Variant "HFE:c.187C>G(p.His63Asp)"
Search results: 12 records
Variant information
Gene:
Variant:
HFE:c.187C>G(p.His63Asp)
Genomic location:
chr6:26091179(hg19)
HGVS:
SO Term | RefSeq |
---|---|
protein_coding | NM_000410.3:c.187C>G(p.His63Asp) |
protein_coding | NM_001300749.1:c.187C>G(p.His63Asp) |
protein_coding | NM_139003.2:c.187C>G(p.His63Asp) |
protein_coding | NM_139004.2:c.187C>G(p.His63Asp) |
protein_coding | NM_139006.2:c.187C>G(p.His63Asp) |
protein_coding | NM_139009.2:c.118C>G(p.His40Asp) |
protein_coding | NM_139007.2:c.77-363C>G |
protein_coding | NM_139008.2:c.77-363C>G |
protein_coding | NM_139010.2:c.77-1734C>G |
protein_coding | NM_139011.2:c.77-2168C>G |
show all |
Alias:
HFE:p.H63D, HFE:H63D, HFE:c.77-2168C>G
dbSNP ID:
GWAS trait:
diastolic blood pressure,systolic blood pressure,reticulocyte count,hemoglobin measurement,mean corpuscular hemoglobin concentration,hematocrit,serum iron measurement,ferritin measurement,transferrin saturation measurement,mean arterial pressure,platelet count,mean corpuscular hemoglobin,hypertension,smoking status measurement,red blood cell distribution width
Modifier statisitcs
Record:
12
Disorder:
10
Reference:
10
Effect type:
Expressivity(11)
,Penetrance(1)
Modifier effect:
Risk factor(6)
,Altered susceptibility(2)
,Altered ferritin level(1)
,Altered forced vital capacity and risk of MI or DIOS(1)
,Altered incidence(1)
,Altered severity(1)
Details:
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Target disease:Abnormality Of The Cardiovascular System (HP:0001626)Effect type:ExpressivityModifier effect:Altered susceptibilityEvidence:P-interaction = 0.03 for tibia and 0.02 for patellaEffect:The HFE H63D polymorphism, appears to enhance susceptibility to the deleterious impact of cumulative lead on PP, possibly via prooxidative or pro-inflammatory mechanisms.Alias in reference:HFE:H63DReference:Title:HFE H63D polymorphism as a modifier of the effect of cumulative lead exposure on pulse pressure: the Normative Aging Study.Species studied:HumanAbstract:Cumulative lead exposure is associated with a widened pulse pressure (PP; the -difference between systolic and diastolic blood pressure), a marker of arterial stiffness and a predictor of cardiovascular disease. Polymorphisms in the hemochromatosis gene (HFE) have been shown to modify the impact of cumulative lead exposure on measures of adult cognition and cardiac function.
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Target disease:Abnormality Of The Liver (HP:0001392)Effect type:ExpressivityModifier effect:Risk factorEvidence:Gene activity studyEffect:The HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin DeficiencyAlias in reference:HFE:c.187C>G(p.His63Asp)Reference:Title:ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency.Species studied:HumanAbstract:The most common and severe disease causing allele of Alpha 1-Antitrypsin Deficiency (1ATD) is Z-1AT. This protein aggregates in the endoplasmic reticulum, which is the main cause of liver disease in childhood. Based on recent evidences and on the frequency of liver disease occurrence in Z-1AT patients, it seems that liver disease progression is linked to still unknown genetic factors.
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Target disease:Arterial Stiffness Measurement (EFO_0004517)Effect type:ExpressivityModifier effect:Altered susceptibilityEvidence:P-interaction = 0.03 for tibia and 0.02 for patellaEffect:The HFE H63D polymorphism, appears to enhance susceptibility to the deleterious impact of cumulative lead on PP, possibly via prooxidative or pro-inflammatory mechanisms.Alias in reference:HFE:H63DReference:Title:HFE H63D polymorphism as a modifier of the effect of cumulative lead exposure on pulse pressure: the Normative Aging Study.Species studied:HumanAbstract:Cumulative lead exposure is associated with a widened pulse pressure (PP; the -difference between systolic and diastolic blood pressure), a marker of arterial stiffness and a predictor of cardiovascular disease. Polymorphisms in the hemochromatosis gene (HFE) have been shown to modify the impact of cumulative lead exposure on measures of adult cognition and cardiac function.
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Target disease:Beta Thalassemia (DOID_12241)Effect type:ExpressivityModifier effect:Altered ferritin levelEvidence:P=0.022Effect:The H63D mutation have higher ferritin levels than beta-thalassemia carriers with the H/H genotype, suggesting that the H63D mutation may have a modulating effect on iron absorption.Alias in reference:HFE:H63DReference:Title:H63D mutation in the HFE gene increases iron overload in beta-thalassemia carriers.Species studied:HumanAbstract:Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism. The HFE gene implicated in this disorder has been identified on chromosome 6 (6p21.3). The most prevalent mutation in HH patients changes the 282 cysteine residue to tyrosine (C282Y). The role of a second mutation which changes the 63 histidine to aspartic acid (H63D) in iron overload has been controversial. The aim of this study was to evaluate the effect of the H63D mutation on the ferritin levels of beta-thalassemia carriers.
