Haemochromatosis gene C282Y homozygotes in an elderly male population

Willis, Gavin; Wimperis, J. Z.; Smith, K.; Fellows, Ian; Jennings, Barbara

doi:10.1016/s0140-6736(99)02195-9

Cited by 64 publications

(38 citation statements)

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“…These frequencies are very similar to those observed in younger populations 26,27 and in a sample of elderly men. 28 We did not find evidence for a significant decrease in the frequency of the HFE C282Y mutation or H63D mutation with age, suggesting that these mutations may remain putative risk factors for chronic diseases thoughout late age. Serum transferrin saturation and serum iron levels were significantly increased in those homozygotes or compound heterozygous for C282Y as well as H63D in both men and women.…”

Section: Discussioncontrasting

confidence: 65%

A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism

et al. 2003

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The C282Y and H63D mutations in the HFE gene are important causes of hemochromatosis. In the elderly, these mutations might be associated with increased morbidity because of the lifelong accumulation of iron. In a population-based sample of the elderly, we determined the value of genotyping for HFE mutations to screen for subclinical hemochromatosis. HFE genotype frequencies were determined in a random group of 2095 subjects (55 years and over). In this random group, we selected within the six genotype groups a total of 342 individuals and measured their serum transferrin saturation, iron and ferritin levels. We also estimated the heritability and parameters needed to evaluate screening, including the sensitivity, specificity, positive and negative predictive values (PPV, NPV) of HFE genotypes. Iron parameters were significantly increased in subjects homozygous, heterozygous or compound heterozygous. The effect of the mutations was more pronounced in men than in women. For the H63D mutation, an allele dose effect was observed. The HFE gene explained about 5% of the variability in serum iron indices. The PPV for hemochromatosis for the C282Y homozygous was 100% in men and 67% in women. The NPV of the wild-type allele was 97% for both men and women. The sensitivity of both mutations was 70% for men and 52% for women and the specificity was 62% for men and 64% for women. Our study shows that the HFE C282Y and H63D are determinants of iron parameters in the elderly and will be effective in detecting individuals at high risk of hemochromatosis. However, when screening based on these two mutations, some individuals with subclinical hemochromatosis will be missed.

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Section: Discussioncontrasting

confidence: 65%

A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism

et al. 2003

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“…Only one of the first 152 homozygotes we detected had clinical hemochromatosis, and the prevalence of symptoms such as arthritis, impotence, and diabetes, thought to be common in hemochromatosis, were no more common in controls than in homozygotes for the C282Y mutation. 46 The studies of Willis et al [47][48][49] support the view that the penetrance of the gene is very low. These data suggest to us that homozygosity for the C282Y mutation of HFE is a necessary, but not a sufficient, condition for the full-blown clinical disorder to develop.…”

Section: Hereditary Hemochromatosismentioning

confidence: 92%

Discrepancies between genotype and phenotype in hematology: an important frontier

Beutler

2001

Blood

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An African American male infant with sickle cell disease has a devastating stroke; an African American soldier is surprised when he is informed that he has sickle cell disease. They are both homozygous for the same mutation. An Ashkenazi Jewish woman with Gaucher disease has a huge spleen and severe thrombocytopenia; her older brother, homozygous for the same 1226G glucocerebrosidase mutation, is found on routine examination to have a barely palpable spleen tip. The fact that clinical manifestations of genetic diseases can vary widely among patients has been recognized for many decades. In the past, however, it could often be attributed to the pleomorphic nature of mutations of the same gene: the patient with severe disease, it was averred, must have a different mutation than the one with mild disease. Even before a precise definition of mutations could be achieved at the DNA level, such an explanation did not serve to clarify the differences that existed between siblings with the same autosomal recessive disease. Such siblings must surely be carrying the same 2 disease-producing alleles. With the advent of sequence analysis of genes, the great extent of phenotype variation in patients with the same genotype has come to be more fully appreciated, but understanding of why it occurs continues to be meager. It is the purpose of this review to explore some of the variations in phenotype seen by hematologists in patients with identical mutations, to indicate where some progress has been made, and to suggest how understanding in this important area may be expanded. (Blood. 2001;98:2597-2602)

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“…Several cross-sectional studies have attempted to examine the mortality risk of being homozygous for the C282Y mutation of the HFE gene by investigating whether homozygotes were underrepresented in older age-groups. 12,13 These studies found that homozygotes were not underrepresented and argued that life-threatening disease might not occur in many C282Y homozygotes. These studies, however, were not cohort studies assessing survival time or mortality risk, and they defi ned their population based on a genetic marker rather than a clinical indicator (eg, transferring saturation).…”

Section: Serum Transferrin Saturation and Mortalitymentioning

confidence: 99%

Elevated Serum Transferrin Saturation and Mortality

Mainous

Gill²,

Carek³

2004

The Annals of Family Medicine

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BACKGROUND A large proportion of US adults have elevated transferrin saturation, an indicator of a predisposition for iron overload. The purpose of this study was to evaluate the relationship between elevated serum transferrin saturation and mortality.METHODS This cohort study was conducted using data from the First Health and Nutrition Examination Survey I (1971Survey I ( -1974 (NHANES I) merged with the NHANES I Epidemiologic Followup Study (1992) (N = 10,714). We used SUDAAN and appropriate weights to make population estimates for the adult US population (aged 25 to 74 years at baseline). All-cause mortality was evaluated in relation to serum transferrin saturation of greater than 45%, greater than 50%, greater than 55%, and greater than 60% using Cox proportional hazards regression. RESULTSIn a Cox proportional hazards model controlling for potential confounders, including comorbid diseases, smoking, and cholesterol, all-cause mortality is signifi cantly greater for persons with a serum transferrin saturation of more than 55%, compared with those with saturations below this cutoff (hazards ratio [HR] =1.60, 95% confi dence interval [CI], 1.17-2.21). No one who died had hemochromatosis as any of the 20 listed causes of death. Many of the underlying causes of death for persons with serum transferrin saturation levels of more than 55% are common causes of death in the general population, although these persons were more likely to have died of cirrhosis and diabetes, a fi nding consistent with iron overload. CONCLUSIONSIn this nationally representative cohort of adults, those with elevated serum transferrin saturation, more than 2% of the adult US population, were at increased risk for all-cause mortality.

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Haemochromatosis gene C282Y homozygotes in an elderly male population

Cited by 64 publications

References 4 publications

A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism

A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism

Discrepancies between genotype and phenotype in hematology: an important frontier

Elevated Serum Transferrin Saturation and Mortality

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