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Penetrance of 845G-->A (C282Y) HFE Hereditary
Haemochromatosis Mutation in the USA

April 10, 2002
Abstraction Template
     
Key variables & Description Article

Reference
Complete the bibliographic reference for the article according to AJE format.

 

 Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G-->A (C282Y) HFE hereditary haemochromatosis mutation in the USA.  Lancet 2002;359:211-218.

Category of HuGE information
Specify the types of information (from the list below) available in the article:

  1. Prevalence of gene variant
  2. Gene-disease association
  3. Gene-environment interaction
  4. Gene-gene interaction
  5. Genetic test evaluation/monitoring

 
  1. Prevalence of gene variant
  2. Gene disease association
  3. Genetic test evaluation/monitoring

Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study.

 

 Purpose:  To determine the penetrance of the C282Y HFE mutation in hemochromatosis as an essential consideration in determining the viability of the previously developed screening test based on this mutation.

Gene(s)
Identification of the following:

  1. Gene name
  2. Chromosome location
  3. Gene product/function
  4. Alleles
  5. OMIM #

 
  1. Gene name: HFE
  2. Chromosome location: 6p21.3
  3. Gene product/function: The HFE protein is an HLA-like protein that is expressed on the surface of duodenal crypt enterocytes and participates in iron uptake and transport. Mutations in this gene appear to cause a loss of ability of these cells to sense the level of body iron stores.
  4. Alleles: 845G-->A (C282Y), 187C-->G (H63D)
  5. OMIM #: 235200

 

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

 

N/A

Health outcome(s)
Identification of the major health outcome(s) studied

 

Hemochromatosis

Study design
Specification of the type of study design(s)
  1. Case-control
  2. Cohort 
  3. Cross-sectional
  4. Descriptive or case series
  5. Clinical trial
  6. Population screening

 

 6. Population screening

Cohort definition
For study designs 2, 3, and 6, define the following if available:
  1. Cohort selection criteria
  2. Exclusion criteria
  3. Gender
  4. Race/ethnicity
  5. Age
  6. Time period
  7. Geographic location
  8. Number of participants

 
  1. Cohort selection criteria: Members of the Kaiser-Permanente medical care program who attended the Health Appraisal Clinic
  2. Exclusion criteria: Previous diagnosis of haemochromatosis, lost questionnaires
  3. Gender: Male and Female
  4. Race/ethnicity: White, mixed White and Hispanic
  5. Age: greater than 26 years (mean = 57 years)
  6. Time period: Not specified
  7. Geographic location:  San Diego, California , USA
  8. Number of participants: 41,038 screened

 
Assessment of environment factors
For studies that include gene-environment interactions, define the following, if available:
  1. Environmental factor
  2. Exposure assessment
  3. Exposure definition
  4. Number of participants with exposure data (%
    of total eligible)

 

 N/A

 

Genotyping
Specify the following:
  1. Gene
  2. DNA source
  3. Methodology
  4. Number of participants genotyped (% of total eligible) 

 
  1. Gene:  HFE
  2. DNA source:  Blood
  3. Methodology:  Mutations analysis was not described 
  4. Participants genotyped: 41 038 patients genotyped (10.1% of an estimated 405000 patients visiting the Health Appraisal Clinic)

 
Results
Describe the major results under each of the following HuGE categories. Include tables when data are provided:
  1. Prevalence of gene variant
  2. Gene-disease association
  3. Gene-environment interaction
  4. Gene-gene interaction
  5. Genetic test evaluation/monitoring

1. Prevalence of genotypes among patients at the Health Appraisal Clinic

Genotype

Men (n=14,577)

Women (n=15,748)

  

#

%

#

%

wt/wt

12601

86.44

13674 

 86.83

C282Y/wt

 1603

 11.00

 1690

 10.73

C282Y/H63D

 300

 2.06

 305

 1.94

C282Y/C282Y

 73

 0.50

  79

  0.50


2. Gene-disease association

Mean transferrin saturations (and 95% confidence intervals) in participants with different genotypes

Genotype

Transferrin saturation (%)

Men*

Women*

wt/wt

26.69 (26.53-26.85)

22.66 (22.51-22.81)

C282Y/wt

30.63 (30.12-31.14)

26.77 (26.30-27.24)

C282Y/H63D

39.59 (38.12-41.06)

32.05 (30.63-33.47)

C282Y/C282Y

64.08 (59.27-68.89)

46.45 (41.76-51.14)

* mean (95% Confidence Interval)

 

  Mean serum ferritin concentrations (and 95% confidence intervals) in participants with different genotypes

Genotype

Serum ferritin concentration (mg/L)

Men**

Women**

wt/wt

118 (116-120)

52 (51-53)

C282Y/wt

122 (117-127)

56 (54-59)

C282Y/H63D

191 (171-212)

70 (63-78)

C282Y/C282Y

395 (287-545)

159 (114-222)

** geometric mean (95% Confidence Interval)


3. A health questionnaire was administered to determine whether there was an association between symptoms of hemochromatosis and genotype.

  • No association was found between genotype and reported limitations in general health, nor in fatigue, arthropathy, darkening of skin, abdominal pain, impotence, depression, weight loss, hair loss, arrhythmias or diabetes.
  • History of hepatitis and liver disorders were more frequent in C282Y/C282Y homozygotes than in wildtype, but significance was minimal.
  • History of hepatitis (OR= 2.1, 95% CI: 1.1-4.0)
  • Liver disorders (OR = 2.1, 95% CI: 0.9-5.1)

 
Conclusion
State the author's overall conclusions from the study

It appears that the association between genotype and symptoms of hemochromatosis is weak or non-existent. If this is true, it may be concluded that penetrance for the C282Y genotype is much lower than previously thought. Thus, although hemochromatosis is one of the most common genetic diseases in the northern European population and is readily treatable, it is not appropriate to use the HFE screening test to diagnose sub-clinical cases of hemochromatosis.

 
Comments
Provide additional insight, including methodologic issues and/or concerns about the study

The results of this study bordered on significance in a number of instances, and no statistical test was performed to determine whether the observed increases in transferrin and serum ferritin were real trends. In addition, the authors failed to address the issue of selection bias. Data collection was performed in a health clinic, which may have indicated that participants were already experiencing some of the non-specific symptoms that the authors tested for, such as fatigue and limitations in general health.

There is great clinical significance in the conclusion that testing for HFE genotype will not necessarily predict development of symptoms of hemochromatosis. However, duplication of these results may be indicated before shaping individual or public practice based on them. Because of the long-term nature of this disease, future studies should employ a prospective cohort design which will be more informative than the cross-sectional design used in this study. In the event that these results are duplicated successfully, it should be considered that genotyping of this sort is not preferred over biochemical measures, such as transferrin and serum ferritin, because of the low penetrance of the HFE gene in hemochromatosis

 
Last Updated August 25, 2004