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Target disease:Breast Cancer (DOID_1612)Effect type:ExpressivityModifier effect:Risk factorEvidence:Assessment of genotype–phenotype associationsEffect:The HFE mutations C282Y and H63D in the causation of MBC and PC, but carriers of both BRCA2 9346(-2)A-->G and an HFE mutation may be at an increased risk.Alias in reference:HFE:H63DReference:Title:Hemochromatosis gene mutations among Finnish male breast and prostate cancer patients.Species studied:HumanAbstract:Hereditary hemochromatosis (HH), the most common genetic disease in northern Europeans, is an autosomal recessive disorder of iron metabolism. The association between hepatocellular carcinoma and HFE homozygosity is well documented, but recently HFE hetero- and homozygosity has also been linked to nonhepatocellular malignancies, including female breast cancer. We hypothesized that C282Y and H63D mutations in the HFE gene could contribute to male breast cancer (MBC) and prostate cancer (PC) susceptibility at the population level in Finland. We screened the 2 major HFE mutations, H63D and C282Y, from 116 MBC cases diagnosed in Finland between 1967 and 1996, 843 consecutive unselected PC cases diagnosed at the Pirkanmaa Hospital District between 1999 and 2001 and 480 anonymous blood donor controls by minisequencing. Our results indicate that the frequencies of the HFE mutations do not significantly differ between MBC and PC patients and the population-based controls. No significantly altered risks for MBC or PC among carriers of the 2 variants were observed. However, HFE mutations were seen twice as often among carriers of a common BRCA2 mutation 9346(-2)A-->G compared with the rest of the MBC cases, indicating that HFE may be an MBC risk modifier gene among BRCA2 mutation carriers. In conclusion, our results indicate a minor role for the HFE mutations C282Y and H63D in the causation of MBC and PC, but carriers of both BRCA2 9346(-2)A-->G and an HFE mutation may be at an increased risk.
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Target disease:Cystic fibrosis (DOID_1485)Effect type:ExpressivityModifier effect:Altered forced vital capacity and risk of MI or DIOSEvidence:Decline in forced vital capacity (p=0.01) and increased risk of mi or dios (p=0.02).Effect:H63D HFE substitutions were associated with a more rapid rate of decline in forced vital capacity (p=0.01) and increased risk of meconium ileus or distal intestinal obstruction syndrome (p=0.02).Alias in reference:HFE:c.187C>G(p.His63Asp)Reference:Title:Mutations in the HFE gene can be associated with increased lung disease severity in cystic fibrosis.Species studied:HumanAbstract:Genetic modifiers contribute to variable disease phenotype in cystic fibrosis (CF). We explored the association between mutations in the hemochromatosis (HFE) gene and disease severity in adults with CF.
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Target disease:Cystic fibrosis (DOID_1485)Effect type:PenetranceModifier effect:Altered incidenceEvidence:Assessment of genotype–phenotype associationsEffect:May enhance the activity of the protein and thus exert a protective effect toward liver diseaseAlias in reference:HFE:p.H63DReference:Title:An MBL2 haplotype and ABCB4 variants modulate the risk of liver disease in cystic fibrosis patients: a multicentre study.Species studied:HumanAbstract:Cystic fibrosis is the most common lethal recessive disorder among Caucasians. Over 1500 mutations have been identified in cystic fibrosis transmembrane conductance regulator disease-gene so far. A large variability of the clinical phenotype has been observed both in cystic fibrosis patients bearing the same genotype, and in affected sibpairs. Thus, genes inherited independently from cystic fibrosis transmembrane conductance regulator could modulate the clinical expression of cystic fibrosis.
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Target disease:Hemochromatosis (DOID_2352)Effect type:ExpressivityModifier effect:Risk factorEvidence:OR=5.7 for H63D/H63D (95% CI: 3.2 to 10.1, AF = 0.01)Effect:C282Y homozygosity confers the highest risk for iron overload but the H63D mutation is also associated with increased risk.Alias in reference:HFE:H63DReference:Title:Contribution of different HFE genotypes to iron overload disease: a pooled analysis.Species studied:HumanAbstract:To determine the contribution of the C282Y and H63D mutations in the HFE gene to clinical expression of hereditary hemochromatosis.
