RESUMO
Iron loading in p.C282Y homozygous HFE hemochromatosis subjects is highly variable, and it is unclear what factors cause this variability. Finding such factors could aid in predicting which patients are at highest risk and require closest follow-up. The degree of iron loading has previously been associated with certain HLA-types and with abnormally low CD8 + cell counts in peripheral blood. In 183 Norwegian, p.C282Y homozygotes (104 men, 79 women) originally found through population screening we determined HLA type and measured total T-lymphocytes, CD4 + and CD8 + cells, and compared this with data on iron loading. In p.C282Y homozygous men, but not in homozygous women, we found that the presence of two HLA-A*03 alleles increased the iron load on average by approximately 2-fold compared to p.C282Y homozygous men carrying zero or one A*03 allele. On the other hand, the presence of two HLA-A*01 alleles, in male subjects, apparently reduced the iron loading. In p.C282Y homozygous individuals, the iron loading was increased if the CD8 + cell number was below the 25 percentile or if the CD4 + cell number was above the 75 percentile. This effect appeared to be additive to the effect of the number of HLA-A*03 alleles. Our data indicate that homozygosity for the HLA-A*03 allele significantly increases the risk of excessive iron loading in Norwegian p.C282Y homozygous male patients. In addition, low CD8 + cell number or high CD4 + cell number further increases the risk of excessive iron loading.
Assuntos
Antígenos HLA/metabolismo , Proteína da Hemocromatose/genética , Ferro/metabolismo , Programas de Rastreamento , Subpopulações de Linfócitos T/imunologia , Alelos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de RiscoRESUMO
OBJECTIVE: In addition to hepatocellular cancer, HFE C282Y homozygotes are reported to have increased risk of colorectal cancer and breast cancer. This study was done to further explore the cancer risk in C282Y homozygotes. MATERIAL AND METHODS: We studied cancer incidence in 292 homozygotes and 62,568 others that participated in the HUNT 2 population screening in 1995-1997. Using Cox proportional hazard models, we estimated cancer hazard ratio as a function of C282Y homozygosity and several screening variables including serum transferrin saturation, alcohol consumption and daily smoking. RESULTS: Cancer was diagnosed in 36 homozygotes, five of which had two cancer diagnoses. The overall cancer incidence was not increased in C282Y homozygotes (hazard ratio 1.10 [95% CI 0.60-2.03] in women and 0.94 [95% CI 0.53-1.66] in men). However, homozygous men had increased risk of colorectal cancer (hazard ratio 3.03 [95% CI 1.17-7.82], p = 0.022) and primary liver cancer (hazard ratio 54.0 [95% CI 2.68-1089], p = 0.009). The risk of breast cancer in homozygous women was not increased (hazard ratio 1.13 [95% CI 0.35-3.72]). Adjusted for other variables including C282Y homozygosity, very low and very high serum transferrin saturation were associated with increased overall cancer incidence. CONCLUSIONS: C282Y homozygosity is associated with increased risk of colorectal cancer and hepatocellular cancer in men. In the general population, individuals with a very low or a very high serum transferrin saturation may have increased cancer risk.
Assuntos
Neoplasias da Mama/genética , Carcinoma Hepatocelular/genética , Neoplasias Colorretais/genética , Antígenos de Histocompatibilidade Classe I/genética , Homozigoto , Neoplasias Hepáticas/genética , Proteínas de Membrana/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Carcinoma Hepatocelular/epidemiologia , Neoplasias Colorretais/epidemiologia , Feminino , Seguimentos , Marcadores Genéticos , Proteína da Hemocromatose , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Noruega/epidemiologia , Modelos de Riscos Proporcionais , Sistema de Registros , Fatores de RiscoRESUMO
OBJECTIVE: Hereditary hemochromatosis (HH) is a genetic condition characterized by increased iron absorption. Most HH cases are homozygous for the C282Y mutation in the HFE gene, but accurate prevalence data for the Norwegian population is lacking. In population studies, serum transferrin saturation (TS) is commonly used as a screening test. However, the sensitivity and specificity of TS in this setting is not well documented. The purpose of this study was to determine the prevalence of the C282Y mutation in the general population, and to evaluate the diagnostic accuracy of the TS test as a screening criterion for finding C282Y homozygotes. MATERIALS AND METHODS: The hemochromatosis screening study in Nord-Trøndelag county, Norway (the HUNT2 study) comprised 65,238 participants. The HUNT biobank contains biological material and data from the participants, and 5000 individuals were randomly selected. Genotyping of the common HFE gene mutations was successful for 4827 samples, from which TS data existed for 4804 individuals. From these data we calculated the population frequency of the C282Y mutation, and the sensitivity and specificity of TS measurements. RESULTS: The prevalence of C282Y homozygosity in the population was 0.75%. Using 55% (men) and 50% (women) as decision limits, the sensitivity of two consecutive elevated TS measurements was 90.0% for men and 55.0% for women, whereas the specificity was 99.6% and 99.4%, respectively. CONCLUSION: An unbiased estimate of the C282Y homozygote prevalence in Norway is 0.75%. Two measurements of TS is an accurate screening test for C282Y homozygosity in men, but not in women.
