Hemochromatosis genotypes and risk of 31 disease endpoints: Meta-analyses including 66,000 cases and 226,000 controls

Ellervik, Christina; Birgens, Henrik; Tybjærg‐Hansen, Anne; Nordestgaard, Børge G.

doi:10.1002/hep.21885

Cited by 137 publications

(114 citation statements)

References 28 publications

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“…Similarly, there was no significant difference between C282Y homozygotes and controls in the prevalence of most other self-reported symptoms commonly associated with hemochromatosis, including diabetes mellitus. The lack of association between HFE mutations and diabetes is consistent with the results of some (16,24,36,37), but not all (32,38) previous studies.…”

Section: Discussionsupporting

confidence: 91%

“…A recent study of first-degree relatives of patients with known C282Y hemochromatosis also found a low prevalence of clinical manifestations in family members who were C282Y homozygotes or C282Y/H63D compound heterozygotes, despite evidence of iron overload in most cases (31). However, a recent meta-analysis (32), based mainly on case-control studies, found an increased risk of liver disease among C282Y homozygotes compared to wild type/ wild type control subjects. In that study, hemochromatosis genotypes were not associated with an increased risk of diabetes mellitus, heart disease, arthritis, stroke or cancer in the overall analysis, although there was an increased risk of diabetes mellitus in C282Y homozygotes compared with controls among subjects of northern European descent.…”

Section: Discussionmentioning

confidence: 99%

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Clinical Manifestations of Hemochromatosis inHFEC282Y Homozygotes Identified by Screening

McLaren

Adams

et al. 2008

Canadian Journal of Gastroenterology

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OBJECTIVE:To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE) mutation (C282Y) identified by screening. METHODS: Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without the HFE C282Y or H63D alleles (ie, wild type/wild type; n=364). RESULTS: Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex-and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects. CONCLUSIONS: Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Clinical Manifestations of Hemochromatosis inHFEC282Y Homozygotes Identified by Screening

McLaren

Adams

et al. 2008

Canadian Journal of Gastroenterology

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“…A recent metaanalysis has shown that HFE genotypes encoding variants C282Y and/or H63D are associated with a 2-to 48-fold increased risk of PCT compared with the wild-type homozygote, with the C282Y/ C282Y conferring the highest risk (19 ). Increased frequencies of C282Y homozygotes, C282Y/H63D compound heterozygotes, and H63D homozygotes were seen in our PCT patients, compared with the general Norwegian population, but no association was seen for S65C.…”

Section: Discussioncontrasting

confidence: 40%

Familial and Sporadic Porphyria Cutanea Tarda: Characterization and Diagnostic Strategies

2009

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Background: Porphyria cutanea tarda (PCT) occurs in sporadic (sPCT) and familial (fPCT) forms, which are generally clinically indistinguishable and have traditionally been differentiated by erythrocyte uroporphyrinogen decarboxylase (UROD, EC 4.1.1.37) activity. We used UROD gene sequencing as the reference standard in assessing the diagnostic accuracy of UROD activity, evaluating the mutation spectrum of the UROD gene, determining the frequency and disease attributes of PCT and its subtypes in Norway, and developing diagnostic models that use clinical and laboratory characteristics for differentiating fPCT and sPCT. Methods: All consecutive patients with PCT diagnosed within a 6-year period were used for incidence calculations. UROD activity analysis, UROD gene sequencing, analysis of hemochromatosis mutations, and registration of clinical and laboratory data were carried out for 253 patients. Results: Fifty-three percent of the patients had disease-relevant mutations, 74% of which were c.578G>C or c.636+1G>C. The UROD activity at the optimal cutoff had a likelihood ratio (LR) of 9.2 for fPCT, whereas a positive family history had an LR of 19. A logistic regression model indicated that low UROD activity, a high uroporphyrin-heptaporphyrin ratio, a young age at diagnosis, male sex, and low alcohol consumption were predictors of fPCT. The incidence of PCT was 1 in 100 000. Conclusions: Two commonly occurring mutations are responsible for the high frequency of fPCT in Norway. UROD activity has a high diagnostic accuracy for differentiating the 2 PCT types, and a model that takes into account both clinical information and laboratory test results can be used to predict fPCT.

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“…There is evidence that HFE C282Y/C282Y (4,5), as well as iron overload independent of HFE genotype (6), both confer a risk of diabetes. There is also evidence for increased risk of premature death due to organ damage in patients with clinically overt hereditary hemochromatosis (7)(8)(9)(10)(11) in individuals from the general population with increased transferrin saturation (TS) (12), independent of HFE genotype (13), and in patients with diabetes and increased TS or HFE genotype from a highly specialized diabetes clinic, the Steno Diabetes Centre (Gentofte, Denmark) (14).…”

mentioning

confidence: 99%

Total and Cause-Specific Mortality by Elevated Transferrin Saturation and Hemochromatosis Genotype in Individuals With Diabetes: Two General Population Studies

et al. 2014

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OBJECTIVEMortality is increased in patients with hereditary hemochromatosis, in individuals from the general population with increased transferrin saturation (TS), and also in patients with type 1 diabetes and increased TS from a highly specialized diabetes clinic. Thus, we have recommended targeted screening for TS in specialized diabetes clinics. Whether mortality is also increased in individuals from the general population with diabetes and increased TS is unknown. RESEARCH DESIGN AND METHODSIn two Danish population studies (N = 84,865), we examined mortality according to baseline levels of TS and hemochromatosis genotype (HFE) G → A substitution at nucleotide 845 in codon 282 (C282Y/C282Y) in individuals with diabetes (type 1, N = 118; type 2, N = 3,228; total, N = 3,346). RESULTSThe cumulative survival rate was reduced in individuals with diabetes with TS ‡50% vs. <50% (log-rank; P < 0.0001), with median survival ages of 66 and 79 years, respectively. The hazard ratio (HR) for TS ‡50% vs. <50% was 2.0 (95% CI 1.3-2.8; P = 0.0004) for total mortality overall (and similar for men and women separately); 2.6 (1.3-5.4; P = 0.008) for neoplasms; and 3.4 (2.0-6.0; P = 0.00002) for endocrinological causes. A stepwise increased risk of total mortality was observed for stepwise increasing TS (log-rank test, P = 0.0001), with an HR for TS ‡70% vs. TS <20% of 4.8 (2.0-12; P = 0.0006). The HR for total mortality in individuals with diabetes for C282Y/C282Y versus wild type/wild type was 3.3 (1.04-10; P = 0.04), and for C282Y/C282Y and TS ‡50% versus wild type/wild type and TS <50% was 6.0 (1.5-24; P = 0.01). Six percent of these premature deaths can possibly be avoided by early screening for TS or HFE genotype. CONCLUSIONSIndividuals with diabetes, ascertained in the general population, with increased TS or HFE genotype have a twofold to sixfold increased risk of premature death.

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Hemochromatosis genotypes and risk of 31 disease endpoints: Meta-analyses including 66,000 cases and 226,000 controls

Cited by 137 publications

References 28 publications

Clinical Manifestations of Hemochromatosis inHFEC282Y Homozygotes Identified by Screening

Clinical Manifestations of Hemochromatosis inHFEC282Y Homozygotes Identified by Screening

Familial and Sporadic Porphyria Cutanea Tarda: Characterization and Diagnostic Strategies

Total and Cause-Specific Mortality by Elevated Transferrin Saturation and Hemochromatosis Genotype in Individuals With Diabetes: Two General Population Studies

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