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Target disease:Hereditary nonpolyposis colon cancer (Orphanet_443909)Effect type:ExpressivityModifier effect:Risk factorEvidence:HR=0.58, P=0.012Effect:The HFE H63D polymorphism seems to be a genetic modifier of disease expression in HNPCC.Alias in reference:HFE:H63DReference:Title:Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age.Species studied:HumanAbstract:Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by germline mutations in DNA mismatch repair genes; however, variation in disease expression suggests that there are potential modifying factors. Polymorphisms of the HFE gene, which cause the iron overload disorder hereditary haemochromatosis, have been proposed as potential risk factors for the development of colorectal cancer (CRC). To understand the relationship between HNPCC disease phenotype and polymorphisms of the HFE gene, a total of 362 individuals from Australia and Poland with confirmed causative MMR gene mutations were genotyped for the HFE C282Y and H63D polymorphisms. A significantly increased risk of developing CRC was observed for H63D homozygotes when compared with combined wild-type homozygotes and heterozygotes (hazard ratio = 2.93, p = 0.007). Evidence for earlier CRC onset was also observed in H63D homozygotes with a median age of onset 6 years earlier than wild type or heterozygous participants (44 vs. 50 years of age). This effect was significant by all tests used (log-rank test p = 0.026, Wilcoxon p = 0.044, Tarone-Ware p = 0.035). No association was identified for heterozygosity of either polymorphism and limitations on power-prevented investigation of C282Y homozygosity or compound C282Y/H63D heterozygosity. In the Australian sample only, women had a significantly reduced risk of developing CRC when compared with men (hazard ratio = 0.58, p = 0.012) independent of HFE genotype for either single nucleotide polymorphisms. In conclusion, homozygosity for the HFE H63D polymorphism seems to be a genetic modifier of disease expression in HNPCC. Understanding the mechanisms by which HFE interrelates with colorectal malignancies could lead to reduction of disease risk in HNPCC.
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Target disease:Nonalcoholic Fatty Liver Disease (DOID_0080208)Effect type:ExpressivityModifier effect:Altered severityEvidence:P=0.005Effect:Associated with the development NAFLD or disease severity.Alias in reference:HFE:c.77-2168C>GReference:Title:Genetic analysis of nonalcoholic fatty liver disease within a Caribbean-Hispanic population.Species studied:HumanAbstract:We explored potential genetic risk factors implicated in nonalcoholic fatty liver disease (NAFLD) within a Caribbean-Hispanic population in New York City. A total of 316 individuals including 40 subjects with biopsy-proven NAFLD, 24 ethnically matched non-NAFLD controls, and a 252 ethnically mixed random sampling of Bronx County, New York were analyzed. Genotype analysis was performed to determine allelic frequencies of 74 known single-nucleotide polymorphisms (SNPs) associated with NAFLD risk based on previous genome-wide association study (GWAS) and candidate gene studies. Additionally, the entire coding region of PNPLA3, a gene showing the strongest association to NAFLD was subjected to Sanger sequencing. Results suggest that both rare and common DNA variations in PNPLA3 and SAMM50 may be correlated with NAFLD in this small population study, while common DNA variations in CHUK and ERLIN1, may have a protective interaction. Common SNPs in ENPP1 and ABCC2 have suggestive association with fatty liver, but with less compelling significance. In conclusion, Hispanic patients of Caribbean ancestry may have different interactions with NAFLD genetic modifiers; therefore, further investigation with a larger sample size, into this Caribbean-Hispanic population is warranted.
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Target disease:Nonalcoholic Fatty Liver Disease (DOID_0080208)Effect type:ExpressivityModifier effect:Risk factorEvidence:From review articleEffect:The C282Y and H63D mutations of the hemochromatosis (HFE) gene represent a common cause of inherited iron overload in individuals of European ancestryAlias in reference:HFE:H63DReference:Title:Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment.Species studied:HumanAbstract:Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome.
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Target disease:Prostate Cancer (DOID_10283)Effect type:ExpressivityModifier effect:Risk factorEvidence:Assessment of genotype–phenotype associationsEffect:The HFE mutations C282Y and H63D in the causation of MBC and PC, but carriers of both BRCA2 9346(-2)A-->G and an HFE mutation may be at an increased risk.Alias in reference:HFE:H63DReference:Title:Hemochromatosis gene mutations among Finnish male breast and prostate cancer patients.Species studied:HumanAbstract:Hereditary hemochromatosis (HH), the most common genetic disease in northern Europeans, is an autosomal recessive disorder of iron metabolism. The association between hepatocellular carcinoma and HFE homozygosity is well documented, but recently HFE hetero- and homozygosity has also been linked to nonhepatocellular malignancies, including female breast cancer. We hypothesized that C282Y and H63D mutations in the HFE gene could contribute to male breast cancer (MBC) and prostate cancer (PC) susceptibility at the population level in Finland. We screened the 2 major HFE mutations, H63D and C282Y, from 116 MBC cases diagnosed in Finland between 1967 and 1996, 843 consecutive unselected PC cases diagnosed at the Pirkanmaa Hospital District between 1999 and 2001 and 480 anonymous blood donor controls by minisequencing. Our results indicate that the frequencies of the HFE mutations do not significantly differ between MBC and PC patients and the population-based controls. No significantly altered risks for MBC or PC among carriers of the 2 variants were observed. However, HFE mutations were seen twice as often among carriers of a common BRCA2 mutation 9346(-2)A-->G compared with the rest of the MBC cases, indicating that HFE may be an MBC risk modifier gene among BRCA2 mutation carriers. In conclusion, our results indicate a minor role for the HFE mutations C282Y and H63D in the causation of MBC and PC, but carriers of both BRCA2 9346(-2)A-->G and an HFE mutation may be at an increased risk.