BMJ  2003;327:132-133 (19 July), doi:10.1136/bmj.327.7407.132

Paper

Longevity and carrying the C282Y mutation for haemochromatosis on the HFE gene: case control study of 492 French centenarians

¹ Unité de Physiopathologie Cellulaire et Moléculaire, CNRS UPR 2163, CHU Purpan, 31059 Toulouse Cedex 3, France, ² Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, 75010 Paris, France

Introduction

Hereditary haemochromatosis is a common autosomal recessive disorder of iron metabolism. Most patients are homozygous for a C282Y mutation in the HFE gene. This mutation is frequent in northern Europe, where one in five to ten people are carriers. People who are heterozygous for the C282Y mutation have slightly but significantly higher values for serum iron and transferrin saturation and are less likely to have anaemia because of iron deficiency.^{1 2}

Iron promotes the generation of free radicals, which leads to mutagenesis, atherosclerosis, inflammation, and bacterial growth. Therefore, genotypes that increase the concentrations of iron for transport and storage may be associated with an increased risk for common diseases, such as cancers and cardiovascular diseases, and for inflammatory and infectious conditions. Other studies, which investigated the associations of C282Y heterozygosity with morbidity, found conflicting results, and consensus has not been reached about whether C282Y is associated with the development of extrahepatic cancers, coronary heart disease, or diabetes.^{1 2}

We hypothesised that people who are heterozygous for the C282Y mutation are under-represented in a centenarian population because many would have died younger from life threatening diseases which are more prevalent in C282Y heterozygotes.

Participants, methods, and results

We recruited 492 French centenarians, who consented personally, through the Chronos Project at the Foundation Jean Dausset (Centre d'Etude du Polymorphisme Humain). ³ The 80 men and 412 women were white, born in France, and more than 99 (mean 103.1) years old on the day we collected blood. We selected 492 controls from unrelated white people who were born in France and matched the centenarians for sex and geographic origin (mean age 51.2 years). The treating doctor completed a detailed health questionnaire and the results of the last blood test were collected for each person. We amplified the HFE gene using a polymerase chain reaction, and we detected the C282Y mutation using denaturing high performance liquid chromatography on a Wave DNA Fragment Analysis System (Transgenomic, Crewe).⁴

The centenarians included 44 heterozygotes and the matched controls contained 42 heterozygotes; the difference is not statistically significant even taking sex into account (table). The odds ratio of becoming centenarian when carrying the C282Y mutation was 1.08 (95% confidence interval 0.70 to 1.66), encompassing the value of 1 expected under the null hypothesis.

View this table: [in this window] [in a new window]   Genotypes at the C282Y mutation site in centenarians and controls*

 

We found two homozygotes for the C282Y mutation among the centenarians and one among the controls; all were women. None had been treated by phlebotomy and none had been diagnosed with haemochromatosis. Distributions of the genotypes in the control and in the centenarian groups satisfied Hardy-Weinberg equilibrium, which is not in favour of a selection against either homozygotes or heterozygotes for the C282Y mutation among centenarians.

Comment

Complications thought to be associated with heterozygosity for the C282Y mutation of the HFE gene, such as carcinomas or cardiovascular diseases, did not deplete a centenarian population of heterozygotes for C282Y. Heterozygosity for C282Y does not seem to be a risk factor for these common life threatening conditions.

Finding people over 99 years old who are homozygous for the C282Y mutation and still alive without treatment confirms that clinical penetrance in homozygotes for the C282Y mutation is incomplete, as recently suggested in a study of more than 41 000 people in California.⁵ That longevity is not compromised by either being a heterozygous or homozygous carrier of the C282Y mutation precludes the recommendation of population genetic testing for C282Y. Rather, alternative strategies should be implemented to improve early detection of hereditary haemochromatosis in people with abnormal indexes of iron metabolism and their close relatives.

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Contributors: HC and MPR conceived and designed the study, analysed the data, and wrote the manuscript. MB, SF, and NB helped with genotypings and analyses. HB is in charge of the Chronos Project at the Foundation Jean Dausset—CEPH and provided the centenarian and control DNAs used for this study. All authors approved the final version of the manuscript. MPR is guarantor.

Funding: European Union (QLK6-CT-1999-02237).

Competing interests: None declared.

Ethical approval: Ethics committee (CCPPRB) of the Hospital Saint-Antoine, Paris.

References

1. Fuchs J, Podda M, Packer L, Kaufmann R. Morbidity risk in HFE associated hereditary hemochromatosis C282Y heterozygotes. Toxicology 2002;180: 169-81.[CrossRef][Medline]
2. Worwood M. HFE Mutations as risk factors in disease. Best Pract Res Clin Haematol 2002;15: 295-314.[Medline]
3. Blanche H, Cabanne L, Sahbatou M, Thomas G. A study of French centenarians: are ACE and APOE associated with longevity? C R Acad Sci III 2001;324: 129-35.[Medline]
4. Fruchon S, Bensaid M, Borot N, Roth MP, Coppin H. Use of denaturing HPLC and a heteroduplex generator to detect the HFE C282Y mutation associated with genetic hemochromatosis. Clin Chem 2003;49: 822-4.[Free Full Text]
5. 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: 211-8.[CrossRef][Web of Science][Medline]

(Accepted April 29, 2003)

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