167K variant (rs58542926) emerges as another key contributor to NAFLD pathogenesis and disease progression. Multiple additional GWAS-identified variants and candidate genes are reviewed for their roles in NAFLD susceptibility and progression.
▶An extensive analysis of the hereditary hemochromatosis gene HFE and neighboring histone genes: associations with childhood leukemiaAssociationN=531Davis CF et al.(2010)· Annals of Hematology
Case-control study of 117 childhood acute lymphoblastic leukemia cases and 414 newborn controls from South Wales investigating the HFE gene and neighboring histone genes. Identified rs807212 as a tagging SNP for the common HFE haplotype with a strong male-specific protective association (adjusted OR=0.27 for heterozygotes, p=0.009) that accounts for the previously reported C282Y risk association. Analysis of 24 SNPs spanning 52 kb in the HFE region revealed complex haplotype structure with male-specific genetic effects.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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